Abstract: MicroRNAs can interfere with a protein function by suppressing their messenger RNA translation or the synthesis of its related factors. The function of brain-derived neurotrophic factor (BDNF) is essential to the proper formation and function of the nervous system and is seen to be regulated by many microRNAs. However, understanding how microRNAs influence BDNF actions within cells requires a wider comprehension of their integrative regulatory mechanisms. Aim: In this literature review, we have synthesized the evidence of microRNA regulation on BDNF in cells and tissues, and provided an analytical discussion about direct and indirect mechanisms that appeared involved in BDNF regulation by microRNAs. Methods: Searches were conducted on PubMed.gov using the terms “BDNF” AND “MicroRNA” and “brain-derived neurotrophic factor” AND “MicroRNA”, updated on September 1st, 2023. Papers without open access were requested from the authors. One hundred and seventy-one papers were included for review and discussion. Results and Discussion: The local regulation of BDNF by microRNAs involves a complex interaction between a series of microRNAs with target proteins that can either inhibit or enhance BDNF expression, at the core of cell metabolism. Therefore, understanding this homeostatic balance provides resources for the future development of vector-delivery-based therapies for the neuroprotective effects of BDNF.

Various autoimmune diseases, including autoimmune hypothyroidism (AHT), are associated with a higher risk of developing mood disorders throughout life. Depression is accompanied by the changes in the levels of inflammatory and trophic factors, including interleukines (IL-1beta, IL-2, IL-6), interferon alpha (IFN-alpha), tumor necrosis factor alpha (TNF-alpha), C-reactive protein (CRP) and brain derived neurotrophic factor (BDNF). Similar disturbances in the cytokine profile are seen in AHT patients and their relatives. Disclosure of the relationship between the co-existence of depression and autoimmune subclinical thyroiditis indicates that the pathomecha-nism of depression may be related to the changes in the immune system, it is possible that both conditions may be caused by the same immune processes. The above hypothesis is indirectly sup-ported by the observations that the treatment with both antidepressants and levothyroxine leads to a decrease in the levels of proinflammatory cytokines with an increase in BDNF concentrations, simultaneously correlating with an improvement in the clinical parameters. However, so far there are no long-term studies determining the causal relationship between depression, thyroid auto-antibodies, and cytokine profile, which could bring us closer to understanding the interrelation-ships between them and facilitate the use of an adequate pharmacotherapy, not necessarily psy-chiatric. We consider the above issues insufficiently investigated but of great importance. This ar-ticle is an overview of the available literature as well as an introduction to our research project.

Depressive disorder in childhood and adolescence is a highly prevalent mood disorder that tends to recur throughout life. Untreated mood disorders can adversely impact a patient's quality of life and cause socioeconomic loss. Thus, an accurate diagnosis and appropriate treatment is crucial. However, until now, diagnoses and treatments are conducted according to clinical symptoms. Objective and biological validation are lacking. This may result in a poor outcome for patients with depressive disorder. Research has been conducted to identify the biomarkers that are related to depressive disorder. Cumulative evidence has revealed that certain immunologic biomarkers in-cluding brain-derived neurotrophic factor (BDNF) and cytokines, gastrointestinal biomarkers, hormones, oxidative stress, and certain hypothalamus-pituitary axis biomarkers are associated with depressive disorder. This article reviews the biomarkers related to the diagnosis and treatment of pediatric depressive disorders. To date, clinical biomarker tests are not yet available for diagnosis or for the prediction of treatment prognosis. However, cytokines such as Interleukin-2, interfer-on-gamma, tumor necrosis factor-alpha, and BDNF have shown significant results in previous studies of pediatric depressive disorder. These biomarkers have the potential to be used for diagnosis, prognostic assessment, and group screening for those at high risk.

This investigation aimed to explore the impact of acute and regular physical exercise on Brain-Derived Neurotrophic Factor (BDNF) levels in individuals with obesity. Using the Population, Intervention, Comparator, Outcome, and Study design (PICOS) approach, the inclusion criteria were defined as follows: i) population - individuals with overweight or obesity of any age or gender; ii) intervention - acute or chronic interventions involving aerobic or anaerobic methodologies; iii) comparator - for acute effect studies, pre- and post-evaluations served as comparators, while interventions included at least one experimental group or the inclusion of a control group; iv) outcome - BDNF variability concerning the applied methodology; v) study design - restricted to experimental studies exclusively. Conducted in August 2022, the searches were carried out on PubMed, Academic Search Complete, and Web of Science. The risk of bias was assessed using the Risk of Bias in Non-randomized Studies (RoBANS) tool. Out of 98 potentially relevant articles, 16 met the eligibility criteria, encompassing 23 trials. Substantial heterogeneity was observed for both acute (I2 = 80.4%) and long-term effects (I2 = 88.7%). Additionally, RoBANS analysis indicated a low risk of bias for the included studies. The study's findings revealed a significant increase in the concentration of circulating BDNF in individuals with obesity compared to the control group following acute exercise. However, such an effect was not evident in the context of long-term physical exercise, with a small effect size (ES = 0.49) recorded in the latter scenario. The observed significant increase in BDNF levels post-acute exercise suggests a potential acute response mechanism contributing to the intricate interplay between exercise and neurotrophic factors in this population. Nevertheless, the absence of a similar effect in the context of long-term physical exercise implies a potential adaptation or ceiling effect. These findings underscore the importance of considering both the duration and nature of exercise interventions when exploring the neurobiological responses associated with obesity and exercise. The study provides valuable insights for future research and clinical implications in understanding the nuanced relationship between exercise, neurotrophic factors, and obesity.

Oleuropein (OLE), a main constituent of olive, displays a pleiotropic beneficial dynamic in health and disease, based mainly on its antioxidant and hypolipidemic properties, and its capacity to protect myocardium during ischemia. Furthermore, OLE activates peroxisome proliferator-activated receptor (PPARα) in neurons and astrocytes, providing neuroprotection against noxious biological reactions that are induced following cerebral ischemia. Current study investigated the effect of OLE in the regulation of various neural plasticity indices, emphasizing the role of PPARα. For this purpose, 129/Sv wild-type (WT) and Pparα-null mice were treated with OLE for three weeks. The present findings revealed that chronic treatment with OLE up-regulated the brain-derived neurotrophic factor (BDNF) and its receptor TrkB in the prefrontal cortex (PFC) of mice via activation of ERK1/2, AKT and PKA/CREB signaling pathways. No similar effects were observed in the hippocampus. The OLE-induced effects on BDNF and TrkB appear to be mediated by PPARα, because no similar alterations were observed in the PFC of Pparα-null mice. Notably, OLE did not affect the neurotrophic factors NT3 and NT4/5 in both brain tissues. Fenofibrate though, a selective PPARα agonist, up-regulated BDNF and NT3 in the PFC of mice, whereas the drug induced NT4/5 in both brain sites tested. Interestingly, OLE provided neuroprotection in differentiated human SH-SY5Y cells against β-amyloid and H2O2 toxicity independently from PPARα activation. In conclusion, OLE and similar drugs acting either as PPARα agonists or via PPARα independent mechanisms could improve synaptic function/plasticity mainly in the PFC and to a lesser extent in the hippocampus, thus beneficially affecting cognitive functions.

Methamphetamine (METH) has the potential to disrupt the activities of neurotransmitters in the Central Nervous System (CNS) and cause neurotoxicity through various pathways. These pathways include increased production of reactive nitrogen and oxygen species, hypothermia, and induction of mitochondrial apoptosis. In this study, we investigated the long-term effects of METH addiction on the structural changes in the amygdala of postmortem human brains, as well as the involvement of the CREB/BDNF and Akt-1/GSK3 signaling pathways. We examined ten male postmortem brains, comparing control subjects with chronic METH users, using immunohistochemistry, Real-time PCR (to measure levels of CREB, BDNF, Akt-1, GSK3, and TNF-α), Tunnel assay, stereology, and assays for ROS, GSSG, and GPX. The findings revealed that METH significantly reduced the expression of BDNF, CREB, Akt-1, and GPX, while increasing the levels of GSSG, ROS, RIPK3, GSK3, and TNF-α. Furthermore, METH was found to induce inflammation and neurodegeneration in the amygdala, with ROS production mediated by the CREB/BDNF and Akt-1/GSK3 signaling pathways.

Objective: The purpose of this study was to investigate the effects of Crocin on brain neuroterophins, cognition, sensory and motor dysfunction and compare to fingolimod effects in experimental model of demyelination with Ethidium Bromide EB in female Wistar rats. Methods: Animals were assigned in to 8 groups; Sham, Sham operated (ShOp), EAE, crocin treated (Cr5,10,20 mg/kg), Vehicle, Fingolompd (Fing) and fingolimod + crocin (Cr+Fing). Demyelination was induced by single dose injection of 10 μl of EB 0.1% into the fourth ventricle of the brain. Crocin and fingolimod were applied for 21 days, daily, oral gavage. BDNF, NGF1, nerve conduction velocities, tail flake latency, balance and behavioral variables were sampled and analyzed by paired t-test and ANOVA test with repeated post hoc measurements. Results: The results showed that crocin improves all studied factors, but remarkable imrovments were observed in dosage of 10 mg/kg. Crocin (10mg/kg) and fingolimod (1mg/kg) significantly improved cognition variables in open field test, sensory and motor nerve conduction velocity, tail flick latency and clinical signs (p<005). In addition, applying of crocin co-administered with fingolimod led to significant increases in all assessed factors, greater than crocin or fingolimod intervention alone (α≤0.001). Conclusion: Based on the current findings, crocin can improve the level of brain neurotrophins, exploratory behavior and nerve conduction after demyelination as close as fingolimod results. So, crocins can be considered as a neuro supportive agent in the management of degenerative diseases maybe similar to fingolimod mechanism.

Growing evidence suggests a possible involvement of the intestinal microbiota in generating new neurons, but a detailed breakdown of the microbiota composition is lacking. In this report, we systematically reviewed preclinical rodent reports addressing the connection between the composition of the intestinal microbiota and neurogenesis and neurogenesis-affecting neurotrophins in the hippocampus. Various changes in bacterial composition from low taxonomic resolution at the phylum level to high taxonomic resolution at the species level were identified. As for neurogenesis, studies predominantly used doublecortin (DCX) as a marker of newly formed neurons or bromodeoxyuridine (BrdU) as a marker of proliferation. Brain-derived neurotrophic factor (BDNF) was the only neurotrophin found researched in relation to the intestinal microbiota. Phylum Actinobacteria, genus Bifidobacterium and genus Lactobacillus found the strongest positive while phylum Firmicutes, phylum Bacteroidetes and family Enterobacteriaceae as well as germ-free status, showed the strongest negative correlation towards neurogenesis or BDNF mRNA expression. Age, short-chain fatty acids (SCFA), obesity and chronic stress were recurring topics in all studies identified. Overall, these findings add to the existing evidence of a connection between microbiota and processes in the brain. To better understand this interaction, further investigation based on analyses of higher taxonomic resolution and clinical studies would be a gain to the matter.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) persists throughout the world with over 65 million registered cases of survivors with post-COVID-19 sequelae, also known as LongCOVID-19 (LongC). LongC survivors exhibit various symptoms that span multiple organ systems, including the nervous system. To search for neurological biomarkers of LongC, we investigated the soluble proteins present in the plasma and the proteins associated with plasma neuronal-enriched extracellular vesicles (nEVs) in 33 LongC patients with neurological impairment (nLongC), 12 COVID-19 survivors without any LongC symptoms (Cov), and 28 pre-COVID-19 healthy controls (HC). COVID-19 positive participants were infected from 2020-2022, not hospitalized, and were vaccinated or unvaccinated before infection. IL-1b was significantly increased in both nLongC and Cov and IL-8 elevated in only nLongC. Both brain-derived neurotropic factor and cortisol were significantly elevated in nLongC and Cov compared to HC. nEVs from people with nLongC had significantly elevated protein markers of neuronal dysfunction, including amyloid beta 42, pTau181 and TDP-43. This study shows chronic peripheral inflammation with increased stress after COVID-19 infection. Additionally, differentially expressed nEV neurodegenerative proteins were identified in people recovering from COVID-19 regardless of persistent symptoms.

Neural precursors (NPs) present in the hippocampus can be modulated by several neurogenic stimuli including environmental enrichment (EE) and antidepressant treatment acting through BDNF-TrkB signaling. We have recently identified NPs in meninges, however menigneal niche response to pro-neurogenic stimuli has never been investigated. To this aim, we analyzed the effects of 4 weeks fluoxetine administration or 1 week EE treatment on NP distribution in mouse brain meninges. Following neurogenic stimuli, although we did not detect modification of meningeal cell number and proliferation, we observed, in meninges, an increased number of β3-Tubulin⁺ immature neuronal cells. Lineage-tracing experiment confirmed that EE-induced β3-Tubulin⁺ immature neuronal cells present in meninges originated from GLAST⁺ radial glia cells. To investigate the molecular mechanism responsible for this response, we studied the BDNF-TrkB interaction. Treatment with ANA-12, a TrkB non-competitive inhibitor, abolished the EE-induced increase of β3-Tubulin⁺ immature neuronal cells in meninges.Overall these data showed, for the first time, that the meningeal niche responded to neurogenic stimuli by increasing the immature neuronal population through TrkB-mediated signaling. A better understanding of the neurogenic stimuli effects on NPs in meninges may be useful to improve the effectiveness of depression and mood disorders treatments.

Knee Osteoarthritis (KOA) is a chronic disease characterized by progressive disability and joint pain. Meniscus chondrocytes apoptosis is the main cause of reduced chondrocyte number and self-repair function. The purpose of this study was to investigate the role of miR-27b-3p in KOA.In this study, we found that the expression of miR-27b-3p was downregulated in cultured IL-1β treated chondrocyte and cartilage tissues in KOA. KOA overexpression evidently reduced IL-1β induced chondrocyte apoptosis and caspase-3 and caspase-9 expression.The upregulated iNOS and COX-2 mRNA and proteins expression was also inhibited by miR-27b-3p mimics. The expression of nitric oxide, PGE2, TNF-α and IL-6 was also inhibited by miR-27b-3p mimics. The target gene of miR-27b-3p was confirmed to be BDNF. TrkB/CREB pathway was proved to be the downstream pathway of miR-27b-3p/BDNF axis.The apoptotic cell percentage and nitric oxide, PGE2, TNF-α and IL-6 expression was induced by BDNF+IL-1β. This induction was inhibited by miR-27b-3p mimics. The cartilage tissues stained with safranin O results showed miR-27b-3p greatly decreased KOA induced cartilage degradation. The expression of BDNF、TrkB and p-CREB was inhibited by len-miR-27b-3p. MiR-27b-3p also reduced the expression of TNF-α、IL-6 and Bax, and increased Bcl-2 expression. These results indicated miR-27b-3p could applied to inhibit the development of KOA and miR-27b-3p/BDNF/TrkB/CREB pathway could serve as novel treatment target to handle KOA.

The purpose of this study was to investigate the effect of circuit training on β-amyloid, BDNF, and cognitive function in untrained obese elderly Korean women. The subjects for the study were aged 65–70 years, composed of the circuit training group(n=12) and control group(n=11). The 60-minute combined exercise was performed 3 times per week for 16 weeks. Exercise intensity was progressively increased from 40% HRR to 70% HRR. The test data were analyzed by paired t-test, independent t-test, and two-way repeated measures ANOVA, and the alpha level of .05 was set for all tests of significance. The findings of this study were as follows: β-amyloid significantly decreased after the exercise group had compared to before the exercise and BDNF and cognitive function significantly increased after the exercise group had compared to before the exercise. However, there were no significant changes in β-amyloid, BDNF, and cognitive function in the control group Therefore, it is suggested that the circuit training used in this study could be an effective exercise method for improving the risk factors of cognitive impairment in obese elderly Korean women.

This review article discusses the involvement of the Brain-Derived Neurotrophic Factor (BDNF) in the control of pain. BDNF, a neurotrophin known for its essential role in neuronal survival and plasticity, has garnered significant attention for its potential implications as a modulator of nociception and pain. This comprehensive review aims to provide insights into the multifaceted interactions between BDNF and pain pathways, encompassing both physiological and pathological pain conditions. I delve into the molecular mechanisms underlying BDNF's involvement in pain processing and discuss potential therapeutic applications of BDNF and its mimetics in managing pain. Furthermore, I highlight recent advancements and challenges in translating BDNF-related research into clinical practice.

Partial negative allosteric modulators (NAM) of the mGlu5 receptor are an excellent alternative to full antagonists and NAMs because they retain some therapeutic effects and, at the same time, have a much broader therapeutic window. Here, we investigated whether partial mGlu5 NAM, M-5MPEP induced a fast and sustained antidepressant-like effect, characteristic of rapid-acting antidepressant drugs (RAADs) like ketamine, in C57BL/6J mice. M-5MPEP caused a rapid, dose-dependent antidepressant-like action in the tail suspension test (TST) 60 min after injection. This effect was antagonized by an AMPA receptor antagonist (NBQX) and a TrkB receptor antagonist (ANA-12) but not by 5HT1A and 5HT2A/2C receptor antagonists. Furthermore, M-5MPEP (30 mg/kg) induced sustained antidepressant-like effects 24 h after the last of four administrations. These effects were revealed in the splash test, designed to measure apathy-like state, and in the TST. Western blot and ELISA analyses indicated the involvement of the TrkB/BDNF pathway in the sustained M-5MPEP effects. Additionally, prolonged effects of M-5MPEP were entirely reversed by the TrkB receptor antagonist ANA-12 in both the splash test and the TST, confirming the critical role of TrkB receptor activation in the sustained antidepressant-like effect of M-5MPEP. Importantly, M-5MPEP enhanced the subthreshold dose of (R)-ketamine in the TST, indicating both substances' convergent mechanisms of action and the possibility of their practical use in treating depression.

The study aimed to determine the relationship between glucose, C-peptide, BDNF, and leptin between mother and fetus and neonatal weight. Methods: In the prospective observational cohort study, we included 66 women with T1DM. According to the z-score for neonatal weight, patients were divided into Healthy weight neonates (n=42) and Overweight neonates (n=24). The maternal blood samples were taken during pregnancy and cesarean section when the umbilical vein blood sample was also withdrawn. The maternal vein sera were analyzed for fasting glucose, CRP, leptin, BDNF, TSH, FT3, and FT4. The umbilical vein sera were analyzed for glucose, C-peptide, leptin, TSH, FT3, FT4, and BDNF concentration. The neonatologist measured the skinfold thickness on the third day of neonatal life. Results: A strong correlation was confirmed between maternal and umbilical vein glucose concentration and maternal glucose and C-peptide in umbilical vein blood. A negative correlation was found between the concentration of BDNF in the umbilical vein and glucose in maternal blood. A strong correlation was seen between BMI and maternal blood leptin concentration, neonatal fat body mass, and umbilical vein blood leptin concentration. Increased odds for Overweight neonates were BMI, BDNF, and TSH in the first trimester of pregnancy. Maternal leptin concentration decreased the odds of Overweight neonates. Conclusions: Maternal glucose concentrations affect the fetus’s glucose, C-peptide, and BDNF concentrations. Leptin levels increase in maternal blood due to increased body mass index, and in the neonate, its fat body mass is responsible for increased leptin concentrations.

Brain-derived neurotrophic factor (BDNF) is a key molecule in promoting neurogenesis, dendritic and synaptic health, and neuronal survival, plasticity, and excitability, all of which are disrupted in neurological and cognitive disorders such as Alzheimer’s disease (AD). Extracellular aggregates of amyloid-β (Aβ) in the form of plaques and intracellular aggregates of hyperphosphorylated tau protein have been identified as major pathological insults in AD brain, along with immune dysfunction, oxidative stress, and other toxic stressors. Although aggregated Aβ and tau lead to decreased brain BDNF expression, early losses in BDNF prior to plaque and tangle formation may be due to other insults such as oxidative stress and contribute to early synaptic dysfunction. Physical exercise, on the other hand, protects synaptic and neuronal structure and function, with increased BDNF as a major mediator of exercise-induced enhancements in cognitive function. Here, we review recent literature on mechanisms behind exercise induced BDNF upregulation and its effects on improving learning and memory and on Alzheimer’s disease pathology. Mechanisms include elevations in peripheral BDNF-inducing hormones such as osteocalcin, FNDC5/irisin, and lactate. The fundamental mechanisms of how exercise impacts BDNF and cognition are unclear but are a prerequisite to developing new biomarkers and therapies to delay or prevent cognitive decline.

Non-suicidal self-injurious behavior (NSSI), prevalent in patients with non-psychotic mental disorders (NPMD), is associated with numerous adverse outcomes. Despite active research into the clinical and psychological aspects of NSSI, the underlying biological mechanisms remain obscure. Early adverse experiences are believed to induce long-lasting changes in neuroendocrine mechanisms of stress control playing a key role in NSSI development. The aim of the study was to evaluate parameters potentially predicting development of NSSI in female patients with NPMD. Eighty female patients over 18 years with NPMD and suicidal ideation (40 with and 40 without NSSI) and 48 age matching women without evidence of mental illness (healthy controls) were enrolled. Diagnostic interviews and self-report measures were used to assess childhood maltreatment, presence, frequency, and characteristics of suicidal and self-injurious thoughts and behaviors, the Beck Depression Inventory scale to assess severity of depression. Hypothalamic-pituitary-adrenal axis markers, hormones, and neurotrophic factors were measured in blood serum. The likelihood of developing NSSI in patients with NPMD was associated with early adverse family history and elevated adrenocorticotropic hormone levels. Dysregulation of hypothalamic-pituitary-adrenal axis as a result of early chronic stress experiences may represent critical biological mechanism promoting the development of NSSI behaviors in patients with NPMD.