Brain-derived Neurotrophic Factor Research Articles

Myokine BDNF highly expressed in Type I fibers inhibits the differentiation of myotubes into Type II fibers.

Myofibers are broadly classified as slow-twitch (Type I) and fast-twitch (Type II) fibers. These two types of myofibers coexist within the same skeletal muscle tissue, determining the contractile and metabolic properties of skeletal muscle tissue by fiber type distribution. By examining each fiber type separately, we confirmed that brain-derived neurotrophic factor (BDNF) gene is highly expressed in Type I fibers. When exposed to BDNF, primary myotubes exhibited reduced expression of Myosin Heavy Chain (MyHC) II, a marker protein characteristic of Type II fibers. BDNF overexpression in regenerating muscle tissue led to a decrease in the distribution of Type IIA fibers. We suggest that BDNF highly expressed in Type I fibers downregulates MyHC II expression in myotubes, eventually inhibiting Type IIA fiber generation.

Peripheral molecular and brain structural profile implicated stress activation and hyperoxidation in methamphetamine use disorder.

Methamphetamine use disorders (MUDs) cause widespread disruptions in metabolomic and immunologic processes, highlighting the need for new therapeutic approaches. The purpose of this study was to find molecular and neuroimaging biomarkers for methamphetamine addiction. In this study, we recruited 231 patients with MUD at varying stages of withdrawal and 40 healthy controls to quantify the blood levels of 52 molecules using enzyme-linked immunosorbent assay. The overall molecular disruption caused by methamphetamine was inversely related to withdrawal time (P = 0.0008), with partial recovery observed after 1 year of follow-up (P = 2.20 × 10-5). Molecules related to stress, immune activation, oxidative products, and cardiac injury were significantly elevated in all MUD groups, while antioxidation enzymes were downregulated. Additionally, the blood level of brain-derived neurotrophic factor was significantly correlated with gray matter volumes in nine brain regions (fusiform gyrus, orbitofrontal cortex, temporal pole, caudate, cerebellum crus, and vermis, adjusted P < 0.05) among patients with MUD. These findings suggest that patients with MUD exhibit elevated levels of immune response, stress, and oxidative stress, which are associated with brain structural abnormalities.

Cytokines and Madness: A Unifying Hypothesis of Schizophrenia Involving Interleukin-22

Schizophrenia is a severe neuropsychiatric illness of uncertain etiopathogenesis in which antipsychotic drugs can attenuate the symptoms, but patients rarely return to the premorbid level of functioning. In fact, with each relapse, people living with schizophrenia progress toward disability and cognitive impairment. Moreover, our patients desire to live normal lives, to manage their daily affairs independently, date, get married, and raise and support a family. Those of us who work daily with schizophrenia patients know that these objectives are rarely met despite the novel and allegedly improved dopamine blockers. We hypothesize that poor outcomes in schizophrenia reflect the gray matter volume reduction, which continues despite antipsychotic treatment. We hypothesize further that increased gut barrier permeability, due to dysfunctional aryl hydrocarbon receptor (AhR), downregulates the gut barrier protectors, brain-derived neurotrophic factor (BDNF), and interleukin-22 (IL-22), facilitating microbial translocation into the systemic circulation, eventually reaching the brain. Recombinant human IL-22 could ameliorate the outcome of schizophrenia by limiting bacterial translocation and by initiating tissue repair. This short review examines the signal transducer and transcription-three (STAT3)/AhR axis and downregulation of IL-22 and BDNF with subsequent increase in gut barrier permeability. Based on the hypothesis presented here, we discuss alternative schizophrenia interventions, including AhR antagonists, mitochondrial transplant, membrane lipid replacement, and recombinant human IL-22.

Role of Cardiovascular Risk in Associations of Brain-Derived Neurotrophic Factor with Longitudinal Brain and Cognitive Trajectories in Older Adults

ABSTRACT Background Higher levels of brain-derived neurotrophic factor (BDNF) have been associated with better neurocognitive outcomes. BDNF is present in cardiovascular tissue, and some evidence suggests it may benefit cardiovascular function. The current study assessed whether there is a mediating and/or moderating role of cardiovascular health in the relationship between BDNF and brain and cognitive outcomes. Method We examined longitudinal data from 397 older adults (aged 54–89;164 females, 233 males) enrolled in the Alzheimer’s Disease Neuroimaging Initiative with available plasma BDNF, medical, neuroimaging, and cognitive assessments. We used path analysis and linear regression to estimate the mediating and moderating roles of two measures of cardiovascular health, the Framingham Risk Score (FRS) and pulse pressure, in the relationships between BDNF and longitudinal changes in brain structure (white matter hyperintensity volume, hippocampal volume, and primary visual cortex volume) and cognitive function (executive function, episodic memory, and language). Results There was no significant association of plasma BDNF with FRS or pulse pressure (ps > 0.31), precluding mediation. There were no robust associations between BDNF and longitudinal change in any brain structural or cognitive measures (ps > .12). Higher FRS was significantly associated with greater increases in WMH volume (ps < .01). FRS and pulse pressure were not associated with any other brain structural or cognitive outcomes (ps > .07). Conclusion These results suggest that cardiovascular health may not play an important role in the influence of BDNF on neurocognitive health in older adults.

Environmental Affordance for Physical Activity, Neurosustainability, and Brain Health: Quantifying the Built Environment’s Ability to Sustain BDNF Release by Reaching Metabolic Equivalents (METs)

Background/Objectives: Unlike enriched environments for rodents, human-built environments often hinder neuroplasticity through sedentary lifestyles, to which exercise can merely overcome its adverse effects. This paper introduces "environmental affordance for physical activity" to quantify the potential of spatial layout designs to stimulate activity and sustain neuroplasticity, mainly hippocampal neurogenesis. Methods: A novel framework links metabolic equivalents (METs) that can be afforded by the spatial layout of the built environment to its role in increasing the brain-derived neurotrophic factor (BDNF)—a biomarker that promotes and sustains adult hippocampal neurogenesis and synaptic plasticity. Equations are developed to assess the built environment’s affordance for physical activity through BDNF changes measurable after brief exposure to the built environment for 20–35 min. Results: The developed equations are evidenced to be feasible to cause BDNF release through low- to moderate-intensity physical activity. This model provides a feasible assessment tool to test the built environment’s effectiveness towards neurosustainability. Conclusions: By sustaining neurogenesis, the environmental affordance for physical activity holds promise for improving mental health and preventing cognitive decline.

Expression Profiles of Brain-Derived Neurotrophic Factor Splice Variants in the Hippocampus of Alzheimer's Disease Model Mouse.

Dysregulation of brain-derived neurotrophic factor (BDNF) has been implicated in Alzheimer's disease (AD). In this study, we investigated the temporal dynamics of BDNF expression in the hippocampus of 5xFAD mice, an AD model, focusing on sex and age differences and Bdnf mRNA splice variants. At 3 months of age, female wild-type (WT) mice exhibited significantly higher Bdnf mRNA levels compared to males. However, this difference was abolished in female 5xFAD mice. At 6 months of age, no sex differences in Bdnf mRNA levels were observed in WT mice, and the levels tended to be lower in female 5xFAD mice. Additionally, a significant decrease in the mRNA levels of full-length tropomyosin-related kinase B (TrkB), a BDNF receptor, was found in female 5xFAD mice at 6 months, while mRNA levels of the truncated TrkB were increased in both male and female 5xFAD mice. Specifically, among the Bdnf mRNA splice variants, the levels of Bdnf exon IIA-IX, exon IIB-IX, exon IIC-IX, and exon IXA mRNA were significantly higher in female WT mice compared to male WT mice at 3 months, but this difference was lost in female 5xFAD mice. These findings suggest that the expression of specific Bdnf splice variants would be maintained at higher levels in the hippocampus of young female mice than in males but may be disrupted in AD model mice. Our study may provide insights into the relationship between sex differences in AD onset and BDNF expression.

Deficiency of muscle-generated brain-derived neurotrophic factor causes inflammatory myopathy through reactive oxygen species-mediated necroptosis and pyroptosis

Idiopathic inflammatory myopathy (commonly known as myositis) is a group of immune-related diseases characterized by muscle damage, weakness, and fatigue with unknown causes. Although overactivated innate immunity is a widely believed cause of myositis onset, the mechanism that provokes and maintains a high immune response in myositis patients is still unclear. This study aims to test if brain-derived neurotrophic factor (BDNF) deficiency per se is sufficient to cause myositis and determine its underlying mechanism. We found that ablating BDNF production in skeletal muscle is sufficient to trigger myositis development in mice. Muscle-specific Bdnf knockout (MBKO) mice displayed extensive myocyte necrosis, mononuclear cell infiltration, and myophagocytosis. In association with these damages, elevated production of pro-inflammatory cytokines such as interleukin (IL) 23, IL-1β, IL-18, and tumor necrosis factor α (TNFα) was found in the muscle of MBKO mice. Disruption of sarcolemma integrity was also detected in MBKO mice, which is a result of necroptosis executioner Mixed lineage kinase domain-like protein (MLKL) and pyroptosis executioner Gasdermin D (GSDMD) activation. Mechanistically, diminishing BDNF synthesis in myotubes enhances the accumulation of mitochondrial reactive oxygen species (mtROS), which sensitizes the cells towards TNFα-induced receptor-interacting protein kinase (RIPs) activation and promotes the formation of NLR family pyrin domain containing 3 (NLRP3)-containing inflammasome. BDNF deficiency-induced cell death could be alleviated by scavenging mtROS, suppressing the activity of GSDMD, or inhibiting receptor-interacting kinase 3 (RIP3). Similarly, supplementation of BDNF mimetics, suppression of RIP3 activity, increasing the intramyocellular antioxidant, or enhancing mitophagy ameliorated the myopathies of MBKO mice and improved their muscle strength. Together, our study demonstrates that insufficient BDNF production in mouse muscle causes the development of pathological features of myositis via enhancing oxidative stress, necroptosis, and pyroptosis in myofibers.

Methylation Patterns of Diabetes and Obesity Susceptibility Genes in Gestational Diabetes Mellitus: A Cross-Sectional Analysis from Karachi, Pakistan.

Background: Women with gestational diabetes mellitus (GDM) and their offspring have an increased risk of adverse perinatal and long-term health outcomes, which may be attributable to epigenetic modification of diabetes and obesity susceptibility genes. We aimed to investigate the methylation patterns of eight genes in GDM and normoglycemic (NG) mothers, and their respective offspring. Methods: This cross-sectional study, conducted at Aga Khan University from August 2019 to December 2022, recruited pregnant women in the first trimester of gestation from the outpatient obstetrics clinic. Participants were classified as NG or GDM based on the Society of Obstetricians and Gynecologists Pakistan. Venous blood samples were collected from mothers and cord blood from neonates. Peripheral blood mononuclear cells were used for DNA extraction and methylation analysis using methylation-specific PCR. Maternal and neonatal clinical data were recorded. Statistical analysis was performed using R, including binary logistic regression to assess the association between various gene methylation levels and GDM. Results: The study found that GDM mothers had significantly higher fasting blood glucose, 2-hr OGTT, and serum carboxymethyl lysine (CML) levels compared to NG mothers, but no significant differences in neonatal birth weight or serum CML levels. Chemerin methylation was significantly lower in GDM mothers and their babies, while NAMPT, MTNR1B, FNDC5, FAT4, and FTO methylation levels were higher in GDM offspring compared to NG offspring. GDM mothers also had higher methylation levels of brain-derived neurotrophic factor gene (BDNF). Multivariable binary logistic regression identified methylation levels of maternal BDNF and neonatal MTNR1B to be independently associated with GDM. Conclusions: Our study shows a trend of epigenetic modifications in both GDM mothers and their offspring in various genes related to metabolism and inflammation, suggesting an intergenerational transmission of increased risk of developing metabolic disorders. These findings emphasize the need for high throughput studies, early screening, tight glucose control during pregnancy, and postnatal follow-up to mitigate long-term health risks.

Localized release of muscle-generated BDNF regulates the initial formation of postsynaptic apparatus at neuromuscular synapses.

Growing evidence indicates that brain-derived neurotrophic factor (BDNF) is produced in contracting skeletal muscles and is secreted as a myokine that plays an important role in muscle metabolism. However, the involvement of muscle-generated BDNF and the regulation of its vesicular trafficking, localization, proteolytic processing, and spatially restricted release during the development of vertebrate neuromuscular junctions (NMJs) remain largely unknown. In this study, we first reported that BDNF is spatially associated with the actin-rich core domain of podosome-like structures (PLSs) at topologically complex acetylcholine receptor (AChR) clusters in cultured Xenopus muscle cells. The release of spatially localized BDNF is tightly controlled by activity-regulated mechanisms in a calcium-dependent manner. Live-cell time-lapse imaging further showed that BDNF-containing vesicles are transported to and captured at PLSs in both aneural and synaptic AChR clusters for spatially restricted release. Functionally, BDNF knockdown or furin-mediated endoproteolytic activity inhibition significantly suppresses aneural AChR cluster formation, which in turn affects synaptic AChR clustering induced by nerve innervation or agrin-coated beads. Lastly, skeletal muscle-specific BDNF knockout (MBKO) mice exhibit structural defects in the formation of aneural AChR clusters and their subsequent recruitment to nerve-induced synaptic AChR clusters during the initial stages of NMJ development in vivo. Together, this study demonstrated the regulatory roles of PLSs in the intracellular trafficking, spatial localization, and activity-dependent release of BDNF in muscle cells and revealed the involvement of muscle-generated BDNF and its proteolytic conversion in regulating the initial formation of aneural and synaptic AChR clusters during early NMJ development in vitro and in vivo.

Nerve Growth Factor and Brain-Derived Neurotrophic Factor in COVID-19

Neurotrophins (NTs) constitute a family of small protein messengers that play a fundamental role in both the central and peripheral nervous systems. In particular, the nerve growth factor (NGF) and the brain-derived neurotrophic factor (BDNF) play a subtle role in the survival, differentiation, and functioning of neuronal populations, as well as in the fine regulation of immune functions. The SARS-CoV-2 infection was characterized by a sequela of symptoms (serious respiratory pathology, inflammatory storm, neurological discomfort, up to the less serious flu-like symptoms), which caused, at the end of 2023, more than 7 million deaths worldwide. Despite the official end of the pandemic, the physical and psychological consequences are currently the object of scientific research, both acute and chronic/long-lasting (Long-COVID-19). Given the multifactorial nature of the outcomes of SARS-CoV-2 infection in adults and children, several studies have investigated the potential involvement of the NGF and BDNF systems in the pathology. This narrative review aims to summarize the most recent evidence on this crucial topic.

Peptidomimetic inhibitors targeting TrkB/PSD-95 signaling improves cognition and seizure outcomes in an Angelman Syndrome mouse model.

Angelman syndrome (AS) is a rare genetic neurodevelopmental disorder with profoundly debilitating symptoms with no FDA-approved cure or therapeutic. Brain-derived neurotrophic factor (BDNF), and its receptor tropomyosin receptor kinase B (TrkB), have a well-established role as regulators of synaptic plasticity, dendritic outgrowth and spine formation. Previously, we reported that the association of postsynaptic density protein 95 (PSD-95) with TrkB is critical for intact BDNF signaling in the AS mouse model, as illustrated by attenuated PLCγ and PI3K signaling and intact MAPK pathway signaling. These data suggest that drugs tailored to enhance the TrkB-PSD-95 interaction may provide a novel approach for the treatment of AS and a variety of neurodevelopmental disorders (NDDs). To evaluate this critical interaction, we synthesized a class of high-affinity PSD-95 ligands that bind specifically to the PDZ3 domain of PSD-95, denoted as Syn3 peptidomimetic ligands. We evaluated Syn3 and its analog D-Syn3 (engineered using dextrorotary (D)-amino acids) in vivo using the Ube3a exon 2 deletion mouse model of AS. Following systemic administration of Syn3 and D-Syn3, we demonstrate improvement in the seizure domain of AS. Learning and memory using the novel object recognition assay also illustrated improved cognition following Syn3 and D-Syn3, along with restored long-term potentiation. A pharmacokinetic analysis of D-Syn3 demonstrates that it crosses the blood-brain barrier (BBB), and the brain influx rate is in the range of CNS therapeutics. Finally, D-Syn3 treated mice showed a partial rescue in motor learning. Neither Syn3 nor D-Syn3 improved gross exploratory locomotion deficits, nor gait impairments that have been well documented in the AS rodent models. These findings highlight the need for further investigation of this compound class as a potential therapeutic for AS and other genetic NDDs.

Development of paroxetine loaded nanotransferosomal gel for intranasal delivery with enhanced antidepressant activity in rats

The aim of this study was to develop paroxetine (PXT) loaded nanotransferosomal gel (PXT-NTFG) for intranasal brain delivery. The process involved fabricating PXT-NTFs (paroxetine-loaded nanotransferosomes) through a thin film hydration method and optimizing them based on parameters such as particle size (PS), zeta potential (ZP), polydispersity index (PDI), and entrapment efficiency (EE). The optimized PXT-NTFs exhibited uniform morphology with a PS of 158.30 ± 2.73 nm, low PDI (0.142 ± 0.072), high ZP (21.00 ± 0.75 mV), and excellent EE (88.09 ± 3.40 %). Characterization through various techniques confirmed the incorporation of PXT into the nanotransferosomes and its conversion to amorphous state. Moreover, PXT-NTFG was formulated with suitable viscosity and mucoadhesive properties. In vitro release studies demonstrated sustained drug release from PXT-NTFG at different pH levels as compared to PXT-NTFs and NTF dispersion. Similarly, ex vivo experiments showed 4 folds enhanced drug permeation from PXT-NTFG when compared with PXT conventional gel. Stability studies indicated that the optimized PXT-NTFs remained stable for four months at 4°C and 25°C. Additionally, improved behavioral outcomes, increased neuronal survival rates, and upregulated brain-derived neurotrophic factor (BDNF) expression was observed in lipopolysaccharide (LPS) induced depressed Sprague-Dawley rats after treatment with PXT-NTFG as compared to PXT-dispersion treated and untreated LPS-control groups. Notably, the formulation led to a significant reduction in brain and plasma TNF-α levels. In conclusion, intranasal PXT-NTFG is a promising formulation with sustained drug release, improved brain targeting and enhanced antidepressant activity.

A sexually dimorphic signature of activity-dependent BDNF signaling on the intrinsic excitability of pyramidal neurons in the prefrontal cortex

Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders with strong genetic heterogeneity and more prevalent in males than females. We and others hypothesize that diminished activity-dependent neural signaling is a common molecular pathway dysregulated in ASD caused by diverse genetic mutations. Brain-derived neurotrophic factor (BDNF) is a key growth factor mediating activity-dependent neural signaling in the brain. A common single nucleotide polymorphism (SNP) in the pro-domain of the human BDNF gene that leads to a methionine (Met) substitution for valine (Val) at codon 66 (Val66Met) significantly decreases activity-dependent BDNF release without affecting basal BDNF secretion. By using mice with genetic knock-in of this human BDNF methionine (Met) allele, our previous studies have shown differential severity of autism-like social deficits in male and female BDNF+/Met mice. Pyramidal neurons are the principal neurons in the prefrontal cortex (PFC), a key brain region for social behaviors. Here, we investigated the impact of diminished activity-dependent BDNF signaling on the intrinsic excitability of pyramidal neurons in the PFC. Surprisingly, diminished activity-dependent BDNF signaling significantly increased the intrinsic excitability of pyramidal neurons in male mice, but not in female mice. Notably, significantly decreased thresholds of action potentials were observed in male BDNF+/Met mice, but not in female BDNF+/Met mice. Voltage-clamp recordings revealed that the sodium current densities were significantly increased in the pyramidal neurons of male BDNF+/Met mice, which were mediated by increased transcriptional level of Scn2a encoding sodium channel NaV 1.2. Medium after hyperpolarization (mAHP), another important parameter to determine intrinsic neuronal excitability, is strongly associated with neuronal firing frequency. Further, the amplitudes of mAHP were significantly decreased in male BDNF+/Met mice only, which were mediated by the downregulation of Kcnn2 encoding small conductance calcium-activated potassium channel 2 (SK2). This study reveals a sexually dimorphic signature of diminished activity-dependent BDNF signaling on the intrinsic neuronal excitability of pyramidal neurons in the PFC, which provides possible cellular and molecular mechanisms underpinning the sex differences in idiopathic ASD patients and human autism victims who carry BDNF Val66Met SNP.

The Val66Met variant of brain-derived neurotrophic factor is linked to reduced telomere length in a military population: a pilot study

In military populations, gene-environment interactions can influence performance and health outcomes. Brain-derived neurotrophic factor (BDNF) is a central nervous system protein that is important for neuronal function and synaptic plasticity. A BDNF single nucleotide polymorphism, rs6265, leads to an amino acid substitution of valine (Val) with methionine (Met) at codon 66 (Val66Met), which may influence an individual’s response to occupational stress, and predispose military members to psychological disorders. Telomere length (TL), a novel measure of biological aging, can be used as a biomarker of stress. Accordingly, telomere shortening may be a surrogate indicator of physiological weathering due to chronic disease and stressful life events. To increase our understanding about the potential effect of the Val66Met mutation on the human stress response, we evaluated the relationships between Val66Met, TL, and mental health symptoms in a military population. In this pilot study (N = 164), we observed an association between Val66Met and reduced TL (p = 0.048). There was no relationship between Val66Met and mental health symptoms. These results support the investigation of gene-environment interactions, and their potential influence on TL due to occupational stress such as military service.

Association of NTRK2 gene with suicidality: a meta-analysis.

Previous studies have shown that genes in brain development pathways may have important roles in affecting risk of suicidal behaviors, with our previous meta-analysis supporting a role of the brain-derived neurotrophic factor (BDNF) gene. NTRK2 is a gene that encodes the neurotrophic receptor tyrosine kinase 2, which is a receptor for BDNF. In the current study, we aim to examine the potential association between NTRK2 single nucleotide polymorphism (SNPs) and suicidal ideation/behaviors. We first conducted a literature search using keywords like 'NTRK2', 'TRKB', and 'suicid*' to identify papers on NTRK2 SNPs and suicidal ideation/behaviors. In addition, we have individual-level genotype data for all the identified SNPs in literature search. We used the R meta package to perform meta-analyses on both the genotype count and the allele count data. Moreover, we performed meta-analyses on specific haplotypes within each haplotype block. Following our literature search and meta-analyses on 20 NTRK2 SNPs across up to 8467 samples, we found three SNPs, rs10868235 [N = 5,318, odds ratio (OR) = 1.34, P = 0.02], rs1867283 (N = 5,134, OR = 0.73, P = 0.04), and rs1147198 (N = 5,132, OR = 1.36, P = 0.03) to be nominally associated with suicidal attempts. Those three findings, however, did not survive multiple-testing corrections. Also, none of the haplotype blocks showed significant involvement in suicidality. Our results suggest that the NTRK2 gene may not have a major role in suicidality. Future efforts, however, should explore gene-gene interaction and pathway analyses.

Effects of high intensity interval training on serum brain-derived neurotrophic factor in individuals with PTSD

BackgroundBrain-derived neurotrophic factor (BDNF) is a protein important for synaptic plasticity and formation of memory. It is suggested to play an important role in the development of psychiatric disorders like post-traumatic stress disorder (PTSD). Individuals with PTSD usually show decreased BDNF levels in serum. Physical exercise has shown to be effective in increasing serum BDNF levels. ObjectiveAs the most beneficial form of exercise to raise serum BDNF levels in individuals with PTSD is yet to be determined, we compared two training protocols and their effects on BDNF release. We expected that a training with higher intensity increases BDNF serum levels more than a low intensity training (LIT). Method40 participants (80% female) diagnosed with PTSD were randomized to either high-intensity interval training (HIIT) or a low intensity training group (LIT). They underwent a 12-day training period. We measured serum BDNF levels pre- and post-exercise on first and last intervention day. BDNF was controlled for platelet counts. ResultsIn the HIIT group there was a significant increase in serum BDNF post-exercise on both days measured, respectively when controlled for platelets. The increase was transient. Both groups did not show an increase in serum BDNF over the course of the 12-day training period. ConclusionA single session of HIIT raised serum BDNF levels in individuals with PTSD transiently. Neither HIIT nor LIT raised serum BDNF levels over the course of 12 days.

Rosiridin Protects Against Aluminum Chloride-Induced Memory Impairment via Modulation of BDNF/NFκB/PI3K/Akt Pathway in Rats

Background and Objectives: Rosiridin is a monoterpene with outstanding monoamine inhibitory activity that is useful to treat depressive episodes and rapid-onset dementia. The current investigation aims to evaluate the neurologically protective impact of rosiridin, which opposes aluminum chloride (AlCl3) and causes memory dysfunction in rats. Materials and Methods: Memory impairment was developed in Wistar rats by administering AlCl3 (100 mg/kg p.o.) orally for 42 days and then supplemented with rosiridin at 10 and 20 mg/kg/p.o. Upon completion of the investigation, the behavior factor was performed utilizing the Y-maze, Morris Water Maze, and open field tests. Estimating numerous biological factors, such as nitric oxide (NO), oxidative stress (malondialdehyde MDA), acetylcholinesterase (AChE), butyrylcholinesterase levels (BuChE), antioxidants (glutathione GSH, catalase CAT, and superoxide dismutases SODs) and neurotransmitter (serotonin-5HT, dopamine-DA, acetylcholine-Ach) in the brain. Furthermore, interleukin-6 (IL-6), IL-1β, tumor necrosis factor (TNF-α), brain-derived neurotrophic factor (BNDF), nuclear factor kappa B (NFᴋB), phosphatidylinositol 3-kinase (PI3K), and pAkt were assessed in the diffused brain cells. Results: The rosiridin-treated group significantly improved in terms of behavioral parameters, including in the Y-maze, Morris Water Maze, and open field tests. Further, rosiridin restored biochemical parameters, including NO, oxidative stress AChE, BuChE, antioxidants, neurotransmitters, IL-6, IL-1β, TNF-α, BNDF, NFᴋB, PI3K, and pAkt compared to AlCl3. Conclusions: The current investigation reveals that rosiridin could ameliorate the impairment of memory that AlCl3 causes in rats via improvements in behavioral and restored biochemical parameters.

Genetic variants in BDNF (rs6265 and rs11030119) and stroke susceptibility: a case-control analysis in South India

Background Stroke occurs when the blood supply to part of the cerebral cortex is blocked, depriving it of oxygen and glucose, leading to cell death. It is a multifactorial disorder influenced by genetic, vascular, and environmental factors. Aim This study investigated the association between two polymorphisms of the brain-derived neurotrophic factor (BDNF) gene, rs6265 and rs11030119, and stroke risk in a South Indian population. Subjects and Methods The study included 163 stroke cases and 160 healthy controls. Genomic DNA was extracted, and genotyping of rs6265 and rs11030119 polymorphisms was done using ARMS-PCR. Allelic and genotype frequencies were calculated, and odds ratios (OR) with 95% confidence intervals (CI) were determined using SPSS version 21.0. Results The rs6265 polymorphism was significantly associated with stroke risk, with the GG genotype more frequent in controls (OR 1.79, 95% CI 1.05–1.76, p = 0.01). The rs11030119 polymorphism showed a positive association, with the AA genotype more prevalent in cases (OR 2.70, 95% CI 1.34–5.44, p = 0.003). Conclusion This study suggests an association between BDNF polymorphisms (rs6265, rs11030119) and stroke risk in a South Indian population. Further research in larger populations is necessary to confirm these findings and explore the mechanisms involved.

The role of immunity in comorbid pain and depression

The narrative review aims to shed light on the influence of inflammation in the comorbid chronic pain and major depressive disorder (MDD). This connection is known to be multifactorial, with a dynamic interaction between genetic and epigenetic factors. However, a growing body of evidence has shown that the co-presence of MDD and pain is underlain by immune mechanisms involved in the persistence of the inflammatory process. In particular, the cytokines released following activation of the innate immune system during inflammation cause changes at the endocrine level that result in glucocorticoid resistance, as well as altering the synthesis and metabolism of some central nervous system (CNS) mediators. Cytokines appear to generate neuroinflammation by activating normally protective microglia. Various other mechanisms, including changes in the function of the glutamatergic, GABAergic, and serotonergic systems are also implicated, but inflammation-induced reduction of BDNF (brain-derived neurotrophic factor) appears to be the deciding factor. In turn, neuroinflammation leads to sickness behavior, which is characterized by anhedonia and social withdrawal. This review explored these mechanisms, which may be at the root of comorbid pain and MDD. Although intriguing, however, most available evidence comes from animal studies, and rigorous clinical exploration is warranted.

Computer-aided Drug Discovery of Epigenetic Modulators in Dual-target Therapy of Multifactorial Diseases.

Numerous studies suggest that common genetic and epigenetic factors such as p53, histone deacetylase (HDAC), brain-derived neurotrophic factor (BDNF), the (Ataxia Telangiectasia mutated) ATM gene, cyclin-dependent kinase 5 (CDK5), glycogen synthase kinase 3 (GSK3) and altered expression of microRNA (miRNA) play a crucial role in cancer and neurodegeneration. As there is growing evidence that epigenetic aberrations in cancer and neurological diseases lead to complex pathophysiological changes, the simultaneous targeting of epigenetic and other related pathways by dual-target inhibitors may contribute to the discovery of more effective and personalized therapeutic options. Computer-Aided Drug Design (CADD) provides comprehensive bioinformatic, chemoinformatic, and chemometric approaches for the design of novel chemotypes of epigenetic dual-target inhibitors, enabling efficient discovery of new drug candidates for innovative treatments of these multifactorial diseases. The detailed anticancer mechanisms by which the epigenetic dual-target inhibitors alter metastatic and tumorigenic properties, influence the tumor microenvironment, or regulate the immune response are also presented and discussed in the review. To improve our understanding of the pathogenesis of cancer and neurodegeneration, this review discusses novel therapeutic agents targeting different molecular mechanisms involved in these multifactorial diseases.