In this study, the potential of whey protein hydrolysate (WPH) containing LDIQK peptide and treadmill exercise to prevent cognitive decline was investigated along with the neuroprotective mechanisms. Cognitive dysfunction was induced in mice by 1 mg/kg scopolamine, followed by administration of WPH at 100 and 200 mg/kg and/or treadmill exercise at 15 m/min for 30 min five days per week. Both WPH administration and treadmill exercise significantly improved memory in mice with scopolamine-induced cognitive impairment, which was attributed to several key mechanisms, including a reduction in oxidative stress based on decreased levels of reactive oxygen species and malondialdehyde in the brain tissue and an increase in acetylcholine by increasing choline acyltransferase and decreasing acetylcholine esterase levels. Exercise and WPH also exerted neuroprotective effects by inhibiting the hyperphosphorylation of tau protein, enhancing the expression of brain-derived neurotrophic factor, and inhibiting apoptosis by reducing the Bax/Bcl2 ratio in conjunction with downregulation of the mitogen-activated protein kinase pathway. Moreover, the impact of WPH and treadmill exercise extended to the gut microbiome, suggesting a potential link with cognitive improvement. These findings suggest that both WPH intake and treadmill exercise are effective strategies for mitigating cognitive impairment, providing promising avenues for treating neurodegenerative diseases.

Alzheimer’s disease (AD) is a neurodegenerative disease that is characterized as a progressive decline in cognitive functions that primarily affects older adults. Alzheimer’s is pathophysiologically characterized by the accumulation of amyloid-beta (Aβ) plaques, neuroinflammation, accumulation of tau proteins in neurofibrillary tangles (NFTs), and tissue loss. These three main characteristics are hallmarks of neurodegeneration. Statins are a class of medications that lower the cholesterol levels in the blood, and their anti-inflammatory effects have gained attention for their potential impact on influencing AD progression. This literature review explores the relationship between the use of statins and AD, examining the effect of statins on cholesterol metabolism, neuroinflammation, apolipoprotein E (ApoE), and Aβ production. This literature review was conducted using PubMed and Google Scholar to summarize the association between statins and AD. The neurodegenerative properties of Alzheimer’s disease have been imaged and documented in both rodent models and humans. Experiments using transgenic mice and knock-in mice have shown that specific human genes enhance neurodegeneration, and the overactivation of glial cells in the brain causes hallmark neuroinflammation. These rodents all subsequently suffered from neurodegeneration and AD symptoms. Humans showed promise of possible AD biomarkers in the blood and brain through the presence of excess isoprostanes and oxysterols, respectively, providing hope for future research into early detection/treatment. There has been evidence that statins exhibit neuroprotective pleiotropic effects in rodent models, showcasing reductions in cellular adhesion molecules (the main molecule in inflammation), oxidative stress, and inflammatory peptides. ApoE is a cholesterol transport protein in the brain and is critical to forming an effective synapse. Statin use has effectively altered the ApoE4 allele and reduced the Aβ production in the brain. However, the mechanism for which statins slow the progression of neurodegeneration in AD is still unclear and warrants further research before it can be officially called a treatment.

Cannabis, renowned for its historical medicinal use, harbours various bioactive compounds—cannabinoids, terpenes, and flavonoids. While major cannabinoids like THC and CBD have received extensive scrutiny for their pharmacological properties, emerging evidence underscores the collaborative interactions among these constituents, suggesting a collective therapeutic potential. This comprehensive review explores the intricate relationships and synergies between cannabinoids, terpenes, and flavonoids in cannabis. Cannabinoids, pivotal in cannabis's bioactivity, exhibit well-documented analgesic, anti-inflammatory, and neuroprotective effects. Terpenes, aromatic compounds imbuing distinct flavours, not only contribute to cannabis's sensory profile but also modulate cannabinoid effects through diverse molecular mechanisms. Flavonoids, another cannabis component, demonstrate anti-inflammatory, antioxidant, and neuroprotective properties, particularly relevant to neuroinflammation. The entourage hypothesis posits that combined cannabinoid, terpene, and flavonoid action yields synergistic or additive effects, surpassing individual compound efficacy. Recognizing the nuanced interactions is crucial for unravelling cannabis's complete therapeutic potential. Tailoring treatments based on the holistic composition of cannabis strains allows optimization of therapeutic outcomes while minimizing potential side effects. This review underscores the imperative to delve into the intricate roles of cannabinoids, terpenes, and flavonoids, offering promising prospects for innovative therapeutic interventions and advocating continued research to unlock cannabis's full therapeutic potential within the realm of natural plant-based medicine.

The ameliorative effect ethanolic extract of M. oleifera (MO) leaves in combination of curcumin against seizures, cognitive impairment & oxidative stress PTZ-induced kindled rats. Molecular docking was performed to predict the potential phytochemical of MO and curcumin against Epilepsy. The effect of pretreatment with leaves of M. oleifera ethanolic extracts (MOEE) (250, 500mg/kg, orally), curcumin (200 and 300 mg/kg, orally), valproic acid used as standards (100mg/kg) and combined effect of MOEE (250mg/kg) and curcumin (200mg/kg) at low dose, on pentylenetetrazole (PTZ)-induced kindling. For the development of kindling the individual Wistar rats (Male) were injected pentyletetrazole (40 mg/kg, i.p.) on every alternate day. Molecular Docking has been done by AutoDock4.2 tool to merge the ligand orientations in the binding cavity. From the RCSB website, the crystal structure of Human Glutathione reductase (PDB ID: 3DK9) was obtained. Curcumin and MOEE showed dose-dependent effect. The combined effects of leaves of MOEE & curcumin significantly improved the seizure score and decreased the number of myo-clonic jerks in compare with standard dose of valproic acid. PTZ kindling induced a significant oxidative stress and cognitive impairment which was reversed by pretreatment with MOEE & curcumin. Glutathione reductase (GR) is an enzyme, which plays key role in the cellular control of reactive oxygen species (ROS). Therefore, activating GR can uplift the antioxidant property, which leads to the inhibition of ROS induced cell death in brain. The combination of ethanolic extract of M. oleifera (MOEE) leaves and curcumin have shown better result than any other combination for antiepileptic effect by virtue of antioxidant effects. As per docking study showed that the chloro-genic acid and quercetin is treated with the combination of curcumin can be much more potential.

Oxidative stress (OS) is a condition in which there is an excess of reactive oxygen species (ROS) in the body, which can lead to cell and tissue damage. This occurs when there is an overproduction of ROS or when the body's antioxidant defense systems are overwhelmed. Quercetin is part of a group of compounds called flavonoids. It is found in high concentrations of vegetables, fruits, and other foods. Over the past decade, a growing number of studies have highlighted the therapeutic potential of flavonoids to modulate neuronal function and prevent age-related neurodegeneration. Therefore, quercetin has been shown to have antioxidant, anticancer, and anti-inflammatory properties, both in vitro and in vivo. Due to its antioxidant character, quercetin alleviates oxidative stress, thus improving cognitive function, reducing the risk of neurodegenerative diseases. On the other hand, quercetin can also help support the body's natural antioxidant defense systems, thus being a potentially practical supplement for managing oxidative stress. This review focuses on experimental studies supporting the neuroprotective effects of quercetin in Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington's disease (HD) and epilepsy.

Monoterpenes as natural products are the subject of increased attention in the search for new pharmacological agents because of their numerous biological activities including antifungal, antibacterial, antioxidant, anticancer, antispasmodic, hypotensive, vasodilating effects, etc. In vitro and in vivo studies reveal their antidepressant, anxiolytic, and memory-enhancing in experimental dementia and Parkinson’s disease effects. Chemical modification of natural substances by conjugation with various synthetic components is a modern method of obtaining new biologically active compounds. The discovery of new potential drugs among monoterpene derivatives is a progressive direction in experimental pharmacology and a promising approach to the therapy of various pathologies. Biologically active substances such as monoterpenes borneol, camphor, geraniol, pinene, and thymol, were used to synthesize compounds with different properties, including analgesic, anti-inflammatory, anticonvulsant, anti-depressant, anti-Alzheimer’s, anti-parkinsonian, antiviral and antibacterial (anti-tuberculosis). Myrtenal is a perspective monoterpenoid with therapeutic potential in various fields of medicine. Its chemical modifications often lead to new or more pronounced biological effects. As an example, conjugation of myrtenal with the known pharmacophore adamantane allows one to enhance some of its key properties. Myrtenal-adamantane derivatives exhibited a variety of beneficial properties – antimicrobial, antifungal, antiviral, anticancer, anxiolytic, and neuroprotective, which are worth examining in more detail and at length.

.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. .

Although transplantation procedures have been developed for patients with end-stagec hepatic insufficiency or other diseases, allograft rejection still threatens patient health and lifespan. Over the last few decades, the emergence of immunosuppressive agents, such as calcineurin inhibitors (CNIs) and mammalian target of rapamycin (mTOR) inhibitors, have strikingly increased graft survival. Unfortunately, immunosuppressive agent-related neurotoxicity is commonly occurred in clinical situations, with the majority of neurotoxicity cases caused by CNIs. The possible mechanisms whereby CNIs cause neurotoxicity include: increasing the permeability or injury of the blood-brain barrier, alterations of mitochondrial function, and alterations in electrophysiological state. Other immunosuppressants can also induce neuropsychiatric complications. For example, mTOR inhibitors induce seizures; mycophenolate mofetil induces depression and headache; methotrexate affects the central nervous system; mouse monoclonal immunoglobulin G2 antibody against cluster of differentiation 3 also induces headache; and patients using corticosteroids usually experience cognitive alteration. Therapeutic drug monitoring, individual therapy based on pharmacogenetics, and early recognition of symptoms have greatly reduced neurotoxic events. Once neurotoxicity occurs, a reduction in the drug dosage, switching to other immunosuppressants, using drugs to treat the neuropsychiatric manifestation, or blood purification therapy have proven to be effective against neurotoxicity. In this review, we summarize the recent topics on the mechanisms of neurotoxicity of immunosuppressive drugs. In addition, some information about neuroprotective effects of several immunosuppressants are also discussed.

3-(3,4-Dichlorophenyl)-5-(1H-indol-5-yl)-1,2,4-oxadiazole was synthesized via the condensation of 3,4-dichlorobenzamidoxime and methyl 1H-indole-5-carboxylate using superbasic medium (NaOH/DMSO). The compound was tested as a potential inhibitor of human monoamine oxidase (MAO) A and B. It demonstrated notable inhibition with an IC50 value of 0.036 μM for MAO-B and isoform specificity. The product was characterized by 1H NMR, 13C NMR, and HRMS. In conclusion, the new active MAO-B inhibitor may serve as a candidate for the future discovery of therapeutic agents for neurodegenerative disorders such as Parkinson’s disease.

Alzheimer’s disease (AD) is an age-related neurodegenerative disease and is clinically characterized by cognitive impairment, memory loss, and personality disorder. Oligomers of amyloid beta-peptides (Aβ) and enhanced oxidative stress in senile plaques are prevalent pathologic hallmarks of AD. In this study, we detected the behavioral performance of Lycium ruthenicum Murray anthocyanin (LRA) -treated rats using the Morris water maze test and then investigated the effect of LRA on oxidative damage, neuronal apoptosis, and inflammatory response induced by Aβ1–42. Our results showed that LRA treatment markedly ameliorated the behavioral performance of Aβ1–42-induced rats and reduced the level of malondialdehyde, formation of protein carbonyl, and 8-hydroxy-2’-deoxygua-nosine. Furthermore, LRA also inhibited activated astrocytes and neuroinflammation via suppression of glial fibrillary acidic protein and tumor necrosis factor-alpha in the hippocampus of Aβ1–42-treated rat brain. These data suggest that LRA could be a potential anti-oxidant and anti-neuroinflammatory agent for the treatment of AD.

The present review focuses on recent clinical trials that analyze the efficacy of intravitreal therapeutic agents for the treatment of dry age-related macular degeneration (AMD), such as neuroprotective drugs, and complement inhibitors, also called immunomodulatory or anti-inflammatory. A systematic literature search was performed to identify randomized controlled trials published prior to January 2019. Patients affected by dry AMD treated with intravitreal therapeutic agents were included. The changes in the correct visual acuity and the reduction in geographic atrophy progression were evaluated. Several new drugs have shown some promising results, including those targeting the complement cascade and agents called neuroprotective. The action potential of the two groups of drugs is to block the complement cascade model for immunomodulating agents, and prevent the degeneration and apoptosis of ganglion cells for the neuroprotectors, respectively. To the best of knowledge, and after extensive studies on the matter, there are still many investigations to be carried out on dry AMD in collaboration between researchers. They will have to identify truly effective molecules, understand the practical potential of pluripotent stem cells, and refine gene therapies. Only in-depth clinical trials will be able to allow the most appropriate and personalized treatments for each dry AMD patient.

Pituitary adenylate cyclase-activating polypeptide receptor 1 (PAC1-R) has a higher affinity for pituitary adenylate cyclase- activating polypeptide (PACAP) than for vasoactive intestinal peptide (VIP). PACAP exerts its neuroprotective effects through PAC1-R. PAC1-R has become a target for drug development, and we targeted PAC1-R to screen small positive allosteric modulator 1 (SPAM1). SPAM1 has a neuroprotective effects, and in the D-galactose (D-gal) mouse model, SPAM1 improved the structure of the hippocampal dentate gyrus and restored the number of neurons. Compared with D-gal model mice, SPAM1 treatment upregulated the expression of Sirtuin 6 (SIRT6) and Lamin B1, and downregulated the expression of YinYang 1 (YY1) and p16. Consistent with this, the same results were obtained in senescent RGC-5 cells. Meanwhile, SPAM1 was also found to up-regulate SIRT6 and down-regulate YY1 expression in normal RGC-5 cells. Then, we further explored the mechanism of SPAM1 neuroprotection by whole transcriptome sequencing and proteomic analysis, and found that SPAM is involved in the longevity regulating pathway, and confirmed the up-regulation of neurofilament light polypeptide and neurofilament medium polypeptide by western blot, thus laying a pharmacological foundation for SPAM1 as a therapeutic agent for neurodegenerative diseases. polypeptide and neurofilament medium polypeptide. Thus, it lays a pharmacological foundation for SPAM1 as a therapeutic drug for neurodegenerative diseases.

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.