Human respiratory beta coronavirus are emerging causes for Public Health Emergencies of International Concern (PHEIC). SARS-CoV2 is circulating worldwide since November 2019. We review here the cardiovascular morbidity and mortality in COVID-19, and data supporting the role for dysregulation of the RAS counterregulatory axis due to binding of SARS-CoV2 S protein to ACE2 receptor. Since this counterregulatory axis provides benefits not only on the cardiovascular front but also in acute lung injury, we speculate on potential use of ACE inhibitors and AT₁R blockers in critically ill COVID-19 patients, and report current evidences.

The nature of the interaction between Th17 cells and the blood-brain barrier (BBB) is critical for the development of autoimmune inflammation in the central nervous system (CNS). TNF-a or IL-17 stimulation is known to enhance the adherence of Th17 cells to the brain endothelium. The brain endothelial cells (bEnd.3) express VCAM-1, the receptor responsible for inflammatory cell adhesion, which binds VLA-4 on migrating effector lymphocytes at the early stage of brain inflammation. The present study examines the effect of the pro-inflammatory cytokines TNF-a and IL-17 on the adherence of Th17 cells to bEnd.3 The bEnd.3 cells were found to increase production of CCL2 and CXCL1 after stimulation by pro-inflammatory cytokines, while CCL2, CCL5, CCL20 and IL17 induced Th17 cell migration through a bEnd.3 monolayer. This interaction between Th17 cells and the brain endothelium appears to be mediated by VCAM-1 and some chemotactic cytokines. This observation may suggest potential therapeutic targets for the prevention of autoimmune neuroinflammation development in the CNS.

Porphyromonas gingivalis is the major pathogenic bacteria found in the subgingival plaque of patients with periodontitis, leading to neuroinflammation. The bacteria destroy periodontal tissue through its virulence factors which are retained in the bacteria’s outer membrane vesicles (OMV). The purpose of this study was to determine the real time effect of intraperitoneal in-jection of P. gingivalis OMV on the production and expression of inflammatory markers as well as histopathological changes in the central nervous system (CNS) of adult zebrafish. Fol-lowing the LD50 (21 µg of OMV), the zebrafish were injected intraperitoneally with 18 µg of OMV and control group with normal saline at 7 different time points. Brains of experimental zebrafish were dissected at desired time points for colorimetric assays, ELISA and histology. This study discovered that nitric oxide and PGE2 were significantly increased at 45 minutes while IL-1β and IL-6 were expressed at subsequent 12- and 24-hours. respectively. Histopatho-logical changes such as blood coagulation, astrocytosis, oedema, spongiosis, and necrosis were also observed between 6- and 24-hours. The two apoptotic enzymes, caspases 3 and 9 were not expressed at any time point. In summary, the OMV induced neuroinflammatory responses and histopathological changes in adult zebrafish were time point dependent

Background: Methadone is a centrally-acting synthetic opioid analgesic widely used in the methadone maintenance therapy (MMT) programs throughout the world. Considering its neurotoxic effects particularly on the cerebellum, this study aims to address the behavioral and histological alterations in the cerebellar cortex associated with methadone administration. Materials and Methods: Twenty-four adult male albino rats were randomized into two groups of control and methadone treatment. Methadone was subcutaneously administered (2.5–10 mg/kg) once a day for two consecutive weeks. The functional and structural changes in the cerebellum were compared to the control group. Results: Our data revealed that treating rats with methadone not only induced cerebellar atrophy, but also prompted the actuation of microgliosis, astrogliosis, and apoptotic biomarkers. We further demonstrated that treating rats with methadone increased complexity of astrocyte processes and decreased complexity of microglia processes. Our result showed that methadone impaired motor coordination and locomotor performance and neuromuscular activity. Additionally, relative gene expression of TNF-α, caspase-3 and RIPK3 increased significantly due to methadone. Conclusions: Our findings suggest that methadone administration has a neurodegenerative effect on the cerebellar cortex via dysregulation of microgliosis, astrogliosis, apoptosis, and neuro-inflammation.

Epilepsy is one of the most prevalent and serious brain disorders, affecting 70 million people worldwide. Antiseizure medications (ASMs) though relieve symptoms and prevent the occurrence of future seizures in epileptic patients have limited effect on epileptogenesis. Addressing the multifaceted nature of epileptogenesis and its association with Nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome-mediated neuroinflammation requires a comprehensive understanding of the underlying mechanisms for development of targeted therapeutic strategies beyond conventional antiseizure treatments. Several types of NLRP3 inhibitors have been developed and their effect has been validated both in vitro and in vivo models of epileptogenesis. In this review, we discuss the advances in understanding the regulatory mechanisms of NLRP3 activation as well as progress made and challenges facing in the development of NLRP3 inhibitors for the treatment of epilepsy.

The fruits and leaves of the black currant (BC, Ribes nigrum) contain phytochemicals with thera-peutic benefits. The current paper reports on a standardized BC gemmotherapy extract (BC-GTE) prepared from fresh buds, and details the extract specific flavonoid content, antioxidant, and an-ti-inflammatory properties, respectively. The main HPLC identified aglyka flavonoids were lute-olin, quercetin, apigenin and kaempferol, while all together, at about 133 phytonutrients could be detected in the reported BC-GTE, so that the BC specific presence of many compounds was re-ported for the first time. We also demonstrated that in adult male Wistar rats pretreated with BC-GTE, and assessed after the LPS injection, the body size modifications of the activated microglial cells in the hippocampal CA1 region were not apparent, and no elevated serum specific TNF-α levels were seen under such LPS induced inflammatory conditions. The specific flavonoid content, and the LPS induced in-flammatory model based experimental data are all suggesting that the assessed BC-GTE seems to feature anti-neuroinflammatory property, holding the promise of a novel GTE based comple-mentary therapeutic approach.

With the term neuroinflammation has defined the typical inflammatory response of the brain closely related to the onset of many neurological diseases. Neuroinflammation is well known, but its mechanisms and pathways are not entirely comprehended. Currently, some progress has been achieved through many efforts and research. Consequently, new cellular and molecular mecha-nisms, diverse from conventional ones, are emerging. In listing some of those that will be the sub-ject of our description and discussion, essential are the important role of peripheral and infiltrated monocytes and clonotypic cells, alterations in gut/brain axis, dysregulation of the apelinergic sys-tem, as well as changes in the endothelial glycocalyx of blood-brain barrier, variation in expres-sion of some genes and levels of the encoding molecules by microRNAs (miRNAs), or other epige-netic factors and distinctive transcriptional factors, as well as the role of autophagy, ferroptosis, sex differences and modifications in the circadian cycle. Such mentioned mechanisms can add significant pieces in understanding the complex etiological puzzle of neuroinflammation. In addi-tion, they could represent biomarkers and targets of neurodegenerative diseases, in increase in our old populations.

The role of astro- and microglial cells in the pathogenesis of epilepsy is currently under active in-vestigation. It is proposed that the activity of these cells may be regulated by agonists of peroxi-some proliferator-activated nuclear receptors (PPARs). The objective of this study was to investi-gate the effects of the PPAR β/δ agonist GW0742 (Fitorine) on the behavior and gene expression of astro- and microglial proteins involved in the regulation of epileptogenesis in rat brain in a lithi-um-pilocarpine model of temporal lobe epilepsy (TLE). A seven-day administration of GW0742 at a dose of 5 mg/kg/day has been shown to suppress TLE-related behavioral hyperactivity in the Open Field test and to attenuate the TLE-induced increase in gene expression and protein levels of astro- and microglial activation markers Gfap and Aif1 in the dorsal hippocampus and temporal cortex. Furthermore, GW0742 reversed the TLE-related increase in Lcn2 gene expression (a marker of the A1 phenotype of astrocytes) in the temporal cortex, the increase in the ratio of Nos2/Arg1 gene expression (markers of the M1/M2 phenotypes of microglia), and the decrease in Arg1 gene ex-pression in the dorsal hippocampus. The results suggest that GW0742 may mitigate behavioral and biochemical abnormalities in a lithium-pilocarpine model of TLE.

The onset of neurodegenerative diseases involves a complex interplay of pathological mecha-nisms, including protein aggregation, oxidative stress, impaired autophagy. This review focuses on the intricate connection between oxidative stress and autophagy in neurodegenerative disor-ders, highlighting autophagy as pivotal in disease pathogenesis. Reactive oxygen species (ROS) play dual roles in cellular homeostasis and autophagy regulation, with disruptions of redox sig-naling contributing to neurodegeneration. The activation of the Nrf2 pathway represents a criti-cal antioxidant mechanism, while autophagy maintains cellular homeostasis by degrading al-tered cell components. The interaction between p62/SQSTM1, Nrf2 and Keap1 forms a regulatory pathway essential for cellular stress response, whose dysregulation leads to impaired autophagy and aggregate accumulation. Targeting the Nrf2-p62/SQSTM1 pathway holds promise for thera-peutic intervention, mitigating oxidative stress and preserving cellular functions. Additionally, the review explores the potential synergy between the endocannabinoid system and Nrf2 signal-ing for neuroprotection. Further research is needed to elucidate the involved molecular mecha-nisms and develop effective therapeutic strategies against neurodegeneration.

Trehalose is a naturally occurring disaccharide that has recently gained significant attention for its neuroprotective properties in various models of neurodegeneration. This review provides an overview of available experimental data on the beneficial properties of trehalose for central nervous system pathological conditions. Trehalose’s impact on neuronal cell survival and function was also examined. As a result, we identified that trehalose’s neuroprotection includes autophagy modulation as well as its capability to stabilize proteins and inhibit the formation of misfolded ones. Moreover, trehalose mitigates oxidative stress-induced neuronal damage by stabilizing cellular membranes and modulating mitochondrial function. Furthermore, trehalose attenuates excitotoxicity-induced neuroinflammation by suppressing pro-inflammatory cytokine release and inhibiting inflammasome activation. A possible connection of trehalose with the gut-brain axis was also examined. These findings highlight the potential therapeutic effects of trehalose in neurodegenerative diseases. According to the conclusions drawn from this study, trehalose is a promising neuroprotective agent as a result of its distinct mechanism of action, which makes this compound a candidate for further research and development of therapeutic strategies to combat neuronal damage and promote neuroprotection in various neurological diseases.

Background: Immunologic and neuro-inflammatory pathways have been found to play a major role in the pathogenesis of many neurological disorders such as epilepsy, proposing the use of novel therapeutic strategies. In the era of personalized medicine and in the face of the exhaustion of anti-seizure therapeutic resources it is worth looking at the current or future possibilities that neuroimmunomodulator or anti-inflammatory therapy can offer us in the management of patients with epilepsy. Methods: We performed a narrative review on the recent advances on the basic epileptogenic mechanisms related to the activation of immunity or neuroinflammation with special attention to current and future opportunities for novel treatments in epilepsy. Results: Neuroinflammation can be considered a universal phenomenon and occurs in structural, infectious, post-traumatic, autoimmune, or even genetically based epilepsies. The emerging research developed in recent years has allowed us to identify the main molecular pathways in-volved in these processes. These molecular pathways could constitute future therapeutic targets for epilepsy. Conclusions: Different drugs current or in development have demonstrated their capacity to inhibit or modulate molecular pathways involved in the immunologic or neuroinflammatory mechanisms described in epilepsy. Some of them should be tested in the future as possible antiepileptic drugs.

Lycopene is a compound of colored origin that shows strong antioxidant activity. The ability to neutralize free radicals by lycopene is the basis of its pro-health effect, including the ability to inhibit the development of many civilization diseases. Therefore, this study focuses on the importance of the antioxidant effect of lycopene in inhibiting the development of such diseases as cardiovascular diseases, diseases of the etiology of etiology, diseases within the nervous system.

Microglia together with other permanent macrophages in central nervous system (CNS) are responsible for regulating the innate immune response of the brain and spinal cord. Upon activation, microglia triggers the release of inflammatory mediators such as cytokines, chemokines, and other proteins related to neuro-inflammation. Elevated levels of neuro-inflammation have been linked to a decline in cognitive performance manifested in Alzheimer’s Disease (AD). There are mounting evidence in the literature to suggest that microglia are responsible for a substantial amount of the synaptic damage seen in AD. Most importantly, scientific studies have suggested that overexpression of microglia-derived neuro-inflammation elevates amyloid beta (Aβ) plaque formation, and hyperactivation of tau protein; the two main pathological characteristic features of AD. Alternatively, Aβ and tau formation further activate microglia to sustain the neuro-inflammation triggering a vicious cascade of neurodegeneration in AD. Here in this review, we discussed the role of microglia associated neuroinflammation for the pathogenesis of AD.

Background: Hypertension is a cardiovascular syndrome with the highest morbidity and mortality worldwide. Hypertension caused by various stress factors is called stress-induced hypertension (SIH). The rostral ventrolateral medulla (RVLM) "neuroinflammatory-sympathetic overactivation" is involved in SIH formation. Melatonin has anti-inflammatory, anti-oxidant and blood pressure lowering effects. The present study is to explore the antihypertensive effects and mechanism of central melatonin which based on microglia derived neuroinflammation. Methods: Stress-induced hypertension (SIH) was induced by electric foot-shock stressors with noise interventions in rats. Melatonin (0.01，0.1，1 mmol/L) was administered to RVLM and then blood pressure (BP) and serum norepinephrine (NE) were monitored to reflect sympathetic vasomotor activity in SIH rats. Excitatory neurotransmitter (Glutamate) and inhibitory neurotransmitter [γ-aminobutyric acid (GABA)] were measured using ELISA kits. Markers of microglia M1 polarization (CD86) and pro-inflammatory cytokines (PICs (IL-1β, TNF-α)) expression in the RVLM were measured by RT-qPCR. Results: (1) Stress-induced increase in blood pressure and serum NE concentration; RVLM microinjection melatonin attenuated the elevation of blood pressure and increase of plasma NE in SIH rats in a dose-dependent manner. (2) The expression of CD86, PICs (IL-1β, TNF-α) and c-fos were increased in SIH rats; RVLM injection melatonin attenuated RVLM neuroinflammation and its effect is concentration-dependent. (3). Stress-induced increase in glutamate concentration in RVLM; RVLM injection melatonin reduced glutamate level and increased GABA level in SIH rats in a concentration-dependent manner. Conclusion: RVLM injection of melatonin inhibits M1 polarization and has anti-hypertensive effects. Melatonin reduces M1 polarization in microglia might be a novel target and a new strategy for anti-stress induced-hypertension.

We previously reported that in multiple sclerosis (MS) patients with a progressive form of the disease, spinal cord periplaques extend distance away from plaque borders and are characterized by the co-occurrence of partial demyelination, astrocytosis and low-grade inflammation. However, transcriptomic analyses comparing periplaques to adjacent normal-appearing white matter (NAWM) areas did not allow providing a comprehensive view of molecular events in astrocytes vs oligodendrocytes. Here, we re-assessed our transcriptomic data with the aim of identifying functionally-relevant co-expression networks that would reflect astrocyte vs oligodendrocyte molecular signatures in periplaques. We identified an astrocytosis-related gene module comprising GFAP, the hub gene CX43/GJA1 and a set of transcripts forming a TGFB/SMAD1/SMAD2 genomic signature. Partial demyelination was characterized by a co-expression network which, besides myelin genes, comprised a highly significant number of translation/elongation-related genes. Interestingly, the main oligodendrocyte-related hub we identified was NDRG1, a gene previously shown to be specifically silenced in the NAWM of MS patients. This result indicated that NDRG1 down-regulation could be an important event in the process of periplaque partial demyelination. To establish a putative link between NDRG1 down-regulation and a cytokine/chemokine signature, we then sought to identify cytokine/chemokine genes whose mRNA levels inversely correlated with those of NDRG1. Following this approach we found 5 candidate immune-related genes whose up-regulation associated with NDRG1 down-regulation: TGFB1, PDGFC, IL-17D, IL-33, and IL-12A. From these results we propose that in the spinal cord of MS patients with progressive forms of the disease, TGFB1 may limit acute inflammation but concurrently induce astrocytosis and an alteration of oligodendrocytes terminal differentiation.

Chronic stress is a major risk factor for various psychiatric diseases, including depression; it induces a range of cellular and structural adaptations, culminating in altered neurocircuitry and subsequent depression. Accumulating evidence suggests that microglial cells orchestrate stress-induced depression. Preclinical studies of stress-induced depression revealed microglial inflammatory activation in regions of the brain that regulate mood. Although studies have identified several molecules that trigger inflammatory responses in microglia, the pathways that regulate stress-induced microglial activation remain unclear. Understanding the exact triggers that induce microglial inflammatory activation can help find therapeutic targets to treat depression. In the current review, we summarize the recent literature on possible sources of microglial inflammatory activation in animal models of chronic stress-induced depression. In addition, we describe how microglial inflammatory signaling affects neuronal health and causes depressive behavior. Finally, we propose ways to target the microglial inflammatory cascade to treat depressive disorders.

RTP801/REDD1 is a stress-regulated protein whose levels are increased in several neurodegenerative diseases such as Parkinson’s, Alzheimer’s, and Huntington’s diseases (HD). RTP801 downregulation ameliorates behavioral abnormalities in several mouse models of these disorders. In HD, RTP801 mediates mutant huntingtin (mhtt) toxicity in in vitro models and its levels are increased in human iPSCs, human postmortem putamen samples and in striatal synaptosomes from mouse models of the disease. Here, we investigated the role of RTP801 in the hippocampal pathophysiology of HD. We found that RTP801 levels are increased in the hippocampus of HD patients in correlation with gliosis markers. Although RTP801 expression is not altered in the hippocampus of the R6/1 mouse model of HD, neuronal RTP801 silencing in the dorsal hippocampus with shRNA-containing AAV particles ameliorates cognitive alterations. This recovery is associated with a partial rescue of synaptic markers and with a reduction of inflammatory events, especially microgliosis. Altogether, our results indicate that RTP801 could be a marker of hippocampal neuroinflammation in HD patients and a promising therapeutic target of the disease.

Background: CCL11 (eotaxin) is a chemokine with an important role in allergic conditions. Recent evidence indicates that CCL11 plays a role in brain disorders as well. Aims: This paper reviews the associations between CCL11 and aging, neurodegenerative, neuroinflammatory and neuropsychiatric disorders.Methods: Electronic databases were searched for original articles examining CCL11 in neuropsychiatric disorders.Results: CCL11 is rapidly transported from the blood to the brain through the brain-blood barrier. Age-related increases in CCL11 are associated with cognitive impairments in executive functions, episodic and semantic memory and, therefore, this chemokine was described as an “endogenous cognition deteriorating chemokine” (ECDC) or “accelerated brain-aging chemokine” (ABAC). In schizophrenia, increased CCL11 is not only associated with impairments in cognitive functions, but also with key symptoms including formal thought disorders. Some patients with mood disorders and premenstrual syndrome show increased plasma CCL11 levels. In diseases of old age, CCL11 is associated with lowered neurogenesis and neurodegenerative processes and, as a consequence, increased CCL11 increases risk towards Alzheimer's Disease. Polymorphisms in the CCL11 gene are associated with stroke. Increased CCL11 also plays a role in neuroinflammatory disease including multiple sclerosis. In animal models, neutralization of CCL11 may protect against nigrostriatal neurodegeneration. Increased production of CCL11 may be attenuated by glucocorticoids, minocycline, resveratrol and anti-CCL11 antibodies.Conclusion: Increased CCL11 production during inflammatory conditions may play a role in human disease including age-related cognitive decline, schizophrenia, mood disorders and neurodegenerative disorders. Increased CCL11 production is a new drug target in the treatment and prevention of those disorders.

The fight against suicide is highly challenging as it may be one of the most complex and at the same time most threatening among all psychiatric phenomena. In spite of its huge impact, and despite advances in neurobiology research, understanding and predicting suicide remains a major challenge for both researchers and clinicians. To be able to identify those patients who are likely to engage in suicidal behaviors and identify suicide risk in a reliable and timely manner, we need more specific, novel biological and genetic markers/indicators to develop better screening and diagnostic methods, and in the next step to utilize these molecules as intervention targets. One such potential novel approach is offered by our increasing understanding of the involvement of neuroinflammation based on multiple observations of increased proinflammatory states underlying various psychiatric disorders including suicidal behavior. The present paper overviews our existing understanding of the association between suicide and inflammation including peripheral and central biomarkers, genetic and genomic markers, and our current knowledge of intervention in suicide risk using treatments influencing inflammation, also overviewing the next steps to be taken and obstacles to be overcome before we can utilize cytokines in the treatment of suicidal behavior.

(1) Background: Triggering receptor expressed on myeloid cells 2 (TREM2) is involved in neu-roinflammation and HIV-associated neurocognitive impairment (NCI). People with HIV (PWH) using cannabis exhibit lower inflammation and neurological disorders. We hypothesized TREM2 dysfunction mediates HIV neuropathogenesis and can be reversed by cannabinoids. (2) Methods: EcoHIV-infected wildtype (WT) and TREM2R47H mutant mice were used to study HIV's impact on TREM2 and behavior. TREM2 and related gene expressions were examined in mono-cyte-derived macrophages (MDMs) from PWH (n=42) and people without HIV (PWoH; n=19) with varying cannabis use via RNA sequencing and qPCR. Differences in membrane-bound and soluble TREM2 (sTREM2) were evaluated using immunocytochemistry (ICC) and ELISA. (3) Results: EcoHIV increased immature and C-terminal fragment forms of TREM2 in WT mice but not in TREM2R47H mice, with increased IBA1 protein in TREM2R47H hippocampi, correlating with worse memory test performance. TREM2 mRNA levels increased with age in PWoH but not PWH. Cannabidiol (CBD) treatment increased TREM2 mRNA alone and with IL1β. RNA-seq showed upregulation of TREM2-related transcripts in cannabis-using PWH compared to naïve controls. IL1β increased sTREM2 and reduced membrane-bound TREM2, effects partially re-versed by CBD. (4) Conclusions: These findings suggest HIV affects TREM2 expression modu-lated by cannabis and CBD, offering insights for therapeutic strategies.

In Parkinson's disease, neuroinflammation is a complex defense mechanism. Activated microglia and Proteinase-activated receptor-2 (PAR2) are key points in the regulation of neuroinflammation. 1-Piperidin Propionic Acid (1-PPA) has been recently described as a novel inhibitor of PAR2. The aim of our study was to evaluate the effect of 1-PPA in neuroinflammation and microglial activation in Parkinson's disease. Protein aggregates and PAR2 expression were analyzed by thioflavin S assay and immunofluorescence in cultured human fibroblasts from Parkinson's patients, treated or not with 1-PPA. A significant decrease of amyloid aggregates and expression of PAR2 were observed after 1-PPA treatment in all patients. A parallel decrease of PAR2 expression, that was higher in sporadic Parkinson’s patients, was also observed both at transcriptional and protein level. In addition, in mouse LPS-activated microglia, the inflammatory profile was significantly downregulated after 1-PPA treatment, with a remarkable decrease of IL-1, IL-6 and TNF-togheter with PAR2 decreased expression.In conclusion, 1-PPA determines reduced neuroglia inflammation and amyloid aggregates formation, suggesting that pharmacological inhibition of PAR2 could be proposed as a novel strategy to control neuroinflammation.

(1) Background: Intracortical microelectrodes (IMEs) are an important part of interfacing with the central nervous system (CNS) and recording neural signals. However, recording electrodes have shown a characteristic steady decline in recording performance owing to chronic neuroinflammation. The topography of implanted devices has been explored to mimic the nanoscale three-dimensional architecture of the extracellular matrix. Our previous work used histology to study the implant sites of non-recording probes and showed that a nanoscale topography at the probe surface mitigated the neuroinflammatory response compared to probes with smooth surfaces. Here, we hypothesized that the improvement in the neuroinflammatory response for probes with nanoscale surface topography would extend to improved recording performance. (2) Methods: A novel design modification was implemented on planar silicon-based neural probes by etching nanopatterned grooves (with a 500 nm pitch) into the probe shank. To assess the hypothesis, two groups of rats were implanted with either nanopatterned (n=6) or smooth control (n=6) probes, and their recording performance was assessed over 4 weeks. Postmortem gene expression analysis was performed to compare the neuroinflammatory response from the two groups. (3) Results: Nanopatterned probes demonstrated increased impedance and noise floor compared to controls. However, the recording performance of the nanopatterned and smooth probes was similar, with active electrode yield for control probes and nanopatterned probes being approximately 50% and 45%, respectively by 4 weeks post-implantation. Gene expression analysis showed 1 gene, Sirt1, differentially expressed out of 152 in the panel. (4) Conclusions: This study provides a foundation for investigating novel nanoscale topographies on neural probes.

Polygonum sibiricum is a traditional Chinese food and medicine homologues with multiple active ingredients and extensive bioactive effects. Polygonum sibiricum polysaccharides (PSP) are one of the main active ingredients with the antidepressant activity, meanwhile the specific mechanisms of its action are still unclear. Recently, it is recognized by researchers that microglia play a double-edged role in neuroinflammation and the transformation of M1/M2 microglial phenotypes appears to be a potential therapeutic strategy in depression. Therefore, the present study evaluated the effects of PSP on microglial M1/M2 polarization and the molecular mechanisms were studied based on the lipopolysaccharide (LPS)-induced BV2 cell activation model. The results show that PSP significantly inhibited NO and LDH release and reduced ROS levels in LPS-induced BV2 cells. PSP could significantly reduce the protein expression level of Iba-1, decreased the mRNA levels of TNF-, IL-1 and IL-6, increased the mRNA level of IL-10. PSP also significantly reduced the protein expression level of CD16/32 and increased it of CD206, reduced the mRNA level and fluorescence intensity of iNOS and increased them of Arg-1. However, PSP pretreatment reversed the alterations of BDNF/TrkB/CREB and Notch/Hes1 pathways in LPS-induced BV2 cells. These results suggested that PSP exerted the anti-inflammatory effects by inhibiting M1 phenotype polarization and promoting microglia polarization toward M2 phenotype, and its regulation of microglia M1/M2 polarization may be associated with modulating the BDNF/TrkB/CREB and Notch/Hes1 pathways.

Positron emission tomography (PET) imaging of Colony Stimulating Factor 1 Receptor (CSF1R) is a new strategy for quantifying both neuroinflammation and inflammation in the periphery since CSF1R is expressed on microglia. AZ683 has high affinity for CSF1R (K_i = 8 nM; IC₅₀ = 6 nM) and >250-fold selectivity over 95 other kinases and, in this paper, we report the radiosynthesis of [¹¹C]AZ683 and initial evaluation of its use in CSF1R PET. [¹¹C]AZ683 was synthesized by ¹¹C-methylation of the desmethyl precursor with [¹¹C]MeOTf in 3.0% non-corrected activity yield (based upon [¹¹C]MeOTf), >99% radiochemical purity and high specific activity. Preliminary PET imaging with [¹¹C]AZ683 revealed no brain uptake in rodents and nonhuman primates suggesting that [¹¹C]AZ683 is a poor candidate for imaging neuroinflammation, but that it could still be useful for peripheral imaging of inflammation.

Background: Inflammatory demyelination and impaired recovery processes result in permanent neurodegeneration and neurological disability in patients with multiple sclerosis (MS). In terms of smoldering MS, chronic neuroinflammation develops in the early period of the disease and leads to confirmed disability accumulation. There is a great need to identify biomarkers of neuro-degeneration and disease progression. Methods: We evaluated the concentrations of the param-eters of brain injury (NF-H, GPAF, S100B, UCHL1) in the cerebrospinal fluid (CSF) and the se-lected interleukins (ILs) in serum of 123 relapsing-remitting MS (RRMS) and 88 progressive MS (PMS) patients. Results: The levels of GFAP, S100B and UCHL were higher in the PMS group compared to RRMS as opposed to the levels of NF-H. We observed a positive correlation be-tween the selected pro-inflammatory cytokines and the parameters of brain injury. The Ex-panded Disability Status Scale score (EDSS) increased with GFA and NF-H levels and correlated with the selected ILs. The concentrations of S100B, UCHL1 and NF-H reflected the duration of MS symptoms. Conclusions: The levels of brain injury parameters in the CSF and the selected serum ILs in MS patients seem to be promising biomarkers to determine neurodegeneration and neuroinflammation in smoldering MS. Further studies are warranted in this respect.

The therapeutic, attenuative, and morphological effects of proprietary neural stem cell-derived extracellular vesicles (NSC EVs, AB126) produced by Aruna Bio, Inc. were assessed in a range of in vitro and in vivo models of stroke. We emphasize that modulation of neuroinflammation is a key target and suggest further studies to advance our understanding of the mechanisms of action and ultimately how best to dose and monitor the benefits of AB126 in stroke patients.

Neurodegenerative diseases (NDs) affect millions of people worldwide, and to date Alzheimer's and Parkinson's disease are the most common NDs. The risk of developing NDs increases dra-matically with age, and genetic and environmental factors can be crucial in their progression. The main feature of NDs is the abnormal presence of specific proteins that can lead to neuronal death, proteotoxic stress, and alteration of catabolic systems, which are major players in the processes of neurodegeneration and neuroinflammation. Despite research efforts to date, the therapies cur-rently in use for the treatment of NDs provide marginal therapeutic benefit, so the focus is now being direct toward the search of natural products that could be a valuable aid in combating these diseases, including the natural compound Andrographis paniculata (Ap) and especially its main constituent Andrographolide (Andro). Preclinical studies have shown that the aqueous extract of Ap is capable to modulate neuroinflammatory and neurodegenerative responses, determining a reduction in inflammatory markers and oxidative stress in various NDs. Therefore, in this review we will focus on the molecular mechanisms through which Ap and Andro are able to modulate the processes of neurodegeneration and neuroinflammation that are major causes of neuronal death and cognitive decline.

Brain pathological changes impair cognition early in disease etiology. There is an urgent need for understanding aging-linked mechanisms of early memory loss to develop therapeutic strategies and prevent the development of cognitive impairment. Tusc2, also named Fus1, is a mitochondrial-resident protein regulating Ca2+ fluxes to and from mitochondria impacting overall health. We reported that Tusc2-/- female mice develop chronic inflammation and age prematurely, causing age- and gender-dependent spatial memory deficits at 5 m.o. Therefore, we investigated Tusc2-dependent mechanisms of memory impairment in mice, comparing changes in resident and brain-infiltrating immune cells. Interestingly, Tusc2-/- female mice demonstrated proinflammatory increase in astrocytes, IFN-γ expression in CD4+T cells and Granzyme-B in CD8+T cells. We also found fewer FOXP3+ T-regulatory cells and Ly49G+ NK and Ly49G+ NKT cells in female Tusc2-/- brain, suggesting a weakened anti-inflammatory response. Moreover, Tusc2-/- hippocampi exhibited Tusc2- and sex-specific protein changes associated with brain plasticity, including mTOR activation, and Calbindin and CamKII dysregulation affecting intracellular Ca2+ dynamics. Overall, data suggest that dysregulation of Ca2+-dependent processes and proinflammatory brain microenvironment heighten in Tusc2-/- mice could underlie cognitive impairment. Thus, strategies to modulate the brain’s Tusc2-, Ca2+, and mitochondria-dependent pathways should be explored to improve cognitive health.

Recent research has unveiled intriguing insights suggesting that the body's immune system may be implicated in Parkinson's disease (PD) development. Studies have observed disparities in pro-inflammatory and anti-inflammatory markers between PD patients and healthy individuals. This finding underscores the potential influence of immune system dysfunction in the genesis of this condition. A dysfunctional immune system can serve as a primary catalyst for systemic in-flammation in the body, which may contribute to the emergence of various brain disorders. The identification of several genes associated with PD, as well as their connection to neuroinflamma-tion, raises the likelihood of disease susceptibility. Moreover, advancing age and mitochondrial dysfunction can weaken the immune system, potentially implicating them in the onset of the dis-ease, particularly among older individuals. Compromised integrity of the blood-brain barrier could facilitate the immune system's access to brain tissue. This exposure may lead to encounters with native antigens or infections, potentially triggering an autoimmune response. Furthermore, there is mounting evidence supporting the notion that gut dysbiosis might represent an initial trigger for brain inflammation, ultimately promoting neurodegeneration. In this comprehensive review, we will delve into the numerous hypotheses surrounding the role of both innate and adaptive immunity in PD.

Homocysteine (Hcy) is a sulfur-containing amino acid that is generated during methionine metabolism. Hyperhomocysteinemia (HHcy) is typically defined as levels >15 micro mols/L. Elevated plasma levels of Hcy can be caused by the deficiency of either vitamin B12 or folate. The active role of homocysteine is quite ambivalent: many studies detected its potential impact on neurological events; others try to identify it as one of the possible risk factors of cardiovascular events, but with a complementary and secondary role. HHcy has been reported in many neurologic disorders, including cognitive impairment and stroke, independent of long-recognized factors such as hyperlipidemia, hypertension, diabetes mellitus, and smoking. Nowadays, homocysteine could be considered as a possible link between a common vascular risk factor and potential alterations in degenerative neuronal disorders. HHcy-induced oxidative stress, endothelial dysfunction, inflammation, smooth muscle cell proliferation, and endoplasmic reticulum stress; all these aspects have been considered to play an essential role in the pathogenesis of several diseases, including atherosclerosis, major stroke, and vascular dementia. Specific models of astrocytes impairment in HHcy-mice, which mimic small vessel disease, have been developed with a three-step investigation (at 6, 10, 14 weeks of B6, B9, and B12 detrimental diet in wild type HHcy mouse). These studies found out that after ten weeks on a diet (at the most after 14 weeks), end-feet disruption occurs. This phenomenon is concomitant to reduced vascular labeling for aquaporin -4-water channels, lower protein/mRNA levels for Kir4.1, and BK potassium channels, associated with a higher expression of MMP-9. The most exciting finding is that microglial activation in this mice model was evident since the precocious time of observation (6-week time) and precedes astrocytic changes. Our research aims to review the possible role of HHcy in neurodegenerative disease and small-vessel disease and to understand its pathogenic impact.

Mild traumatic brain injuries (mTBIs) are highly prevalent and can lead to chronic behavioral and cognitive deficits, often associated with the development of neurodegenerative diseases. The formation of reactive oxygen species (ROS) and oxidative stress have been implicated in mTBI-mediated axonal injury and pathogenesis. However, the underlying mechanisms and contributing factors are not completely understood. In this study, utilizing a murine model of repetitive mTBI (r-mTBI) involving five closed-skull concussions in young adult C57BL/6J mice, we observed a significant elevation of Na+/H+ exchanger protein (NHE1) expression in GFAP+ reactive astrocytes, IBA1+ microglia, and OLIG2+ oligodendrocytes across various brain regions (including the cerebral cortex, corpus callosum, and hippocampus). This elevation was accompanied by astrogliosis, microgliosis and the accumulation of amyloid precursor protein (APP). Concurrently, r-mTBI mice displayed impaired motor learning and spatial memory deficits. However, post-r-mTBI administration of a potent NHE1 inhibitor, HOE642, attenuated locomotor and cognitive functional deficits as well as gliosis, oxidative stress, axonal damage, and white matter damage. These findings underscore the role of NHE1 upregulation in r-mTBI-induced oxidative stress, axonal damage, and gliosis, suggesting NHE1 as a promising therapeutic target to alleviate mTBI-induced injuries and restore neurological function.

There is an urgent need to better understand the mechanisms involved in scar formation in brain. It is well known that astrocytes are critically engaged in this process. Here we analyze in-cipient scar formation one week after a discrete ischemic insult to the cerebral cortex. We show that the infarct border zone is characterized by pronounced changes in the organization and subcellular localization of the major astrocytic protein AQP4. Specifically there is a loss of AQP4 from astrocytic endfoot membranes that anchor astrocytes to pericapillary basal laminae and a disassembly of the supramolecular AQP4 complexes that normally abound in these membranes. This disassembly may be mechanistically coupled to a downregulation of the newly discovered AQP4 isoform AQP4ex. AQP4 has adhesive properties and is assumed to facilitate astrocyte mo-bility by permitting rapid volume changes at the leading edges of migrating astrocytes. Thus, the present findings provide new insight in the molecular basis of incipient scar formation.

Oxidative stress and chronic inflammation, both at the systemic and central level, are critical early events in atherosclerosis and Alzheimer’s disease (AD). Purpose. To investigate the oxidative stress, inflammatory, and Tau-phosphorylation lowering effects of pomegranate polyphenols (PP) (punicalagin, ellagic acid, peels, and arils extracts). Methods. We used flow cytometry to quantify protein expression of proinflammatory cytokines (IL-1β) and anti-inflammatory mediators (IL-10) in THP-1 macrophages, as well as M1/M2 cell-specific markers (CD86 and CD163) expression in human microglia HMC3 cells. IL-10 protein expression was also quantified in U373-MG human astrocytes. The effect of PP on human amyloid beta 1-42 (Aβ1-42)-induced oxidative stress was assessed in microglia by measuring ROS generation and lipid peroxidation, using respectively two ′,7′-dichlorofluorescein diacetate (DCFH-DA) and thiobarbituric acid reactive substances (TBARS) tests. Neuronal viability and cell apoptotic response to Aβ1-42 toxicity were assayed using the MTT (3-(4, 5-dimethyl thiazolyl-2)-2, 5-diphenyltetrazolium bromide) assay and the annexinV-FITC apoptosis detection kit; respectively. Finally, flow cytometry analysis was also performed to evaluate the ability of PP to modulate Aβ1-42-induced Tau-181 phosphorylation (pTau-181). Results. Our data indicate that PP was significantly (p<0.05) effective in countering Aβ1-42-induced inflammation through increasing the anti-inflammatory cytokines (IL-10) (in U373-MG astrocytes and THP1 macrophages) and decreasing proinflammatory markers (IL-1β) expression in THP1 macrophages. PP was also significantly (p<0.05) effective in inducing the phenotypic transition of THP-1 macrophages and microglial cells from M1 to M2 by decreasing CD86 and increasing CD163 surface receptor expression. Moreover, our treatments have a significant (p<0.05) beneficial impact on oxidative stress, illustrated in the reduction of TBARS and ROS generation. Our treatments have significant (p<0.05) cell viability improvement capacities and anti-apoptotic effects on human H4 neurons. Furthermore, our results suggest that Aβ1-42 significantly (p<0.05) increases pTau-181. This effect was significantly (p<0.05) attenuated by arils, peels, and punicalagin and drastically reduced by ellagic acid treatments. Conclusion. Our results are attributed to PP's anti-inflammatory, antioxidant, anti-apoptotic, and anti-Tau pathology potential. Future studies should aim to extend our knowledge of the potential role of PP on A1-42-induced neurodegeneration, mainly its association with the tauopathy involved in AD.

Neuroinflammation and brain oxidative stress are recognized as significant contributors to hypertension including salt sensitive hypertension. Extracellular vesicles (EVs) play an essential role in intercellular communication in various situations, including physiological and pathological ones. Based on this evidence, we hypothesized that EVs derived from the brains of hypertensive rats with salt sensitivity could trigger neuroinflammation and oxidative stress during hypertension development. To test this hypothesis, we compared the impact of EVs isolated from the brains of hypertensive Dahl Salt Sensitive rats (DSS) and normotensive Sprague Dawley (SD) rats on inflammatory factors and mitochondrial reactive oxygen species (mtROS) production in primary neuronal cultures and brain cardiovascular relevant regions, including the hypothalamic paraventricular nucleus (PVN) and lamina terminalis (LT). We found that brain-derived DSS-EVs significantly increased mRNA levels of proinflammatory cytokines (PICs) and chemokines, including TNFα, IL1β, CCL2, CCL5, and CCL12, as well as the transcriptional factor NF-κB in neuronal cultures. DSS-EVs also induced oxidative stress in neuronal cultures, as evidenced by elevated NADPH oxidase subunit CYBA coding gene mRNA levels and persistent mtROS elevation. When DSS-EVs were injected into the brains of normal SD rats, mRNA levels of PICs, chemokines, and the chronic neuronal activity marker FOSL1 were significantly increased in the PVN and LT. Furthermore, DSS-EVs caused mtROS elevation in brain PVN and LT, particularly in neurons. Our study reveals a novel role for brain-derived EVs from hypertensive rats in triggering neuroinflammation, upregulating chemokine expression, and inducing excessive ROS production. These findings provide insight into the complex interactions between EVs and hypertension-associated processes, offering potential therapeutic targets for hypertension-linked neurological complications.

Intercellular adhesion molecule 1 (ICAM-1/CD54), a transmembrane glycoprotein, has been considered as one of the most important adhesion molecules during leukocyte recruitment. It is encoded by the ICAM1 gene and plays a central role in inflammation. It’s crucial role in many inflammatory diseases such as ulcerative colitis and rheumatoid arthritis are well established. Given that neuroinflammation, underscored by microglial activation, is a key element in neurodegenerative diseases such as Parkinson’s disease (PD), we investigated whether ICAM-1 has a role in this progressive neurological condition and if so, elucidate the underpinning mechanisms. Specifically, we were interested in potential interaction between ICAM-1, glial cells and ferroptosis, an iron-dependent form of cell death that has recently been implicated in PD. We conclude that there exist direct and indirect (via glial cells and T cells) influences of ICAM-1 on ferroptosis and that further elucidation of these interactions can suggest novel intervention for this devastating disease.

Strong evidence indicates that insulin resistance contributes to the development of Alzheimer´s disease by promoting inflammation, oxidative stress, and blood vessel damage. Conversely, neuroinflammation induces insulin resistance by targeting insulin signaling molecules: the insulin receptor substrates 1 and 2 (IRS1/2). In addition, neuroinflammation is strongly linked to reduced levels of brain-derived neurotrophic factor (BDNF) expression. BDNF is a key factor for neuronal survival, and its expression is compromised in neurodegenerative disorders. In this study, we show that, in a triple-transgenic (3xTg) mice model of Alzheimer’s disease, the BDNF and IRS2 but not the IRS1 mRNA expression levels were reduced in the hippocampus, together with higher levels of TNFα, compared with wild-type mice. Subgroups of control and 3xTg mice received short and long treatments of Abscisic Acid (ABA), a phytohormone with anti-inflammatory and insulin-sensitizing capabilities. We found that the short ABA treatment can increase the IRS1 and IRS2 mRNA expression both in wild-type and 3xTg mice, concomitant with reducing pro-inflammatory cytokine TNFα in 3xTg mice. However, earlier, and thus longer treatments are required to rescue the BDNF mRNA levels. Our data strongly confirm that ABA administration is a potential treatment to prevent Alzheimer´s disease, via lowering neuroinflammation, potentially rescuing insulin signaling molecules and BDNF mRNA expression.

The dynamic equilibrium of iron homeostasis has an important role in sustaining metabolic and neurological functions during human life. Iron excretion is modest and unregulated hence this overall equilibrium is tightly regulated in normal conditions by increasing deficient or limiting excessive iron assimilation. Here we focus on neural tissue overload, dyshomeostasis that is preceded by excessive assimilation, disturbances in internal homeostasis or both. Normal steps in iron homeostasis include its uptake across the apical membrane of the enterocytes in a mildly acidic duodenal milieu by the major importer of ferrous iron, Divalent Metal Transporter 1 (DMT1) (Nramp2/DCT1/SLC11A2, solute carrier family 11 member 2) [1, 2], responsible for the uptake of Non-Transferrin Bound Iron (NTBI) and divalent metals [3], passage through enterocytes bound to a chaperone and crossing the basal membrane via the only known cellular ferrous iron exporter, ferroportin [4] with the iron bound to transferrin (Tf) as it exits. Cells in peripheral tissues largely utilize circulating iron after uptake by receptor-mediated endocytosis of Tf-bound Iron [5]. Derangement of duodenal NTBI absorption of iron and heavy metals is influenced by systemic iron metabolism associated with inflammation that leads to iron accumulation into peripheral tissues and potential development of neurodegenerative diseases, involving distribution and fine regulation of DMT1 also in the central nervous system, where inflammatory-related acidosis influences DMT1 uptake, via its action as a proton cotransporter. Pharmacological strategies to inhibit NTBI transport selectively will be illustrated in relationship to protection, particularly neuroprotection, against iron overload associated with acidosis, inflammation, neuroinflammation and subsequent neurodegeneration.

One of the major obstacles confronting the formulation of a mechanistic understanding for Alzheimer’s disease (AD) is its immense complexity – a complexity that traverses the full structural and phenomenological spectrum, including molecular, macromolecular, cellular, neurological and behavioural processes. This complexity is reflected by the equally complex diversity of risk factors associated with AD. However, more than merely mirroring disease complexity, risk factors also provide fundamental insights into the aetiology and pathogenesis of AD as a neurodegenerative disorder since they are central to disease initiation and subsequent propagation. Based on a systematic literature assessment, this review has identified 30 risk factors for AD and then extended the analysis to further identify neuroinflammation as a unifying mechanism present in all 30 risk factors. Although other mechanisms (e.g. vasculopathy) were present in multiple risk factors, dysfunction of the neuroimmune-neuroinflammation axis was uniquely central to all 30 identified risk factors. Though the nature of the neuroinflammatory involvement varied, activation of microglia and the release of pro-inflammatory cytokines was a common pathway shared by all risk factors. This observation provides further evidence for the importance of immunopathic mechanisms in the aetiopathogenesis of AD.

The pathogenesis of Cerebral Small Vessel Disease (CSVD) is largely unknown. Endothelial disfunction has been suggested as the turning point in CSVD development. In this study we tested the effect of plasma from CSVD patients on human cerebral microvascular endothelial cells with the aim of describing the pattern of endothelial activation. Plasma samples from 3 groups of young subjects have been tested: PTs (subjects affected by early stage CSVD); CTRLs (control subjects without abnormalities at MRI scanning); BDs (blood donors). Human Brain Endothelial Cells 5i (HBEC5i) were treated with plasma and total RNA was extracted. RNAs were pooled to reduce gene expression-based variability and NGS analysis was performed. Differentially expressed genes were highlighted comparing PTs, CTRLs and BDs with HBEC5i untreated cells. No significantly altered pathway was evaluated in BD related treatment. Regulation of p38 MAPK cascade (GO:1900744) was the solely pathway altered in CTRLs related treatment. Indeed, 36 different biological processes turned out to be deregulated after PTs treatment of HBEC5i, i.e., the cytokine-mediated signaling pathway (GO:0019221). Endothelial cells activate inflammatory pathways in response to stimuli from CSVD patients’ plasma, suggesting the pathogenetic role of neuroinflammation from the early asymptomatic phases of cerebrovascular disease.

Parkinson’s disease is a neurodegenerative disorder characterized by oxidative stress and immune activation in the nigro-striatal pathway. Simvastatin regulates cholesterol metabolism and protects from atherosclerosis disease. Simvastatin or tween-80 was administered 7 days before sterotaxic intrastriatal administration of MPP+ (1-methyl-4-phenylpyridine) in rats. Fluorescent lipidic product formation, dopamine levels, and circling behavior were considered damage markers. Twenty-four h and six days after, the animal group lesioned with MPP+ showed significant damage in relation to the control group. Animals pretreated with simvastatin reduced significantly the MPP+-induced damage compared to MPP+ treated group. As apoptosis promotes neuroinflammation and neuronal degeneration in Parkinson’s disease, and since there is not currently a proteomic map of the Nigro striatum of rats, and assuming a high homology among the identified proteins in other rat tissues, we based the search for rat protein homologs related to the establishment of inflammation response. We demonstrate that most proteins related to inflammation are decreased in the simvastatin-treated rats. Furthermore, differential expression of antioxidant enzymes in striated tissue of rat brains was found in response to simvastatin. These results suggest that simvastatin could prevent striatal MPP+-induced damage and for the first time the molecular mechanisms involved in this protective effect.

Migraine and neuropathic pain (NP) are evocative of painful, disabling, chronic conditions which exhibit resembling symptoms and thus considered to share a common etiology. Calcitonin gene-related peptide (CGRP) has gained credit as a target for migraine management; nevertheless, the efficacy and the applicability of CGRP modifiers warrant search for more effective therapeutic targets for pain management. This scoping review overviews human studies of common pathogenic factors in migraine and NP to explore potential novel therapeutic targets. CGRP causes inflammation in the meninges; monoclonal antibodies and inhibitors target CGRP. Gluta-mate-induced hyperexcitability and subsequent sensitization are closely linked to an alteration of the tryptophan (Trp)-kynurenine (KYN) metabolic system; the Trp-KYN system may serve as a potential target. Microglial overaction is observed in migraine and NP; modifying the microglial activity may be a possible approach. Cytokine-induced inflammation is a leading hypothesis of the pathogenesis of the conditions; alleviating neuroinflammation may complement a pain-relieving armamentarium. Transient receptor potential (TRP) ion channels evoke the release of several substances; TRP ion channels may potentially emerge as new targets. The endocannabinoid system plays a major role in the pain trafficking pathway; modification of the system may open a new path toward discovery of new analgesics. Here we highlight the mechanism of those common pathogenic factors to explore therapeutic targets for innovative pain management in migraine and NP.

Chronic pain is an unpleasant sensory and emotional experience that persists or recurs more than three months and may extend beyond the expected time of healing. Recently nociplastic pain has been introduced as a descriptor of mechanism of pain, which is due to disturbance of neural processing without actual or potential tissue damage, appearing to replace a concept of psychogenic pain. An interdisciplinary task force of the International Association for the Study of Pain (IASP) compiled a systematic classification of clinical conditions associated with chronic pain, which was published in 2018 and will officially come into effect in 2022 in the 11th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-11) by the World Health Organization. ICD-11 offers the option for recording the presence of psychological or social factors in chronic pain; however, cognitive, emotional, and social dimensions in the pathogenesis of chronic pain are missing. Earlier pain disorder was defined as a condition with chronic pain associated with psychological factors, but it was replaced with somatic symptom disorder with predominant pain in Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) in 2013. Recently clinical nosology is trending toward highlighting neurological pathology of chronic pain, discounting psychological or social factors in the pathogenesis of pain. This review article discusses components of the pain pathway, the component-based mechanisms of pain, central and peripheral sensitization, roles of chronic inflammation, and the involvement of tryptophan-kynurenine pathway metabolites, exploring participations of psychosocial and behavioral factors in central sensitization of diseases progressing into development of chronic pain, comorbid diseases that commonly present a symptom of chronic pain, and psychiatric disorders that manifest chronic pain without obvious actual or potential tissue damage.

As an essential component of our innate immune system, the complement system is responsible for our defense against pathogens. The complement cascade has complex roles in the central nervous system (CNS), most of what we know about it stems from its role in brain development. However, in recent years, numerous reports have implicated the classical complement cascade in both brain development and decline. More specifically, complement dysfunction has been implicated in neurodegenerative disorders, such as Alzheimer’s disease (AD), which is the most common form of dementia. Synapse loss is one of the main pathological hallmarks of AD and correlates with memory impairment. Throughout the course of AD progression, synapses are tagged with complement proteins and are consequently removed by microglia which express complement receptors. Notably, astrocytes are also capable of secreting signals that induce the expression of complement proteins in the CNS. Both astrocytes and microglia are implicated in neuroinflammation, another hallmark of AD pathogenesis. In this review, we provide an overview of previously known and newly established roles for the complement cascade in the CNS and we explore how complement interactions with microglia, astrocytes, and other risk factors such as TREM2 and ApoE4, modulate the processes of neurodegeneration in both amyloid and tau models of AD.

Neuropathic pain (NP) affects about the 8% of the general population. Current analgesic therapies have limited efficacy, making NP one of the most difficult to treat pain conditions. Evidence indicates that excessive oxidative stress can contribute to the onset of chronic NP and several natural antioxidant compounds have showed promising efficacy in NP models. Thus, the aim of the present study was to investigate the pain-relieving activity of honokiol (HNK)-rich standardized extract of Magnolia officinalis Rehder &amp; E. Wilson bark (MOE), well known for its antioxidant and anti-inflammatory properties, in the spared nerve injury (SNI) model. The molecular mechanisms were investigated in spinal cord samples from SNI mice and in LPS-stimulated BV2. MOE and HNK showed antioxidant activity. MOE (30 mg/kg p.o.), produced an antiallodynic effect in the absence of locomotor impairment. MOE treatment reduced spinal p-p38, p-JNK1, iNOS, p-p65, IL-1ß and Nrf2 overexpression, increased IL-10 and MBP levels and attenuated the Notch signaling pathway by reducing Jagged1 and NEXT. All these effects were prevented by the CB1 antagonist AM251. HNK reduced the proinflammatory state of LPS-stimulated BV2 cells and reduced Jagged1 overexpression. MOE and HNK, by modulating oxidative and proinflammatory responses, might represent interesting candidates for NP management.

The intricate mechanisms of the immune response elicited by vaccines and the interplay between the immune system and the central nervous system (CNS) are poorly understood. This review explores these mechanisms, emphasizing the interplay between the immune system and the central nervous system (CNS). A critical aspect is the examination of how vaccine-induced immune responses can interact with the CNS, influencing neuroinflammation and neuroimmune interactions. Furthermore, the link between vaccination and persistent symptoms observed in long-COVID patients is discussed. Vaccination initiates a complex cascade of events, starting with the production of specific proteins, such as S1/S2 spike proteins, leading to robust immune activation in the axillary lymph nodes. The role of macrophages and antigen-presenting cells (APCs) in cytokine production, antigen presentation, and the stimulation of B and T cells highlights the sophistication of the adaptive immune response. The migration of immune cell-derived exosomes to the brain plays a dynamic role in CNS inflammation, neurodegenerative processes and long COVID. On the other hand, the prolonged presence of viral and vaccine-derived spike proteins may contribute to the complex pathophysiology of Long-COVID, shedding light on the delicate balance between beneficial immune responses and possible adverse neurological outcomes of vaccination. It is worth rigorous monitoring and further research to understand the mechanisms of neuroinflammation and the persistence of spike proteins and their long-term effects on the brain, emphasising the importance of a nuanced approach to vaccine safety and efficacy in the context of COVID-19 and beyond.Principio del formulario

Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a rare neurodevelopmental disease caused by mutations in the X-linked CDKL5 gene. CDD is characterized by a broad spectrum of clinical manifestations, including early-onset refractory epileptic seizures, intellectual disability, hypotonia, visual disturbances, and autism-like features. The Cdkl5 knockout (KO) mouse recapitulates several features of CDD, including autistic-like behavior, impaired learning and memory, and motor stereotypies. These behavioral alterations are accompanied by diminished neuronal maturation and survival, reduced dendritic branching and spine maturation, and marked microglia activation. There is currently no cure or effective treatment to ameliorate the symptoms of the disease. Aerobic exercise is known to exert multiple beneficial effects in the brain, not only by increasing neurogenesis, but also by improving motor and cognitive tasks. To date, no studies have analyzed the effect of physical exercise on the phenotype of a CDD mouse model. In view of the positive effects of voluntary running on the brain of mouse models of various human neurodevelopmental disorders, we sought to determine whether voluntary daily running, sustained over a month, could improve brain development and behavioral defects in Cdkl5 KO mice. Our study showed that long-term voluntary running improved hyperlocomotion and impulsivity behaviors, and memory performance of Cdkl5 KO mice. This is correlated with increased hippocampal neurogenesis, neuronal survival, spine maturation, and inhibition of microglia activation. These behavioral and structural improvements were associated with increased BDNF levels. Given the positive effects of BDNF on brain development and function, the present findings support the positive benefits of exercise as an adjuvant therapy for CDD.

Mild traumatic brain injury (mTBI) or concussion accounts for the bulk of all head injuries and represents a major health concern. Although an mTBI event may not manifest in neurobehavioral impairment, repeated injuries, known as repeated mTBI (rmTBI), can result in a cumulative effect that may progress to long-term cognitive and functional deficits. To date, there is no FDA-approved drug for TBI in general and rmTBI in particular. In previous studies, we have demonstrated the neuroprotective role of mitoquinone (MitoQ), a mitochondrial antioxidant, in an open head injury model and a model of repeated mild TBI (rmTBI) at a chronic time point (30 days). In this work, we set out to assess the neuroprotective potential of MitoQ at acute (3 days) and subacute time points (7 days) post-injury in a controlled cortical impact model of rmTBI. C57BL/6 male mice were injected intraperitoneally with MitoQ (5 mg/kg) one hour after the first mTBI, and three days after the first injury in both the 3-day and 7-day MitoQ + rmTBI subgroups, with an additional injection four days after the second injection in the 7-day group. Cognitive function was evaluated using the Morris water maze (MWM) while gross and fine motor functions were evaluated by the pole climbing, grip strength, and ladder rung tests. Dihydroethidium (DHE) staining was performed to evaluate oxidative stress while qRT-PCR was used to measure the gene expression of different antioxidant enzymes. Also, immunofluorescence staining was performed on brain tissue to assess the degree of microgliosis and astrocytosis. Our results showed that MitoQ conferred significant protection on days 3 and 7 post-injury against fine motor function impairment induced by rmTBI. Moreover, MitoQ enhanced cognitive function and reduced astrogliosis, microgliosis, and levels of oxidative stress on day 7 post-injury. However, antioxidant gene expression generally remained unaffected. In light of our results, MitoQ administration may be considered a preventive approach that helps to alleviate the neurological manifestations associated with rmTBI early before symptoms progress to long-term deficits.

The development of 3D cerebral brain organoids which accurately resemble aspects of the human brain permits a more accurate characterization of physiological processes and neurological diseases. Cerebral organoids can be grown from stem cell lines with various genetic backgrounds allowing multiple neurodegenerative diseases to be modeled. While dysfunction in neurotransmission of patients with neurodegenerative diseases is expected, the impact of chronic neurodegeneration on the response to viral infection of the CNS is poorly understood. For instance, several mosquito-borne viruses like Dengue virus and West Nile Virus cause post-viral parkinsonism. How CNS infection might impact a host with inherent CNS dysfunction such as Parkinson’s Disease in poorly understood. This preliminary, observational study aimed to understand dysfunction in intrinsic and innate expression of a patient with a neurodegenerative disease and a non-affected individual in relation to potential viral infection in the CNS. Cerebral organoids were generated from human induced pluripotent stem cells with a normal genetic background or with idiopathic Parkinson’s Disease. After differentiation and maturation, organoid size, gene expression and immunofluorescence were evaluated to assess neurotransmission and innate immunity. While there was no significant difference in size of the organoids with a normal or Parkinson’s genetic background, gene expression studies identified multiple differences in innate immunity and neurotransmission. Immunofluorescence also identified differences in protein expression related to neurotransmission and innate immunity. Of note, organoids derived from a Parkinson’s patient exhibited endogenous up-regulation of dopamine and muscarinic acetylcholine receptors, GABA, glycine, and glutamate targets, and the majority of cytokines. This expression pattern suggests a chronic state of neuroexcitation and neuroinflammation in this population of organoids.

As the global population ages, the prevalence of neurodegenerative diseases has become a major public health concern. The adoption of a less sedentary lifestyle has been shown to have a beneficial effect on cognitive decline, but the molecular mechanisms responsible are less clear. Here we provide a detailed analysis of the complex molecular, cellular, and systemic mechanisms underlying age-related cognitive decline and how lifestyle choices influence these processes. A review of the evidence from animal models, human studies, and postmortem analyses emphasizes the importance of integrating physical exercise with cognitive, multisensory, and motor stimulation as part of a multifaceted approach to mitigating cognitive decline. We highlight the potential of these non-pharmacological interventions to address key aging hallmarks—such as genomic instability, telomere attrition, and neuroinflammation—and underscore the need for comprehensive and personalized strategies to promote cognitive resilience and healthy aging.

Perinatal brain injury is a major public health problem burdened with high morbidity, mortality and severe neurological sequelae. Despite advances in neonatal life-saving technologies, neonatal encephalopathy lacks specific and effective treatment. Therefore, mechanisms of central nervous system changes associated with perinatal brain injury have been a hot topic of neonatology research. In recent years, researchers have shifted more focus from neurons themselves to perineuronal cells and intercellular interactions. As a member of the nervous system network, astrocytes are one of the dominant glial cells that regulate ion homeostasis, blood flow, and antioxidant function in the brain. Their changes in molecular mechanisms (e.g., alterations in RNA regulatory networks) during brain injury storms deserve further attention. Non-coding RNAs participate in and promote reactive pathophysiologic changes in astrocytes. The review summarizes and discusses the role of non-coding RNAs in astrocytes in recent years in studies of neonatal brain injury. It focuses on the most studied disease-related ncRNAs: miRNAs, lncRNAs and circRNAs, and hopes to provide possible directions for pathophysiological studies and therapeutic approaches of neonatal brain injury.

Background & Objective. Perinatal hypoxia acutely triggers the release of cytokines and chemokines from neurons, astrocytes and microglia. In response to hypoxia-ischemia resting/ramified microglia proliferate and undergo activation, with the production of proinflammatory molecules. The brain damage extension seems to be related with both the severity of hypoxia and the balance between pro and anti-inflammatory host response. Methods: In this preliminary study we compared in 10 neonates with hypoxic ischemic encephalopathy (HIE), during therapeutic hypothermia (TH), plasmatic cytokines and other inflammatory molecules levels: monocytic chemotactic-protein-1 (CCL2/MCP-1), CXCL8, glial fibrillary acidic protein (GFAP), Interferon gamma (IFN y), Interleukin 10 (IL-10), IL-18, IL-6, CCL3, ENOLASE2, Colony Stimulating Factor(GM-CSF), IL-1b, IL-12p70, IL-33, Tumor Necrosis Factor alpha(TNF), collected at four different time points during TH (24 hours, 25-48 hours, 49-72 hours) , and after the rewarming (7-10 days from birth). Five of enrolled babies had pathological brain MRI (“cases”) and 5 had a normal examination (“controls”). Cytokines were measured by Magnetic Luminex Assay (Luminex SV 013-17 (14), instrument Biorad Bio-Plex 100 s.n. LX 10005039304). MRI images were classified according to the Barkovich score. Results: Mean levels of all cytokines and molecules at time T1 were not significantly different in the two groups of patients. Comparing samples paired by day of collection, the greatest differences between cases and controls were found at times T2 and T3, during TH. After rewarming, some molecules showed an upward trend. At T4, levels tended to be close again (with the exception of IL-6, IL10 and IL18). Infants with worse MRI showed plasmatic GFAP levels higher than those with normal MRI, while their IL-18 was lower. Mean levels of CCL3MIP1alpha, GMCSF, IL1BETA overlapped throughout the observation period in both the groups of neonates. Conclusion. In children with worse brain MRI we found high levels of GFAP and of IL-10 at T4, considered respectively an early biomarker of brain damage and a predictor of adverse outcome, according to the literature, and a trend towards low IL-18 levels. We found the greatest, although not significant, difference between molecules levels in cases and controls at time points T2 and T3, during TH. With the rewarming some molecules showed an upward trend. We cannot exclude that the small sample size may prevent significance in the differences from being achieved.

.Vitamin A (retinol) and its derivatives (retinoids) assume critical roles in neural development, cellular differentiation, axon elongation, programmed cell apoptosis and various fundamental cellular processes. Retinoids function by binding to specific nuclear receptors, such as retinoic acid receptors (RARs) and retinoid X receptors (RXRs), activating specific signaling pathways in the cells. Disruption of the retinoic acid signaling pathway can result in neuroinflammation, ox-idative stress, mitochondrial dysfunction and neurodegenerative processes, and has been asso-ciated with a range of neurodegenerative diseases. The present study explores the potential therapeutic application of our innovative synthetic retinoid, Ellorarxine, also known as DC645 and NVG0645, for the treatment of neurodegenerative disorders in vitro. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) tetrazolium assay, lactate dehy-drogenase (LDH) assay, enzyme-linked immunosorbent assay (ELISA), senescence-associated (SA) β-galactosidase (β-gal) staining and immunofluorescence staining were performed. The re-sults showed that no cytotoxicity was detected at the experimental concentrations of Ellorarxine. Ellorarxine significantly reduced cell death, increased mitochondrial viability, reduced the num-ber of senescent cells, modulated cytokine release and regulated cellular autophagy. Furthermore, Ellorarxine also increased Cyp26 and selectively RARβ expression. These results make Ellorarxine a promising drug candidate that should be further investigated in the treatment of neurodegenerative diseases. .

Between 25 and 30% of the nearly one million military personnel who participated in the 1991 Persian Gulf War became ill with chronic symptoms ranging from gastrointestinal to nervous system dysfunction. This disorder is now referred to as Gulf War Illness (GWI) and the underlying pathophysiology has been linked to exposure-based neuroinflammation caused by organophosphorous (OP) compounds coupled with high circulating glucocorticoids. In a mouse model of GWI we developed, corticosterone was shown to act synergistically with an OP (diisopropylflurophosphate) to dramatically increase proinflammatory cytokine gene expression in the brain. Because not all Gulf War participants became sick, the question arises as to whether differential genetic constitution might underlie individual differences in susceptibility. To address this question of genetic liability, we tested the impact of OP and glucocorticoid exposure in a genetic reference population of 30 inbred mouse strains. We also studied both sexes. The results showed wide differences among strains and overall that females were less sensitive to the combined treatment than males. Furthermore, we identified one OP-glucocorticoid locus and nominated a candidate gene—Spon1—that may underlie the marked differences in response.

Hyperbaric oxygen (HBO) treatment has been proven to attenuate neuroinflammation in rats. This study aimed to determine the potential mechanism underlying the anti-inflammatory effects of HBO treatment on burn-induced neuroinflammation in rats. Thirty-six adult male Sprague–Dawley (SD) rats were randomly assigned to the following six groups (n = 6 per group): (1) sham burn with sham HBO treatment, (2) sham burn with HBO treatment, (3) burn with 1-week sham HBO treatment, (4) burn with 2-week sham HBO treatment, (5) burn with 1-week HBO treatment, and (6) burn with 2-week HBO treatment. SD rats that received third-degree burn injury were used as a full-thickness burn injury model. Subsequently, we analyzed the expression of proteins involved in the galectin-3 (Gal-3)-dependent Toll-like receptor-4 (TLR-4) pathway through enzyme-linked immunosorbent assay (ELISA), immunohistochemistry (IHC) analysis, and Western blotting, and a behavior test was also conducted. The behavior test revealed that HBO treatment significantly suppressed mechanical hypersensitivity in the burn with HBO treatment group compared with the burn with sham HBO treatment group (p < 0.05). ELISA results showed that tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1β) levels in the dorsal horn of the spinal cord and the skin were significantly decreased in the burn with HBO treatment group compared with the burn with sham HBO treatment group (p < 0.05). Western blotting results demonstrated that HBO treatment significantly reduced the expression of Gal-3 and TLR-4 in the dorsal horn of the spinal cord in the burn with HBO treatment group compared with the burn with sham HBO treatment group (p < 0.05). IHC analysis results showed that the expression of Gal-3, TLR-4, CD68, and CD45 in the dorsal horn of the spinal cord was significantly lower in the burn with HBO treatment group than in the burn with sham HBO treatment group (p < 0.05), and the expression of CD68 and macrophage migration inhibitory factor (MIF) in the right hind paw skin was significantly lower. The expression of vimentin and fibroblast growth factor (FGF) in the right hind paw skin was significantly higher after HBO treatment (p < 0.05). This study proved that early HBO treatment relieves neuropathic pain, inhibits the Gal-3-dependent TLR-4 pathway, and suppresses microglia/macrophage activation in a rat model.

Withania somnifera (WS), also known as ashwagandha, is a popular botanical supplement used to treat various conditions including memory loss, anxiety and depression. Previous studies from our group showed an aqueous extract of WS root (WSAq) enhances cognition and alleviates markers for depression in Drosophila. Here, we sought to confirm these effects in the 5xFAD mouse model of β-amyloid (Aβ) accumulation. Six- to seven-month-old male and female 5xFAD mice were treated with WSAq in their drinking water at 0 mg/mL, 0.5 mg/mL or 2.5 mg/mL for four weeks. In the fourth week of treatment, spatial memory, anxiety and depressive-like symptoms were evaluated. At the conclusion of behavioral testing, brain tissue was harvested, immunohistochemistry was performed, and the cortical expression of antioxidant response genes was evaluated. Both concentrations of WSAq improved spatial memory and reduced depressive and anxiety-related behavior. These improvements were accompanied by a reduction in Aβ plaque burden in the hippocampus and cortex and an attenuation of neuroinflammatory markers. Antioxidant response genes were upregulated in the cortex of WSAq treated mice. Oral WSAq treatment could be beneficial as a therapeutic option in AD for improving disease pathology and behavioral symptoms. Future studies focused on dose optimization of WSAq administration and further assessment of the mechanisms by which WSAq elicits its beneficial effects will help inform the clinical potential of this promising botanical therapy.

E2F4 was initially described as a transcription factor with a key function in the regulation of cell quiescence. Nevertheless, a number of recent studies have established that E2F4 can also play a relevant role in cell and tissue homeostasis as well as tissue regeneration. For these non-canonical functions, E2F4 can also act in the cytoplasm, where it is able to interact with many homeostatic and synaptic regulators. Since E2F4 is expressed in the nervous system, it may fulfill a crucial role in brain function and homeostasis, being a promising multifactorial target for neurodegenerative diseases and brain aging. The regulation of E2F4 is complex as it can be chemically modified through acetylation, from which we present evidence in the brain, as well as methylation, and phosphorylation. The phosphorylation of E2F4 within a conserved threonine motif induces cell cycle re-entry in neurons, while a dominant negative form of E2F4 (E2F4DN), in which the conserved threonines have been substituted by alanines, has been shown to act as a multifactorial therapeutic agent for Alzheimer’s disease (AD). We have generated transgenic mice neuronally expressing E2F4DN. We have recently shown using this mouse strain that expression of E2F4DN in 5xFAD mice, a known murine model of AD, improved cognitive function, reduced neuronal tetraploidization, and induced a transcriptional program consistent with modulation of amyloid-beta (Abeta) peptide proteostasis and brain homeostasis recovery. 5xFAD/E2F4DN mice also showed reduced microgliosis and astrogliosis in both cerebral cortex and hippocampus at 3-6 months of age. Here we have analyzed the immune response in 1 year-old 5xFAD/E2F4DN mice, concluding that reduced microgliosis and astrogliosis is maintained at this late stage. In addition, the expression of E2F4DN also reduced age-associated microgliosis in wild-type mice, thus stressing its role as a brain homeostatic agent. We conclude that E2F4DN transgenic mice represent a promising tool for the evaluation of E2F4 as a therapeutic target in neuropathology and brain aging.

SARS-CoV-2 Omicron variant spike RBD epitopes in complex with spike (S) -protein D614G mutations now predominate globally and increase infectivity by assembling more functional S proteins into the virion. On average, homeopathic medicine contains less than one molecule per dose on average. Single variable SphericalHarmonicY, LaguerreL, WhittakerM, SphericalBesselJ, LegendreP, LegendreQ, LaguerreL, ChebyshevT, and Hypergeometric1F1 Functions pFqarise in connection with the power series solution of the Schrodinger equation or in the summation of perturbation expansions in quantum mechanics. A quantum interpretation of the homeopathic method is presented here through a novel algebraic topology approach to supersymmetry and symmetry breaking in quantum fields and quantum gravity theory with the aim of developing a wide range of physical-based drug design applications in a Small Molecule Quantized Water Memory Network suggesting that the Hidden Black Hole Paradox of Information Loss might be solved under suitable conditions.

Preterm infants often experience frequent intermittent hypoxia (IH) episodes which is associated with neuroinflammation. We tested the hypotheses that early caffeine and/or non-steroidal in-flammatory drugs (NSAIDs) confer superior therapeutic benefits for protection against IH-induced neuroinflammation than late treatment. Newborn rats were exposed to IH or hy-peroxia (50% O2) from birth (P0) to P14. For early treatment, the pups were administered: 1) dai-ly caffeine citrate (Cafcit, 20 mg/kg IP loading on P0, followed by 5 mg/kg from P1-P14); 2) ke-torolac topical ocular solution in both eyes from P0 to P14; 3) ibuprofen (Neoprofen, 10 mg/kg loading dose on P0 followed by 5 mg/kg/day on P1 and P2); 4) caffeine+ketorolac co-treatment; 5) caffeine+ibuprofen co-treatment; or 6) equivalent volume saline. On P14, animals were placed in room air (RA) with no further treatment. For late treatment, pups received similar treatments from P15-P21 (caffeine and/or ketorolac), or P15-P17 (ibuprofen). RA control were similarly treated. At P21, whole brains were assessed for histopathology, apoptosis, mye-lination, and biomarkers of inflammation. IH caused significant inflammation, reduced mye-lination, and apoptosis in preterm rat brains, an effect that was improved predominantly with combined caffeine/NSAID early treatment. Early caffeine/NSAID co-treatment confers syner-gistic neuroprotection against IH-induced damage.

Dysfunction and selective loss of retinal ganglion cells (RGCs) is a known cause of vision loss in glaucoma and other neuropathies where ocular hypertension (OHT) is the major risk factor. We investigated the impact of transient non-ischemic OHT spikes (spOHT) on RGC function and viability in vivo to identify cellular pathways linking low-grade repetitive mechanical stress to RGC pathology. We found that repetitive spOHT had an unexpectedly high impact on intraocular homeostasis and RGC viability, while exposure to steady OHT (stOHT) of similar intensity and duration failed to induce pathology. The repetitive spOHT induced a rapid activation of the inflammasome, marked by the upregulation of NLRP1, NLRP3, AIM2, caspases -1, -3/7, -8, gasdermin D (GsdmD) and the release of interleukin-1β (IL-1β) and other cytokines into the vitreous. Similar effects were also detected after 5 weeks of exposure to chronic OHT in an induced glaucoma model. The onset of these immune responses in both spOHT and glaucoma models preceded a 50% deficit in pattern electroretinograms (PERG) amplitude, and significant loss of RGCs at 7 days post-injury. Inactivation of inflammasome complexes in NLRP1-/- , Casp1-/- and GsdmD-/- knockout animals, significantly suppressed the spOHT induced inflammatory response and protected RGCs. Our results demonstrate that mechanical stress produced by acute repetitive spOHT or chronic OHT is mechanistically linked to inflammasome activation, which leads to RGC dysfunction and death.

Introduction: A central role for neuroinflammation in epileptogenesis has recently been suggested by several investigations. This systematic review explores the role of inflammatory mediators in epileptogenesis, its association with seizure severity, and its correlation with drug-resistant epilepsy (DRE). Material and Methods: The study analysed articles published in JCR journals from 2019 to 2024, including retrospective, prospective, case-control, or cross-sectional studies. It combined MESH and free terms for "Epileptogenesis" and "Neuroinflammation" and included searches for biomarkers previously reported in narrative reviews. Results: The study analysed 243 articles related to epileptogenesis and neuroinflammation, with 356 from selective searches by biomarker type. After eliminating duplicates, 324 articles were evaluated, with 272 excluded and 52 evaluated by authors. 21 articles were included in the qualitative evaluation, including 18 case-control studies, 2 case series, and 1 prospective study. This systematic review provides acceptable support for five biomarkers: TNF-a and some of its soluble receptors (sTNFr2), HMGB1 and TLR-4, CCL2 and IL-33. Discussions: Certain receptors, cytokines, and chemokines are examples of neuroinflammation-related biomarkers that may be crucial for the early diagnosis of refractory epilepsy or may be connected to the control levels of epileptic patients. Their value will be better defined by future studies.

Many of the potential immune therapeutic targets are similarly affected in adult-onset neurodegenerative diseases such as Alzheimer’s (AD) disease, Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD), but also in a seemingly distinct Niemann-Pick type C disease with primarily juvenile-onset. This strongly argues for an overlap in pathogenic mechanisms. The commonly researched immune targets include various immune cell subsets such as microglia, peripheral macrophages, or regulatory T cells (Tregs), the complement system, and other soluble factors. In this review, we will compare these neurodegenerative diseases from a clinical point of view and point out the common pathways and mechanisms of protein aggregation, neurodegeneration and/or neuroinflammation that could potentially lead to shared treatment strategies. We also describe the common therapeutic approaches in treating the immune dysfunctions in these disorders, moving from immunization to microbiome regulation and stem cell treatment.

Glaucoma is a group of ocular diseases that causes irreversible blindness worldwide and is characterized by a multifactorial degeneration of optic nerve and retinal ganglion cells (RGCs), leading to vision loss. One of the significant risk factors in glaucoma pathogenesis is glia-driven neuroinflammation. Impairment of mitochondrial dynamics and bioenergetics is associated with glaucomatous neurodegeneration and is linked to neuroinflammation. Apolipoprotein A-I binding protein (AIBP) binds to toll-like receptor 4 (TLR4) and facilitates the removal of excess cholesterol from the plasma membrane in activated cells, suggesting the regulation of cholesterol-driven inflammation by inhibiting the TLR4-associated lipid rafts. AIBP is localized in mitochondria and regulates mitophagy by ubiquitination of mitofusin 1 and 2. We observed elevated intraocular pressure-induced AIBP deficiency in glaucomatous neurodegeneration. We also observed that AIBP deficiency activated TLR4 in Müller glia, triggered mitochondrial dysfunction in both RGCs and Müller glia and impaired visual function. In mouse models of glaucoma, AIBP treatment protects RGCs by reducing inflammatory responses. Here, our review focuses on investigating the role of AIBP in the retina and examining the underlying mechanism by which AIBP contributes to the pathogenesis of glaucoma, aiming to provide new insight into the therapeutic potential for the treatment of glaucoma.

In healthy adult brain, glial cell line-derived neurotrophic factor (GDNF) is exclusively expressed by neurons and in some instances, it has furthermore been shown to derive from a single neuronal subpopulation. Secreted GDNF acts in a paracrine fashion by forming a complex with GDNF family receptor α1 (GFRα1) which is mainly expressed by neurons and can act in cis as a membrane-bound or in trans as a soluble factor. The GDNF/GFRα1 complex signals through interaction with RET (“rearranged during transfection”) or with a lower affinity with neural cell adhesion molecule (NCAM). GDNF can also signal independently from GFRα1 via interaction with syndecan-3. RET being expressed by neurons involved in several pathways: nigro-striatal dopaminergic neurons, motor neurons, enteric neurons, sensory neurons, etc. could be the main determinant of the specificity of GDNF pro-survival effect. In injured brain, de novo expression of GDNF occurs in glial cells. Neuroinflammation has been reported to induce GDNF expression in activated astrocytes and microglia, infiltrating macrophages, nestin-positive neural stem cells and neuron/glia (NG2) progenitors. This disease-related GDNF overexpression can be either beneficial or detrimental depending on the localization in the brain and the level and duration of glial cells activation. Some reports also describe upregulation of RET and GFRα1 in glial cells, suggesting that GDNF could modulate neuroinflammation.

Huntington’s disease (HD) is a rare but progressive and devastating neurodegenerative disease characterized by involuntary movements, cognitive decline, executive dysfunction, and neuropsychiatric conditions such as anxiety and depression. It follows an autosomal dominant inheritance pattern. Thus, a child who has a parent with the mutated huntingtin (mHTT) gene has a 50% chance of developing the disease. Since HTT protein is involved in many critical cellular processes including neurogenesis, brain development, energy metabolism, transcriptional regulation, synaptic activity, vesicle trafficking, cell signaling, and autophagy, its aberrant aggregates lead to disruption of numerous cellular pathways and neurodegeneration. Essential heavy metals are vital at low concentrations, however, at higher concentrations, can exacerbate HD by disrupting the glial-neuronal communication, and/or causing dysbiosis (disturbance in the gut microbiota, GM), both of which can lead to neuroinflammation and further neurodegeneration. Here, we discuss in detail the interactions of iron, manganese and copper with glial-neuron communication and GM and indicate how this knowledge may pave the way for development of a new generation of disease-modifying therapies in HD.

Owing to the complexity of neurodegenerative diseases, multiple cellular types need to be targeted simultaneously in order for a given therapy to demonstrate any major effectiveness. Ultrasound-sensitive coated microbubbles (in a targeted nanoemulsion) are available. Versatile small-molecule drug(s) targeting multiple pathways of Alzheimer's disease pathogenesis are known. By incorporating such drug(s) into the targeted LCM/ND lipid nanoemulsion type, one obtains a multitasking combination therapeutic for translational medicine. This multitasking therapeutic targets cell-surface scavenger receptors (mainly SR-BI), making possible for various Alzheimer's-related cell types to be simultaneously searched out for localized drug treatment in vivo. Besides targeting cell-surface SR-BI, the proposed LCM/ND-nanoemulsion combination therapeutic(s) include a characteristic lipid-coated microbubble [LCM] subpopulation (i.e., a stable LCM suspension); such LCM substantially reduce the acoustic power levels needed for accomplishing temporary noninvasive (transcranial) ultrasound treatment, or sonoporation, if additionally desired for the Alzheimer's patient.

Neuroinflammatory responses are implicated in the pathogenesis of neurodegenerative diseases. In neurodegenerative diseases, neuroinflammatory reactions to neuronal injury are modulated by microglial cells, which are vital innate immune cells in the central nervous system. Activated microglial cells release proinflammatory cytokines, mediators, and neurotoxic factors that induce fatal neuronal injury. The present study investigated the anti-neuroinflammatory effects of cudratricusxanthone L (1), which was isolated from Cudrania tricuspidata. This compound reduced the levels of lipopolysaccharide-stimulated inflammatory mediators and cytokines, including nitric oxide, prostaglandin E2, interleukin (IL)-1β, tumor necrosis factor-α, IL-6, and IL-12. These effects suggested that cudratricusxanthone L (1) suppressed the nuclear factor-kappa B (NF-κB) signaling pathway. Specifically, cudratricusxanthone L (1) also attenuated the phosphorylation of Jun kinase and inhibited p38 mitogen-activated protein kinase (MAPK) signaling in BV2 and rat primary microglial cells. These results indicated that cudratricusxanthone L (1) effectively repressed neuroinflammatory processes in BV2 and rat primary microglial cells by inhibiting NF-κB and the MAPK signaling pathway.

Abstract: Background: chronotype is generally defined as the variability of the phase angle of en-trainment, while the latter reflects the relationship between the timing of a certain rhythm (e.g., sleep-wake cycle) and the timing of an external temporal cue. Individuals can be placed on a spectrum from "morning types" (M types), to "evening types" (E types). E-chronotype has been proposed as a transdiagnostic risk factor for psychiatric conditions and associated with psycho-pathological dimensions. Eveningness seems correlated with both suicidal ideation (SI) and suicidal behavioral (SB), through several possible mediating factors. Immunological alterations also have been linked to later chronotypes and SI/SB. Objective: This narrative review aims to summarize the evidence supporting the possible association between chronotypes and suicide, with the eventual mediating role of neuroinflammation and several psychopathological dimensions. Material and methods: A search of literature (2003-2023) was conducted, using various databases: PUBMED, EMBASE, Scopus, UpToDate, PsycINFO, Cochrane Library. English-language articles were col-lected and screened for eligibility. Results: Despite the apparent absence of a direct correlation between E-chronotype and suicidality, E-chronotype promotes a chain of effects that could be in-volved in an increased risk of SB, in which with neuroinflammation possibly play an intriguing role and some psychopathological dimensions may stand out.

Cellular therapies have started an important new therapeutic direction for Autistic Spectrum Disease (ASD), and the ample diversity of ASD pathophysiology and the different types of cell therapies need an equally ample effort for studying the applicable ASD causes and the specific benefits of cell therapies via clinical studies.CORDUS Clinical Study is a crossover study in which autologous cord blood was administered intravenously to 56 patients between January 2019 and July 2023, and has compared its efficacy versus an individualized combination of supplements; both treatments were administered in a different sequence to all participants. Treatment efficacy was evaluated pre- and post- treatments by an independent psychotherapist with ATEC, Q-CHAT and a 16-item comparative table score, after interviews with the children’s parents and therapists.Cord blood was beneficial in the group of 3–7-year-old children (n=28; 3 out of 4 children – 78.57% - improved scores), but was much less effective in kids older than 8 years or with body weight of more than 35 kg (n=28; 1 out of 10 children improved scores). Individualized supplements were more efficacious than cord blood in 5 cases out of 28, while in 23 kids cord blood brought more improvement than supplements; 6 kids registered minor or no improvement. Statistically significant improvements were seen after cord blood infusion on areas such as verbalization and social interaction, but not on irritability or aggressive behavior; also ample individual differences were noted. No serious adverse reactions were noted during and after cord blood or supplement administration.

Multiple sclerosis (MS) is a persistent inflammatory disease affecting the central nervous system. Bruton's tyrosine kinase (BTK) is an enzyme crucial in the communication process of B cells, which have a significant impact on the development of MS. Recently, BTK inhibitors have emerged as a promising treatment strategy for MS due to their ability to modulate the immune system. In this study, an extensive literature search was performed utilizing multiple databases, such as PubMed, Embase, and Scopus to examine the potential use of BTK inhibitors in managing cognitive disorders experienced by individuals with MS. We found that BTK inhibitors targeting microglia offer potential advantages for managing neurodegeneration associated with cognitive impairments in MS patients by slowing down degeneration processes effectively. Their ability to impact microglial function and penetrate the CNS positions them as promising candidates for improving cognitive function. This study suggests that BTK inhibitors provide new possibilities for managing inflammatory and neurodegenerative phases of MS through their effects on microglia activation pathways. Further research and clinical trials are necessary to fully explore their efficacy in treating MS while addressing barriers related to cognitive impairment.

Arboviruses of medical and veterinary significance have been identified on all 7 continents with every human and animal population at risk for exposure. Like arboviruses, chronic neurodegenerative diseases like Alzheimer’s and Parkinson’s disease are found wherever there are humans. Viral parkinsonism has been documented for a variety of human pathogens though there are few studies that evaluate the effects of viral infection on degenerative neurological diseases. Significant differences in baseline gene and protein expression have been determined between Human Induced Pluripotent Stem Cell lines derived from a non-Parkinson’s disease individual and from an individual with reported Parkinson’s disease. While the organoids generated from each cell line were physically indistinguishable, significant differences were observed in gene and protein expression for neurotransmission and immunity. It was hypothesized that these inherent differences would impact cerebral organoid responses to viral infection. In this preliminary observational study, cerebral organoids from a non-Parkinson’s and Parkinson’s patient were infected with Chikungunya virus and observed for 2 weeks. Parkinson’s organoids lost mass and exhibited a dysfunctional antiviral response. Neurotransmission data from both non-Parkinson’s and Parkinson’s organoids had dysregulation of IL-1, IL-10, IL-6. These cytokines are associated with mood and could be contributing to persistent depression seen in patients following CHIKV infection. Both organoid types had increased expression of CCR5 and CXCL10 which are linked to demyelination, highlighting a potential mechanism for virus-associated parkinsonism. The dysfunctional antiviral response of Parkinson’s organoids highlights the need for more research in neurotropic infections in a neurologically compromised host.

Neurodegenerative disorders such as Parkinson’s disease (PD), Alzheimer’s disease (AD), Amyloidal lateral sclerosis (ALS), and Huntington disease (HD) are the most concerned disorders due to the lack of effective therapeutics and dramatic rise in affected cases. Although these disorders have diverse clinical manifestations, yet they all share a common cellular stress response. These cellular stress responses including neuroinflammation, oxidative stress, proteotoxicity, and ER-stress, which combats with stress conditions, but the overwhelming cellular stress response induces cell damage. Small molecules such as flavonoids could reduce cellular stress and have gained much attention in recent years. Evidence has shown the potential use of flavonoids in several ways such as antioxidants, anti-inflammatory, and anti-apoptotic, yet their mechanism is still elusive. This review provides an insight into the mechanistic ways of flavonoids against cellular stress response that prevent the pathogenesis of neurodegenerative disorders.

White adipose tissue (WAT) and gut are involved as inducers of neuroinflammation when they detect injury and trigger inflammation. The autonomous nervous system innervates both tissues, although the roles of the sympathetic, parasympathetic and enteric nervous systems have not been fully elucidated. Here, we revisited the participation of both types of inflamed peripheral tissue in neuroinflammation. We first analyzed how inflamed peripheral WAT plays a key role in neuroinflammation once metainflammation is installed. Second, we described the impact of insulin resistance (IR) on hypothalamic dysfunction, T2DM and neurodegenerative diseases. Finally, we analyzed the gut-brain axis, examining cell interactions, soluble factors, the sensing of microbes and the role of the intestinal microbiota and mucosal barriers in neuroinflammation. Since intestinal mucosa and secondary lymphoid organs are densely innervated by the sympathetic, parasympathetic, and enteric nervous systems, we analyzed bidirectional crosstalk between different tissues, neurons, and immune systems in healthy and pathological circumstances to restore normal tissues functions, and consequently homeostasis.

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized mainly by the gradual decay in neuronal function as a consequence of diverse degenerating events primarily including mitochondria dysfunction and cascades of neuro-immune reactions. Besides the acquired harmful reactive oxygen species (ROS), neurotoxins, and amyloid-beta (Aβ) and TAU pathologies in neurons, accumulating evidence with time underlined the roles of cytokines and growth factors in the AD pathogenesis. It may help us in evaluating the propensities and specific mechanism(s) of cytokines and factors impacting neuron upon apoptotic decline. Proinflammatory cytokines often induce inflammation in AD and AD-like pathogenesis in response to the apoptotic scenarios where some growth factors are involved in cytokinetic reactions to activate microglia and causing inflammation in AD. In this report, we comprehensively reviewed role of cytokines and chemokines in immune response to AD and neuropsychiatry. We provided insights into the neuroinflammation and the role of diverse factors including the pro-/anti-inflammatory cytokines, APP, TAU phosphorylation, glycation end products, complement system, and the role of glial cells. Also, we discussed the pathogenic and protective role of macrophage migration inhibitory factors, choroid plexus-, neurotrophic- and hematopoietic -related growth factors in AD. We further shed light on the availability and accessibility of the cytokines across the blood-brain barrier in AD pathophysiology. Taken together, the emerging role of these factors in AD pathology emphasized the importance of building novel strategies for an effective therapeutic/neuropsychiatric management of AD in clinics.

Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disease, characterized by progressive degeneration of upper and lower motor neurons in the cortex and spinal cord. Although the pathogenesis of ALS remains unclear, evidence on the role of the clonotypic immune system is growing. Adaptive immunity cells often appear changed in number or activation profile peripherally and centrally. However, their role in ALS appears conflicting. Data, from human and animal model studies, currently reported in literature show that each subset of lymphocytes and their mediators may mediate a protective or toxic mechanism in ALS, affecting both its progression and risk of death. In the present review article and attempt is made to shed light on the actual role of the cellular clonotypic immunity in ALS by integrating recent clinical studies and experimental observations.

Diabetes mellitus (DM) is the most common metabolic disease in humans, and its prevalence is increasing worldwide in parallel with the obesity pandemic. A lack of insulin or insulin resistance, and consequently hyperglycemia, leads to many systemic disorders, among which diabetic encephalopathy (DE) is a long-term complication of the central nervous system (CNS), characterized by cognitive impairment and motor dysfunctions. The role of oxidative stress and neuroinflammation in the pathomechanism of DE has been proven. Fractalkine (CX3CL1) has unique properties as an adhesion molecule and chemoattractant, and by acting on its only receptor, CX3CR1, it regulates the activity of microglia in physiological states and neuroinflammation. Depending on the clinical context, CX3CL1-CX3CR1 signaling may have neuroprotective effects by inhibiting the inflammatory process in microglia or, conversely, maintaining/intensifying inflammation and neurotoxicity. This review discusses the evidence supporting that the CX3CL1-CX3CR1 pair is neuroprotective and other evidence that it is neurotoxic. Interrupting the vicious cycle within neuron-microglia interactions may be a therapeutic goal in DE by limiting the inflammatory response.

The term neuroinflammation defines the reactions of astrocytes and microglia to alterations in homeostasis in the diseased central nervous system (CNS), the exacerbation of which contributes to the neurodegenerative effects of Alzheimer's disease (AD). Local environmental conditions, such as the presence of proinflammatory molecules, mechanical properties of the extracellular matrix (ECM) and local cell-cell interactions, are determinants of glial cell phenotypes. In AD, the load of the cytotoxic/proinflammatory amyloid β peptide (Aβ) is a microenvironmental component increasingly growing in the CNS, imposing time-evolving challenges on resident cells. This study aimed at investigating the temporal and spatial variations of the effects produced by this process on astrocytes and microglia, either directly or by interfering in their interactions. Ex vivo confocal analyses of hippocampal sections from the mouse model TgCRND8 at different ages have shown that overproduction of Aβ peptide induced early and time persistent disassembly of functional astroglia syncytium and promoted a senile phenotype of reactive microglia, hindering Aβ clearance. In the late stages of disease, these patterns were altered in the presence of Aβ-plaques, surrounded by typically reactive astrocytes and microglia. Morphofunctional characterization of peri-plaque gliosis revealed a direct contribution of astrocytes in plaque buildup that might result in shielding Aβ-peptide cytotoxicity and, as a side effect, in exacerbating neuroinflammation.

Major depressive disorder (MDD) and substance use disorder (SUD) are of immense medical and social concerns. Although significant progress on neuronal involvement in mood and reward circuitries has been achieved, only relatively recently the role of glia in these disorders have attracted attention. Detail understanding of the glial function in these devastating diseases could offer novel interventions. Here, following a brief review of circuitries involved in mood regulation and reward perception, specific contribution of the neurotrophic factors, neuroinflammation and gut microbiota to these diseases are highlighted. In this context, the role of specific glial cells (e.g., microglia, astroglia, oligodendrocytes and synantocytes) on phenotypic manifestation of MDD or SUD are emphasized. In addition, potential use of this knowledge in developing novel therapeutics is touched upon.

Autism spectrum disorder (ASD) is a neurodevelopmental disease characterized by persistent deficits in social interaction and communication, repetitive movements, abnormal focusing on objects, or activity that can significantly affect the quality of life of the afflicted. Brain neuronal and glial cells have been implicated. It has a genetic component but can also be triggered by environmental factors or drugs. For example, prenatal exposure to valproic acid (VPA) or acetaminophen (APAP) or ingestion of propionic acid (PPA) can increase the risk of ASD. Recently, epigenetic influences on ASD have been brought to the forefront of investigations on the etiology, prevention, and treatment of this disorder. Epigenetics refers to DNA modifications that alter gene expression without making any changes to the DNA sequence. Although an increasing number of pharmaceuticals and environmental chemicals are being implicated in the etiology of ASD, here we specifically focus on the molecular influence of the above-mentioned drugs on epigenetic alterations in neuronal and glial cells and their potential connection to ASD. It is concluded that a better understanding of these phenomena can lead to more effective interventions in ASD.

Intracortical microelectrode arrays (MEAs) can be used in a range of applications, from basic neuroscience research to providing an intimate interface with the brain as part of a Brain-Computer Interface (BCI) system aimed to restore function for people living with neurological disorders or injuries. Unfortunately, MEAs tend to fail prematurely, leading to a loss in functionality for many applications. An important contributing factor in MEA failure is oxidative stress resulting from chronically inflammatory-activated microglia and macrophages releasing reactive oxygen species (ROS) around the implant site. Antioxidants offer a means for mitigating oxidative stress and improving tissue health and MEA performance. Here, we investigate using the clinically available antioxidant dimethyl fumarate (DMF) to reduce the neuroinflammatory response and improve MEA performance in a rat MEA model. Daily treatment of DMF for 16 weeks resulted in a significant improvement in the recording capabilities of MEA devices during the sub-chronic (Weeks 5-11) phase (42% active electrode yield vs. 35% for control). However, these sub-chronic improvements were lost in the chronic implantation phase, as a more exacerbated neuroinflammatory response occurs in DMF-treated animals by 16 weeks post-implantation. Yet, neuroinflammation was indiscriminate between treatment and control groups during the sub-chronic phase. Although worse for chronic use, a temporary improvement (&lt;12 weeks) in MEA performance is meaningful. Providing short-term improvement to MEA devices using DMF can allow for improved use for limited-duration studies. Further efforts should be taken to explore the mechanism behind a worsened neuroinflammatory response at the 16-week time point for DMF-treated animals to assess its usefulness to specific applications.

Mild TBI (mTBI) accounts for most TBI cases, the leading cause of morbidity and mortality worldwide. Despite their high incidence, mTBI pathophysiology remains largely unknown. Recent studies have shown that the inflammatory response is activated early after mTBI and can persist for several weeks or months. However, limited evidence on the utility of inflammatory biomarkers as predictors of clinical outcomes in mTBI was previously provided. Thus, this study aims to provide an overview of the current knowledge on the role of inflammation in the pathogenesis of mTBI and the potential of some inflammatory biomolecules as biomarkers of mTBI. Thus, it was shown that the increase of IL-6, TNF-α, and IL-1β plasma levels could be implicated in the development of the early post-concussion symptoms. On the other hand, the persistence of the increased plasmatic concentrations of IL-10 and IL-8 for as long as six months following the brain injury event could suggest chronic inflammation leading to neuroinflammation and late or persistent symptoms. In this context, our findings showed that the inflammatory biomarkers could be relevant in diagnosing or predicting recovery or long-term outcomes of mTBI.

Due to the complexity of Alzheimer's disease, multiple cellular types need to be targeted simultaneously in order for a given therapy to demonstrate any major effectiveness. Ultrasound-sensitive coated microbubbles (in a targeted lipid nanoemulsion) are available. Versatile small molecule drug(s) targeting multiple pathways of Alzheimer's disease pathogenesis are known. By incorporating such drug(s) into the targeted LCM/ND lipid nanoemulsion type, one obtains a multitasking combination therapeutic for translational medicine. This multitasking therapeutic targets cell-surface scavenger receptors (mainly SR-BI), making possible for various Alzheimer's-related cell types to be simultaneously searched out for localized drug treatment in vivo. Besides targeting cell-surface SR-BI, the proposed LCM/ND-nanoemulsion combination therapeutic(s) include a characteristic lipid-coated microbubble [LCM] subpopulation (i.e., a stable LCM suspension); such film-stabilized microbubbles are well known to substantially reduce the acoustic power levels needed for accomplishing temporary noninvasive (transcranial) ultrasound treatment, or sonoporation, if additionally desired for the Alzheimer's patient.

Autism Spectrum Disorder (ASD), a neurodevelopmental disorder, is increasingly diagnosed and significantly affects communication, behavior, and social interaction. The current diagnostic framework, guided by the DSM-5, has limitations that may lead to clinical gaps due to overlapping symptoms of ASD and other disorders. This study proposes a comprehensive approach to enhance ASD diagnosis through clinical stratification based on comorbidities. We applied precision medicine techniques to identify and categorize ASD into ten clinical profiles. Our findings contribute to a more profound understanding of ASD, including its varied clinical manifestations and comorbidities, and facilitate the development of personalized therapeutic strategies.

Inflammation involves the activation of innate immune cells and is believed to play an important role in the development and progression of both infectious and non-infectious diseases such as neurodegeneration, rheumatoid arthritis or cancer. Inflammation in the brain is marked by the upregulation of the translocator protein (TSPO) in microglia. Moreover, high TSPO levels are found, for example in macrophages during rheumatoid arthritis and in malignant tumor cells compared to its relatively low physiological expression. The same applies for cycloxygenase-2 (COX-2), which is constitutively expressed in the kidney, brain, thymus and gastrointestinal tract, but induced in microglia, macrophages and synoviocytes during inflammation. This puts TSPO and COX-2 in the spotlight as important targets for the diagnosis of inflammation. Imaging modalities, such as positron emission tomography and single-photon emission tomography, can be used to localize inflammatory processes and to track their progression over time. They could also enable to monitor the efficacy of therapy and predict its outcome. This review focuses on the current development of PET and SPECT tracers not only for the detection of neuroinflammation, but also for emerging diagnostic measures in infectious and other non-infectious diseases like rheumatic arthritis, cancer, cardiac inflammation and in lung diseases.

Autistic spectrum disease (ASD) is an increasingly common diagnosis nowadays with a prevalence of 1-2% in most countries. Its complex causality – a combination of genetic, immune, metabolic and environmental factors - is translated into pleiomorphic developmental disorders of various severity, which have in common two main aspects: repetitive, restrictive behaviors, and difficulties in social interaction varying from awkward habits and verbalization to complete lack of interest from the ASD child for the outside world. The wide variety of ASD causes also makes it very difficult to find a common denominator – a disease biomarker and medication – and currently there is no commonly used diagnostic and therapeutic strategy besides clinical evaluation and psychotherapy.It is known that inflammation is present in a majority of ASD children, and blood inflammatory markers, together with metabolic, electrophysiological markers and imagistics are useful for ASD diagnostic validation and treatment; however, they tend to leave out a sizeable proportion of ASD kids who do not have such modifications. Genetic testing – whole exome sequencing or targeted profiling on about 500 ASD-linked genes- may also provide good insight into pathophysiology, however many times its results are more restrictive rather than offering additional therapeutic options.Here we describe a new biomarker for ASD - the neuron-specific enolase (NSE) - which was elevated above the normal clinical range (less than 16.3 ng/mL) in the vast majority of ASD kids tested in our study (40 of 41, or 97.5%). This finding opens up a new direction for diagnostic confirmation, dynamic evaluation and therapeutic intervention for ASD kids.

Microglial cells, the resident macrophages of the CNS, exist in a process-bearing, ramified/surveying phenotype under resting conditions. Upon activation by cell damaging factors they get transformed to an amoeboid phenotype releasing various cell products including pro-inflammatory cytokines, chemokines, proteases, reactive oxygen/nitrogen species and the excytotoxic ATP and glutamate. In addition, they engulf pathogenic bacteria or cell debris and phagocytose them. However, already resting/surveying microglia has a number of important physiological functions in the CNS; they e.g. shield small disruptions of the blood-brain barrier by their processes, dynamically interact with synaptic structures and clear surplus synapses during development. In neurodegenerative illnesses they aggravate the original disease by a microglia-based compulsory neuroinflammatory reaction. Therefore, the blockade of this reaction improves the outcome of Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, amyotrophic lateral sclerosis, etc. The function of microglia is regulated by a whole array of purinergic receptors classified as P2Y12, P2Y6, P2Y4, P2X4, P2X7, A2A, A3, and being targets for endogenous ATP, ADP, or adenosine. ATP is sequentially degraded by the ecto-nucleotidases and 5’-nucleotidase enzymes to the weak adenosine agonist inosine as an end-product. The appropriate selective agonists/antagonists for purinergic receptors as well as the respective enzyme inhibitors may profoundly interfere with microglial functions and reconstitute the homeostasis of the CNS disturbed by neuroinflammation.

Abstract: The brain endothelial cell (BEC) glycocalyx (ecGCx) is a BEC surface coating consisting of a complex interwoven polysaccharide (sweet husk) mesh-like network of membrane-bound proteoglycans, glycoproteins, and glycosaminoglycans (GAGs) covering the apical luminal layer of the brain endothelial cells. The ecGCx may considered as the 1st barrier of a tripartite blood-brain barrier (BBB) consisting of 1) ecGCx; 2) BECs; (3) extravascular compartment of pericytes, extracellular matrix, and perivascular astrocytes, Perturbations of this barrier allow for increased permeability in the postcapillary venule that will be permissive to both fluids, solutes, and proinflammatory peripherally-derived leukocytes into the perivascular spaces (PVS) to result in enlargement as well as increased neuroinflammation. The ecGCx is known to have multiple functions, which include its physical and charge barrier, mechanical transduction, regulation of vascular permeability, modulation of inflammatory response, and anticoagulation functions. This review discusses each of the listed functions in detail and utilizes multiple transmission electron micrographs and illustrations to allow for a better understanding of the ecGCx structural and functional roles as it relates to enlarged perivascular spaces (EPVS). This is the 5th review of a series quintet that discuss the importance of EPVS from the perspective of the cells of brain barriers. Attenuation and/or loss of the ecGCx results in brain barrier disruption with increased permeability to proinflammatory leukocytes, fluids and solutes, which accumulate in the postcapillary venule perivascular spaces. This accumulation results in obstruction and results in EPVS with impaired waste removal of the recently recognized glymphatic system. Importantly, EPVS are progressively being regarded as a marker of cerebrovascular and neurodegenerative pathology.

Multiple Sclerosis (MS) is a neurodegenerative disease that mainly affects young adults. The high prevalence of the disease and its impact on patients' quality of life led to priority being given to the etiopathogenesis of the disease to identify possible modifiable factors and consequent effective intervention strategies. Recent hypotheses suggest that the etiopathogenesis of MS is multifactorial and includes factors related to the immune system, neuroinflammation and neuro-degeneration. In this scenario, sleep has a close - although indirect - relationship with MS, through its relationship with each of those factors. In particular, the role of cytokines in immune system impairment and neuroinflammation, mitochondrial dysfunction and oxidative stress in neurodegeneration all are associated with sleep in different forms. Furthermore, melatonin in relation with vitamin D has a potential therapeutic effect in MS sleep-related problems. Given the growing interest of research in the mechanisms underlying MS and therapies able to alleviate MS-related symptoms at all stages of the disease, a more in-depth study of the role of sleep disturbances and the factors intrinsically related to sleep and MS could be useful both to investigate the etiopathogenetic factors of MS and to develop potential non-invasive intervention strategies for MS treatment.

Neurodegenerative diseases encompass a broad spectrum of profoundly disabling disorders that impact millions of individuals globally. While their underlying causes and pathophysiol-ogy display considerable diversity and remain incompletely understood, a mounting body of evidence indicates that the disruption of blood-brain barrier (BBB) permeability, resulting in brain damage and neuroinflammation, constitutes a shared characteristic among them. Con-sequently, targeting the BBB has emerged as an innovative therapeutic strategy for address-ing neurological diseases. Within this review, we not only explore the neuroprotective, neu-rotrophic, and immunomodulatory benefits of mesenchymal stem cells (MSCs) in combating neurodegeneration but also delve into their recent role in modulating the BBB. We will delve into the cellular and molecular mechanisms through which MSC treatment impacts primary age-related neurological disorders like Alzheimer’s disease, Parkinson’s disease, and stroke as well as immune-mediated conditions such as multiple sclerosis. Our focus will center on how MSCs participate in the modulation of cell transporters, matrix remodeling, stabilization of cell-junction components, and restoration of BBB network integrity in these pathological con-texts.

Neuroinflammation, defined as inflammatory reactions mediated by cytokines, chemokines, reactive oxygen species, and secondary messengers in the central nervous system (CNS) including the brain and spinal cord is the basis of many neurological disorders. Recently, erythropoietin (EPO) has been considered and studied as a modulator of neuroinflammation. On this article minireview of pathophysiology of neuroinflammation and the neuroprotective effects of EPO is discussed and a case of subacute huge subdural hematoma with double mydriasis operated urgently, treated with low daily dose (vs high dose once or twice a month in the literature) of EPO and recovered fully and discharged home with good consciousness is reported. In addition, the probable unfavorable outcome of erythropoietin administration in patients with neuroinflammation in COVID-19 is considered.

The cytokine-producing nucleotide-binding domain leucine-rich repeat and pyrin-containing receptor 3 (NLRP3) inflammasome is generally recognized to play a central role in the immune response to vaccination and NLRP3 activity is known to be increased by both aluminum adjuvants and by oxidative stress. Thus, the presence of oxidative stress may place individuals at higher risk for exaggerated or prolonged inflammatory responses and related side effects from vaccination. We here examine the relationship between oxidative stress and NLRP3 inflammasome activity, particularly in the context of aluminum-adjuvanted vaccines, and its implications for subpopulations of individuals with restricted antioxidant capacity.

Abstract: Astrocytes (ACs) are the most abundant human cell in the brain and importantly, are the master connecting and communicating cells that provide structural and functional support of brain cells at all levels of organization. Further, they are recognized to be the guardians and housekeepers of the brain. Protoplasmic perivascular astrocyte endfeet and their basal lamina form the delimiting outermost barrier (glia limitans) of the perivascular spaces in postcapillary venules and are important for the clearance of metabolic waste and comprise the glymphatic system, which is critically dependent on the proper waste removal by the pvACef polarized aquaporin 4 water channels. Also, the protoplasmic perisynaptic astrocyte endfeet (psACef) are important in cradling the neuronal synapses that serve to maintain homeostasis and serve a functional and supportive role for synaptic transmission. Enlarged perivascular spaces (EPVS) are emerging as important aberrant findings on magnetic resonance imaging (MRI) and associate with white matter hyperintensities, lacunes, aging, accepted to be biomarkers for cerebral small vessel disease, increased in obesity, metabolic syndrome, and type 2 diabetes. Knowledge is exponentially expanding regarding EPVS along with the glymphatic system, since EPVS are closely associated with impaired glymphatic function and waste removal from the brain to the cerebrospinal fluid and systemic circulation. This review intends to focus on how the pvACef play a crucial role in the development of EPVS.

As the world endures the coronavirus disease 2019 (COVID-19) pandemic, conditions of 35 million vulnerable individuals struggling with substance use disorders (SUDs) worldwide have not received sufficient attention for their special health and medical needs. Many of these individuals are complicated by underlying health conditions, such as cardiovascular and lung diseases and undermined immune systems. During the pandemic, access to the healthcare systems and support groups is greatly diminished. Current research on COVID-19 has not addressed the unique challenges facing individuals with SUDs, including the heightened vulnerability and susceptibility to the disease. In this systematic review, we will discuss the pathogenesis and pathology of COVID-19, and highlight potential risk factors and complications to these individuals. We will also provide insights and considerations for COVID-19 treatment and prevention in patients with SUDs.

1) Background: Impeded resolution of inflammation contributes substantially to the pathogenesis of Alzheimer's disease (AD); consequently, resolving inflammation is pivotal to the amelioration of AD pathology. This can potentially be achieved by the treatment with specialized pro-resolving lipid mediators (SPMs), which should resolve neuroinflammation in brains. 2) Methods: Here, we report the effects of long-term treatment with a SPM, maresin like 1 (MarL1), on AD pathogenesis in a transgenic 5xFAD mouse model. 3) Results: MarL1 treatment reduced Aβ overload, curbed the loss of neurons in brains especially cholinergic neurons associated with cleaved-caspase-3-associated apoptotic degeneration, reduced astrogliosis and microgliosis and the pro-inflammatory M1 polarization of microglia, curbed the AD-associated decline in an-ti-inflammatory Iba1+Arg-1+-M2 microglia, reduced astrogliosis-associated level of neuroin-flammatory TNF-α, inhibited phenotype switching of pro-inflammatory neurotoxic A1 astrocytes and N1 neutrophils, promoted polarization of inflammation-resolving neuroprotective A2 as-trocytes, promoted the blood–brain-barrier-associated tight-junction protein claudin-5 and de-creased neutrophil leakage in 5xFAD brains, and induced the switch of neutrophils toward the inflammation-resolving N2 phenotype. 4) Conclusion: Long-term administration of MarL1 mit-igates AD-related neuropathogenesis in brains by curbing neuroinflammation and neurodegen-eration. These findings provided the preclinical leads and mechanistic insights for the develop-ment of MarL1 into an effective modality to ameliorate AD pathogenesis.

Much evidence now indicates a direct crosstalk between thyroid hormones (THs) and the immune system. We previously showed that THs behave as anti-inflammatory agents in human leukemic THP-1 monocytes, but a potential neuroprotective effect of THs in microglia have been under-investigated. Microglia, the primary innate immune cells of the brain, play a pivotal role in the regulation of neuroinflammation and nongenomic integrin αvβ3-mediated action of THs appear to be involved. Integrin αvβ3 was highly expressed in activated BV-2 cells, while it was decreased by THs. In addition, THs facilitated wound healing in BV-2 murine microglia cells activated by lipopolysaccharide (LPS), through integrin αvβ3 and reactive oxygen species (ROS), with tetrac (a metabolite of TH) potentiated the inhibition of migration. Nitric oxide (NO) played a role with different mechanisms in the presence of either T3 or T4. Our data showed the capability of TH and analogues to modulate the M1-to-M2 microglial transition and suggest a new spectrum of actions in the central nervous system (CNS).

Neuroinflammation is considered to be a significant component in a range of neuropathologies. Unfortunately, whilst its role is well recognized, the options for therapeutic intervention are limited. As such, there is a need to identify novel targets in order to increase treatment options. Given its role as both a neurotransmitter and an immune modulator, substance P and its NK1 receptor have been widely studied as a potential therapeutic target. There is evidence that NK1 receptor antagonists may exert beneficial effects in a range of conditions, including traumatic brain injury and stroke. Blocking the NK1 receptor has been shown to reduce blood-brain barrier dysfunction, reduce cerebral oedema, and reduce the levels of pro-inflammatory cytokines. These actions are associated with improved survival and functional outcomes. The NK1 receptor has also been shown to be involved in the inflammatory reaction to CNS infection, and hence antagonist may have some benefit in reducing infection-driven inflammation. However, the NK1 receptor may also play a role in the host immune response to infection, and so here, the potential beneficial and detrimental effects need to be carefully balanced. As such, the purpose of this review is to provide a summary of the involvement of substance P in acute inflammation, particularly in the context of traumatic brain injury and stroke.

Traumatic spinal cord injury (SCI) elicits an acute inflammatory response which comprises numerous cell populations. It is driven by the immediate response of macro-phages and reactive M1 microglia, which triggers activation of genes responsible for the dysregulated microenvironment within the lesion site and in the spinal cord parenchyma immediately adjacent to the lesion. Recently published data indicate that microglia induces astrocyte activation and determines the fate of astrocytes. Conversely, astrocytes have the potency to trigger microglial activation and control their cellular functions. Here we review current information about the release of diverse signaling molecules (pro-inflammatory vs anti-inflammatory) in individual cell phenotypes (microglia, astrocytes, blood inflammatory cells) in acute and subacute SCI stages, and how they contribute to delayed neuronal death in a the surrounding spinal cord tissue which is spared and functional but reactive. In addition, temporal correlation in progressive degeneration of neurons and astrocytes and their functional interactions after SCI are discussed. Finally, the review highlight the time-dependent transformation of reactive mi-croglia (M1) and astrocytes (A1) into their neuroprotective phenotypes (M2a, M2c and A2) which are crucial for spontaneous post-SCI locomotor recovery. We also provide sug-gestions on how to increase functional outcome after SCI and discuss key therapeutic approaches.

The neurologic effects of long-COVID are a therapeutic challenge. This article discusses the immunologic manifestations of long-COVID and proposes a non-androgenic, synthetic analog of dehydroepiandrosterone (DHEA), bromo-epi-androsterone (BEA), as a candidate for clinical trials for this exigent collection of neurologic conditions. Moreover, because there is an association between long-COVID and Alzheimer’s disease, the evaluation of BEA in long-COVID may serve as a proxy for its effect on neuroinflammatory biomarkers of Alzheimer’s disease that are shared with long-COVID.

This review explores the application of the conservative management model for pain to sports-related concussions (SRCs), framing concussions as a distinct form of pain syndrome with a pathophysiological foundation in central sensitization. Drawing parallels with proven pain management models, we underscore the significance of a proactive approach to concussion management. Recognizing concussions as a pain syndrome allows for the tailoring of interventions in alignment with conservative principles. This review first covers the epidemiology and controversies surrounding prolonged concussion recovery and persistent post-concussion symptoms (PPCS). Next, the pathophysiology of concussions is presented within the central sensitization framework, emphasizing the need for early intervention to mitigate the neuroplastic changes that lead to heightened pain sensitivity. Five components of the central sensitization process specific to concussion injuries are highlighted as targets for conservative interventions in the acute period: peripheral sensitization, cerebral metabolic dysfunction, neuroinflammation, glymphatic system dysfunction, and pain catastrophizing. These proactive interventions are emphasized as pivotal in accelerating concussion recovery and reducing the risk of prolonged symptoms and PPCS, in line with the philosophy of conservative management.

Parkinson’s disease (PD) is a progressive neurodegenerative disease characterized by resting tremor, bradykinesia, rigidity, postural instability, that also includes non-motor symptoms such as mood dysregulation. Dopamine (DA) is the primary neurotransmitter involved in this disease, but cholinergic imbalance has also been implicated. Current intervention in PD is focused on replenishing central DA, which provides remarkable temporary symptomatic relief but does not address the neuronal loss and the progression of the disease. It has been well established that neuronal nicotinic cholinergic receptors (nAChRs) can regulate DA release and that nicotine itself may have neuroprotective effects. Recent studies have identified nAChRs in nonneuronal cell types including glial cells, where they may regulate inflammatory responses. Given the crucial role of neuroinflammation in dopaminergic degeneration, and the involvement of microglia and astrocytes in this response, glial nAChRs may provide a novel therapeutic target in prevention and/or treatment of PD. In this review, following a brief discussion of PD, we focus on the role of glial cells and specifically their nAChRs in PD pathology and/or treatment.

Histamine (HA), a biogenic monoamine, exerts its pleiotropic effects through four H1R–H4R histamine receptors, which are also expressed in brain tissue. Together with the projections of HA-producing neurons located within the tuberomammillary nucleus (TMN), which innervate most areas of the brain, they constitute the histaminergic system. Thus, while remaining a mediator of the inflammatory reaction and immune system function, HA also acts as a neurotransmitter and a modulator of other neurotransmitter systems in the central nervous system (CNS). Although the detailed causes are still not fully understood, neuroinflammation seems to play a crucial role in the etiopathogenesis of both neurodevelopmental and neurodegenerative (neuropsychiatric) diseases, such as autism spectrum disorders (ASD), attention-deficit/hyperactivity disorder (ADHD), Alzheimer's disease (AD) and Parkinson's disease (PD). Given the increasing prevalence/diagnosis of these disorders and their socioeconomic impact, the need to develop effective forms of therapy has focused researchers' attention on the brain's histaminergic activity and other related signaling pathways. This review presents the current state of knowledge concerning the involvement of HA and the histaminergic system within the CNS in the development of neurodevelopmental and neurodegenerative disorders.