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Ischemic stroke is a leading cause of mortality and disability worldwide, and there is an urgent need for safe dietary agents with neuroprotective potential. Water-soluble tomato concentrate (WSTC), a tomato-derived functional ingredient approved in Europe for cardiovascular health, was evaluated for its protective effects against cerebral ischemia-reperfusion injury. Using a middle cerebral artery occlusion/reperfusion rat model and oxygen-glucose deprivation/reoxygenation neuronal model, we demonstrated that WSTC improved cerebral perfusion, reduced infarct volume, alleviated histopathological damage, and enhanced neurological recovery. Mechanistic studies integrating transcriptomics, network pharmacology, and molecular assays revealed that WSTC inhibited oxidative stress and neuronal apoptosis while activating the ERK/CREB/BDNF signaling pathway. These findings provide the first comprehensive evidence that WSTC confers multi-target neuroprotection and highlight its translational potential as a safe, plant-based functional food ingredient for promoting brain health and reducing ischemic injury. Show less

Brain-derived neurotrophic factor (BDNF) is a key neurotrophin due to its role in neuron process outgrowth, plasticity, and neuronal survival. Aerobic exercise can induce BDNF release and may ultimately maximize post-stroke recovery. This study aimed to determine if a program of moderate-to-high-intensity aerobic exercise increased concentrations of BDNF in subacute stroke survivors compared to usual care. A parallel-group, RCT was undertaken in people with subacute stroke undergoing rehabilitation. Participants were randomly allocated to usual care (control group) or usual care plus an 8-week program of moderate-high intensity treadmill walking (3 x 30 min sessions per week) (experimental group). Serum BDNF was collected by blinded assessors at baseline (Week 0), at the end of the intervention period (Week 8), and at 6 months follow up (Week 26). Sixty-seven participants ( As concentrations of BDNF increased immediately after a program of aerobic exercise, this may present a potential neurobiological mechanism to enhance recovery after stroke. Show less

The accumulation of CAG nucleotide duplicates in the huntingtin (HTT) gene triggers a neurological ailment described as Huntington's disease (HD), which is an irreversible, progressive, and inherited condition and affects both motor and cognitive abilities, resulting in a range of symptoms, including irregular gestures (chorea, dyskinesia), psychological disorders, and advanced dementia. Agomelatine is a novel antidepressant and melatonin analog. It exerts a synergistic pharmacological mechanism, combining stimulation of both MT1/MT2 melatonergic receptors with inhibition of 5-HT2C receptors. It was evaluated for its potential neuroprotective impact against HD triggered by 3-nitropropionic acid (3-NP) in rats. Four groups were established using a total of 40 rats: Group I (CTRL), Group II (AGO), Group III (3-NP), and Group IV (AGO + 3-NP). Deficits in motor function provoked by 3-NP were alleviated by agomelatine, as evidenced by increased ambulation and rearing frequencies, alongside a notable decline in immobility time of the open field assessment, elevated final falloff time of the rotarod assessment, and improved grip strength. Agomelatine also improved synaptic plasticity and neuronal survival by optimizing the expression and activity of the BDNF/TrKB/PI3K/AKT pathway and inhibiting apoptosis, microglial, and astrocytic activation. Furthermore, agomelatine administration reduced the expression of ROCK1, suppressing the release of inflammatory responses. Finally, agomelatine possessed neuroprotective activity, as proved by enhancing motor activity and histopathological abnormalities via improving the BDNF/TrKB/PI3K/AKT survival cascade and suppressing the ROCK1 inflammatory pathway. Show less

4-Methylethcathinone (4-MEC), a synthetic cathinone with psychostimulant properties, is increasingly abused as a "designer drug". However, its molecular mechanisms, particularly those related to neuroplasticity regulation, remain poorly understood. Caveolin-1 (CAV1) is a scaffolding protein of membrane lipid rafts and has been confirmed to organize multiple synaptic signaling proteins to regulate synaptic signaling and neuroplasticity. Herein, we investigated whether CAV1 modulates 4-MEC-induced alterations in the BDNF-TrkB signal pathway and neuroplasticity markers in human SH-SY5Y neuroblastoma cells and a mouse-conditioned place preference (CPP) model. Using qRT-PCR and Western blotting, we demonstrated that 4-MEC significantly upregulated CAV1 mRNA and protein levels, as well as components of the BDNF-TrkB signaling pathway and neuroplasticity markers (GAP43, MAP2, SYP). siRNA-mediated CAV1 knockdown abolished 4-MEC-induced increases in these proteins and neuroplasticity-related mRNAs, whereas CAV1 overexpression potentiated these effects. Additionally, molecular docking predicted potential binding sites between 4-MEC and CAV1. Meanwhile, protein docking also predicted the potential binding sites between CAV1 and TrkB, and co-immunoprecipitation confirmed their physical interactions in SH-SY5Y cells. In the mice exposed to 4-MEC in the CPP paradigm, we observed similar upregulation of CAV1, BDNF-TrkB signaling pathway components, and neuroplasticity markers in the brain. These findings identify CAV1 as a potential critical mediator of 4-MEC's neuroadaptive effects through the BDNF-TrkB signal pathway to regulate neuroplasticity. It suggests a possible novel molecular target for synthetic cathinone toxicity, with potential implications for forensic research. Show less

Disruption of metabolic interactions between astrocytes and neurons, in particular of the lactate shuttle, may contribute to neurodevelopmental and psychiatric disorders such as autism spectrum disorder (ASD) and schizophrenia. The enzyme glycine decarboxylase (GLDC), predominantly expressed in astrocytes, degrades glycine and plays a critical role in regulating NMDA receptor function and cellular metabolism. Here, we investigated whether administration of lactate would reverse schizophrenia-like phenotypes in a mouse model for psychosis with 4 copies of the Gldc gene (4cG mice). Adult male and female 4cG and wildtype mice were subjected to acute L-lactate intraperitoneal administration one hour before behavioral testing and brain collection for biochemical assays. Y-maze spontaneous alternation test, prepulse inhibition of acoustic startle test, and the three-chamber social interaction test were performed for behavioral analysis, and Western blots for protein estimations. In 4cG mice, acute lactate administration one hour before assessment rescued short-term memory deficits, acoustic startle habituation deficits, and normalized deficits in social preference behavior. Furthermore, lactate treatment restored the expression of PGC1α, a master regulator of mitochondrial biogenesis, and brain-derived neurotrophic factor (BDNF), a protein essential for synaptic plasticity. The results suggest a role for astrocytic metabolism in modulating neuronal function, and potential molecular mechanisms underlying the reversal of behavioral phenotypes. The results indicate that exogenous lactate may reverse key pathophysiological and behavioral deficits in a mouse model for schizophrenia and that lactate supplementation may be useful as a therapeutic strategy for schizophrenia and related disorders. Show less

Chemotherapy-induced peripheral neuropathy (CIPN) remains a major unmet challenge in oncology, affecting treatment adherence and patient quality of life. Despite its prevalence, reliable predictive biomarkers and targeted neuroprotective strategies remain elusive. This study integrates clinical data, whole-genome sequencing, and translational research to identify genetic determinants of CIPN susceptibility and validate therapeutic approaches. Through comprehensive analysis of patients with colorectal cancer, including neurophysiological evaluations and CIPN-specific quality-of-life assessments, we identified the Show less

Fragile X Syndrome (FXS) is the most common inherited intellectual disability and a leading monogenic cause of autism spectrum disorder (ASD). As a synaptic disorder, FXS involves the loss of Fragile X messenger ribonucleoprotein 1 (FMRP), leading to abnormal dendrite development and immature dendritic spines. Serotonergic signaling, essential for neuronal development and circuit remodeling, has been implicated in ASD and related conditions, including FXS, raising the possibility that serotonergic modulation could ameliorate neurodevelopmental impairments. This study investigated the therapeutic potential of psilocybin, a serotonergic compound, in the validated Fmr1- Show less

The role of central histamine in diabetes induced behavioral despair is still an enigma. Therefore, the current research explored the plausible impact of the central histaminergic activity on the expression of diabetes-induced behavioral despair in mice using the tail suspension test (TST) and surose preference test (SPT) along with changes in the levels of BDNF and phosphorylated CREB (pCREB) in the whole brain, hippocampus, PFC, and amygdala. Post-streptozotocin (STZ) (200 mg/kg, i.p.) injection, on the 4 Show less

Cognitive impairment in schizophrenia (SCZ) is associated with neuroinflammation and neurotrophic dysregulation. The role of pro-inflammatory interleukins and brain-derived neurotrophic factor (BDNF) in cognitive deficits remains unclear. We aimed to examine the associations between IL-1β, IL-2, IL-6, BDNF, and cognitive function in patients with SCZ with typical or atypical antipsychotics. Participants included 162 healthy controls (mean age = 33.6 ± 2.0 years), 88 patients with SCZ receiving typical antipsychotics (36.4 ± 6.4 years), and 62 receiving atypical antipsychotics (34.0 ± 4.0 years). Cognitive performance was evaluated using a battery of attentional, executive, and visuospatial working memory tasks. Data were analyzed using machine-learning approaches, multivariate statistics, and structural equation modeling. SCZ Patients exhibited marked cognitive impairments alongside lower BDNF concentrations and elevated interleukin levels, with the greatest deviations observed among those receiving typical antipsychotic treatment. Higher medication dosages and longer illness duration were associated with greater cognitive decline and stronger neuroimmune dysregulation. The findings indicate that elevated cytokines and reduced neurotrophic support may contribute to cognitive impairment, whereas persistent cognitive dysfunction can further amplify inflammatory activity. This complexity suggests the need to broaden current assessment approaches and systematically examine biomarkers together with clinical features. Show less

Brain-derived neurotrophic factor (BDNF) plays a role in neuroplasticity, appetite regulation, and reward processing. Its possible involvement in eating disorders (EDs) has been investigated; however, contradictory findings and substantial methodological heterogeneity have prevented definitive conclusions. To systematically evaluate peripheral BDNF levels in individuals with EDs, healthy controls and recovered individuals. A systematic review with meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement (CRD420250654199). Observational studies and randomized controlled trials comparing BDNF levels in individuals with and without EDs were included. The Newcastle-Ottawa Scale and risk-of-bias tool for randomized trials were used. Twenty-one studies were included. BDNF serum levels were significantly lower in acute anorexia (AN) compared with healthy controls (Standardized Mean Difference [SMD] = -0.49;p < 0.001,n = 17), with significance maintained after excluding outliers (SMD = -0.41; p < 0.001,n = 8). No significant difference was found between recovered AN and controls. Bulimia nervosa (BN) individuals showed significantly lower BDNF serum levels (SMD = -0.72;p < 0.001,n = 4). Longitudinal studies showed a significant increase in serum BDNF levels after recovery (SMD = 1.78;p = 0.003,n = 6). These findings support a predominantly state-related association between peripheral BDNF levels and illness stage in AN and BN, rather than a stable condition-specific. Evidence for binge-eating disorders is extremely limited, relying on a single eligible study. Interpretation is constrained by methodological heterogeneity, variability in recovery definitions, and the largely correlational nature of the evidence. Further standardized, high-quality longitudinal studies are needed to clarify whether peripheral BDNF alterations reflect state-related mechanisms, trait vulnerability, or dynamic biological changes across illness stages. Show less

Polycystic ovary syndrome (PCOS), a prevalent endocrine disorder characterized by hyperandrogenism, has been increasingly associated with a high risk of autism spectrum disorder (ASD) in offspring. The emerging interaction between reproductive endocrinology and neurodevelopmental biology suggests that excessive androgen exposure during gestation may perturb neurotrophic signaling and impair neural circuit formation. Brain-derived neurotrophic factor (BDNF) acts through tropomyosin receptor kinase B receptor to activate downstream phosphoinositide 3-kinase/protein kinase B and extracellular signal-regulated kinase/mitogen-activated protein kinase pathways, both of which are fundamental to neuronal survival and synaptogenesis. Disruption of these signaling cascades under hyperandrogenic conditions may lead to altered neuroarchitecture, impaired synaptic connectivity, and ASD-like behavioral phenotypes. Clinical and experimental studies also implicate aberrant BDNF expression in ovarian dysfunction, oocyte maturation deficits, and placental steroidogenic imbalance, highlighting a shared endocrine-neurodevelopmental axis in PCOS. Moreover, androgen excess may induce epigenetic modifications and post translational alterations of BDNF or tropomyosin receptor kinases B receptors, further compromising downstream signaling. These molecular events can dysregulate the transcriptional control of multiple synaptic and neurodevelopmental genes, thereby promoting atypical neuronal circuit formation. Understanding the interaction between BDNF signaling and androgen excess provides a mechanistic framework to explain how maternal endocrine imbalance influences neurodevelopment of offspring. This review integrates multidisciplinary findings spanning clinical cohorts, animal models, and molecular studies to delineate how androgen-BDNF interactions amplified by epigenetic, transcriptional, and post translational dysregulation underpin key neurodevelopmental disruptions observed in ASD. Furthermore, it emphasizes the translational potential of targeting BDNF-related pathways as early biomarkers or therapeutic entry points to mitigate the intergenerational neurodevelopmental consequences of PCOS. Show less

Electroconvulsive therapy (ECT) proves to be an effective intervention in severe cases of major depressive disorder (MDD), especially when there is resistance to pharmacological treatment. The neurotrophic hypothesis proposes that an increase in brain-derived neurotrophic factor (BDNF) is one of the mechanisms responsible for the therapeutic response. The aim of this study is to investigate the effects of ECT on peripheral levels of BDNF, measured in serum and plasma, and analyze clinical outcomes associated with this intervention, as well as identify methodological variables that may influence findings. A systematic review and meta-analysis of studies published between 1995 and 2025 on the PubMed, Scopus and Web of Science databases were conducted, following Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Studies of BDNF in serum (14) and plasma (6) were performed separately. Clinical effectiveness was evaluated according to average standardized differences in depression scores. Meta-regressions in the R software identified the impact of four moderators: type of ECT, number of sessions, type of anesthetic and the time blood sample was taken. ECT was associated with an increase in BDNF levels in both biological matrices, especially in studies with plasma (I Show less

Lumbrokinase belongs to a group of fibrinolytic enzymes, particularly tissue plasminogen activator (tPA), which can facilitate the proteolytic maturation of brain-derived neurotrophic factor (BDNF). Drugs administered via oral or intravenous routes are often metabolized in the liver or kidneys, and these delivery methods for brain-targeted therapies must overcome the natural barriers of the central nervous system (CNS). Intranasal drug delivery via the nose-to-brain route has emerged as a promising approach to bypass these barriers, enhance drug penetration into the brain, and minimize exposure to peripheral organs. In this study, we demonstrate that intranasally administered lumbrokinase successfully reached the brain. Behaviorally, lumbrokinase significantly improved chronic social defeat stress (CSDS)-induced social avoidance and cognitive impairments. At the molecular level, CSDS increased hippocampal precursor BDNF (proBDNF) expression and reduced mature BDNF (mBDNF) compared with control mice. Importantly, lumbrokinase treatment promoted the expression of tPA and plasmin, thereby restoring the proBDNF/mBDNF balance in the hippocampus and reversing stress-induced maladaptive behaviors. Additionally, lumbrokinase increased TrkB, PSD95, and enhanced phosphorylation of PI3K, AKT, and mTOR in the hippocampus, indicating improved synaptic signaling and plasticity. In conclusion, this study demonstrates that intranasal delivery enables lumbrokinase to reach the brain effectively, providing robust therapeutic benefits against CSDS-induced behavioral and cognitive deficits. Enhancing plasmin-mediated BDNF maturation through non-invasive intranasal enzyme delivery may represent a promising approach for treating stress-related mood disorders. Show less

Conflicting results on the association of the Using combinations of various key terms, articles in PubMed, Google Scholar, and Web of Science, written in English were collected until October 31, 2024. Data were extracted independently by two authors and analyzed using Review Manager 5.4. Fifteen studies that are compliant with the HWE, providing a total of 14,184 participants were included in this meta-analysis after applying predefined inclusion/exclusion criteria based on study design, DSM-based diagnosis, and availability of genotype counts. Most pooled models demonstrated low to moderate heterogeneity with significant associations in the recessive model only. In the subgroup analysis, a significant effect was observed in the PD-uncategorized cohort. The Our updated meta-analysis suggests that the Show less

Hypertension is a global target for noncommunicable diseases, and meditation-based interventions (MBIs) benefit patients with hypertension (HTN). The primary objective of this scoping review is to map the globally published MBI studies on patients with HTN. The secondary goal is to identify the role of brain-derived neurotrophic factor (BDNF) in HTN. Based on the Arksey and O'Malley protocol of the Joanna Briggs Institute framework for scoping review, 5 electronic databases were searched with search terms related to HTN and meditation. The open-access articles in the English language published between 1985 and 2024 were selected. The selected articles involved MBIs. All the studies were uploaded to the Rayyan software. Two reviewers worked independently and in duplicate to screen the studies first for title and abstract, and then for full text. Data were extracted based on the template for the intervention description and replication checklist. The data were summarized and reported as a narrative summary. In total, 966 studies were identified. After removing 429 duplicates, 537 studies were screened for their titles and abstracts. 467 studies were excluded based on the inclusion and exclusion criteria, 18 were not retrieved, and 20 were excluded with reasons. Finally, the full texts of 70 studies were read. 32 eligible studies were included in this review. The studies were divided into 3 categories based on meditation and into 7 categories based on outcome. Moreover, no study involving human subjects has analyzed the level of BDNF in HTN patients receiving MBIs. MBIs have shown promising results among HTN patients. There is a research gap in studies related to BDNF and meditation among hypertensive patients. The limitation of the review is the inclusion of open-access articles published only in the English language. Hypertension, Meditation, Mindfulness, Brain-Derived Neurotrophic Factor. Show less

Brain-derived neurotrophic factor (BDNF) is a neurotrophin important for neuronal survival and synaptic plasticity that also plays a role in metabolic regulation (energy homeostasis and appetite control). Lower circulating BDNF levels have been associated with obesity, metabolic risk factors, and poorer cognitive and mental health outcomes, whereas higher levels are linked to more favorable profiles. In this study we sought to systematically evaluate the effects of dietary weight-loss interventions on circulating BDNF levels in adults with overweight or obesity. A comprehensive literature search of PubMed, Web of Science, Scopus, and Google Scholar was conducted from inception through April 2025 to identify clinical trials investigating dietary weight-loss or calorie-restriction interventions in adults with overweight or obesity that reported data regarding circulating BDNF outcomes. Eligible studies were clinical trials with interventions lasting ≥4 weeks to investigate circulating BDNF concentrations before and after dietary interventions that were conducted in adults (≥18 years old) with baseline overweight or obesity. This systematic review was conducted in accordance with Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) 2020 guidelines. Risk of bias was assessed using the Cochrane risk-of-bias tool. Data on study design, participant characteristics, dietary interventions, and BDNF outcomes were extracted and synthesized qualitatively. A summary table of the included studies was generated. Fifteen clinical studies (n = 862 total participants) met inclusion criteria (11 randomized trials and 4 single-arm trials). Diet modalities included continuous calorie restriction (typically 20%-30% caloric deficit), intermittent fasting (eg, alternate-day fasting, time-restricted eating), ketogenic diets (KDs), Mediterranean-type diets, and other weight-loss diets. Duration of interventions ranged from 6 to 26 weeks. Responses to BDNF varied by intervention. In adults with overweight/obesity, weight-loss dietary interventions demonstrated heterogeneous effects on circulating BDNF. We categorized the included studies into 3 groups based on the effects of dietary weight loss on BDNF: increases, no significant change, or decreases. Approximately half of the studies showed no significant effect, while a few interventions showed a decrease. Intermittent fasting regimens and certain dietary patterns (eg, the Mediterranean-DASH [Dietary Approaches to Stop Hypertension] [MIND] diet, and the KD) tend to elevate BDNF levels, whereas continuous calorie restriction often shows no change, and very rapid weight loss may paradoxically reduce BDNF in some cases. These findings suggest that diet-induced weight loss can influence neurotrophic status, potentially modulating brain health. However, results are inconsistent across studies. Overall, interventions involving intermittent calorie restriction, MIND, and/or KD, more frequently reported BDNF increases, whereas continuous calorie restriction produced mixed results. Show less

Experimental autoimmune uveoretinitis (EAU) shows degeneration of retinal neurons, including retinal ganglion cells (RGCs), already in its early phase. Based on our previous study demonstrating the attenuation of EAU by brain-derived neurotrophic factor (BDNF), whose retinal levels were increased by visual stimulation (VS), this study evaluated the effect of VS on BDNF protein expression in brain visual centers, its retrograde transport to the retina, and RGC survival in healthy and EAU mice. 14-day VS increased BDNF expression in the superior colliculus (SC) but not in the lateral geniculate nucleus and primary visual cortex in healthy and EAU mice compared to their unstimulated groups. Furthermore, VS increased numbers of BDNF-positive neurons and astrocytes in the retinorecipient superficial SC (sSC) in healthy and EAU mice, although stimulated EAU mice showed a modest reduction in BDNF-positive neurons compared to stimulated healthy mice. In contrast, unstimulated EAU mice exhibited a marked loss of sSC BDNF-positive neurons and astrocytes compared to unstimulated healthy mice. Additionally, VS promoted retrograde axonal transport of fluorescently labeled BDNF from the sSC to the retina, where it was detected in RGCs, inner retinal neurons, and Müller cells (MCs). These results suggest that VS-induced increases in BDNF expression in the sSC and its retrograde transport to the retina may directly affect multiple types of retinal neurons and MCs, on which BDNF can exert neurotrophic and protective effects. The overall attenuation of EAU histopathology and retinal inflammation, along with improved survival of RGCs in VS-treated EAU mice, is consistent with this suggestion. Show less

The study aimed to investigate whether involvement in a stable romantic partnership is associated with differences in peripheral brain-derived neurotrophic factor (BDNF) levels. In a cross-sectional study, 60 healthy adults (32 women; mean age 27.4 ± 4.1 years) were classified as in a stable relationship ( Participants in a relationship showed higher PLT-BDNF (4.36 ± 1.22 vs 2.85 ± 0.67 ng/mg; t(58) = 5.90, Our results would indicate that a stable romantic partnership is associated with higher intraplatelet and serum BDNF levels. These findings support an association between current committed romantic relationship status and peripheral BDNF measures in healthy adults. Show less

To investigate longitudinal changes in neuroimmune biomarkers during acute exacerbations of chronic obstructive pulmonary disease (AECOPD), their modulation by standard therapy, and prognostic implications for 90-day outcomes. In a prospective cohort, 266 hospitalized AECOPD patients were stratified into worsened ( Compared with controls, AECOPD patients exhibited higher IL-6, TNF-α, PD-1, and MMP-9, alongside reduced BDNF and IL-10. Stable patients demonstrated partial biomarker normalization, whereas worsened patients retained a pro-inflammatory profile. Corticosteroids and antibiotics attenuated cytokine elevations, and oxygen therapy facilitated BDNF recovery. Low BDNF and high MMP-9 predicted spirometric decline, while elevated PD-1 and MMP-9 were associated with increased 90-day readmission risk. A dual-axis model incorporating neurotrophic and immune exhaustion markers outperformed GOLD classification for risk prediction. Neuroimmune biomarkers capture recovery heterogeneity in AECOPD. The proposed dual-axis model improves prognostic accuracy and may inform personalized management strategies. Show less

Species from octopi to humans engage in play. This review examines how epigenetic mechanisms, such as DNA methylation, may regulate play behaviour across taxa. We frame play through historical definitions, categorizing it into object, locomotor, and social forms, and examine how each may be linked to epigenetic shifts, for example in brain-derived neurotrophic factor (BDNF) expression. We then explore the role of domestication in enhancing play via methylation of stress and sociality genes, comparing domesticated chickens, dogs, and foxes to their wild kin. We link the neurobiology of play, spanning the hypothalamic-pituitary-adrenal (HPA) axis and reward circuits, to epigenetic modulation. Assessing the evolutionary fitness advantages of play, we compare adaptive benefits against the surplus resource theory. Despite its presence in many taxa, there remains limited direct evidence for a role of epigenetic mechanisms in play, and we urge research into the developmental and adaptive roles of play across a wider range of species. Show less

Major depressive disorder (MDD) is a prevalent and disabling psychiatric condition in Saudi Arabia, with genetic susceptibility remaining incompletely characterized. Reduced brain-derived neurotrophic factor (BDNF) activity has been implicated in MDD. The Val66Met polymorphism (rs6265), involving the substitution of valine (Val, G allele) with methionine (Met, A allele), impairs activity-dependent BDNF secretion. This study examined the frequency of Val66Met and its association with MDD in a Saudi cohort. A case-control study was conducted, including 87 patients with MDD (44 males, 43 females; mean age 44.2 ± 11.5 years) and 87 healthy controls (39 males, 48 females; mean age 28.7 ± 8.4 years). Genotyping was performed using tetra-primer amplification refractory mutation system-polymerase chain reaction. Unadjusted and age- and sex-adjusted logistic regression analyses were applied under genotype-specific, dominant, recessive, and allelic models. The Val/Val (GG) genotype was more frequent in controls than patients (54.0% vs. 34.5%), whereas the Met/Met (AA) genotype was detected exclusively in patients (21.8% vs. 0%; χ The BDNF Val66Met polymorphism is associated with MDD susceptibility in Saudis. The Met (A) allele, particularly in homozygosity, confers increased risk, while the Val/Val genotype appears protective, supporting population-specific genetic contributions to depression. Show less

A converging mechanistic theme across mental disorders involves impaired neuroplasticity and reduced brain-derived neurotrophic factor (BDNF). Glucagon-like peptide-1 receptor agonists (GLP-1RAs), used for type 2 diabetes and obesity, have shown neuroprotective potential, but whether these effects are mediated by BDNF is unclear. This systematic review synthesised molecular evidence linking GLP-1RA administration to BDNF changes and evaluated their contribution to illness progression in neurodegenerative and psychiatric disorders. A systematic search of PubMed, Ovid and Google Scholar from inception to September 6, 2025, identified studies reporting BDNF-related outcomes following GLP-1RA treatment. Eligible studies included primary in vivo or in vitro research on GLP-1RAs in models of neurodegenerative or psychiatric disorders. Risk of bias was assessed using SYRCLE and QUIN tools. The initial search yielded 300 records, of which 18 met the inclusion criteria. Across these studies, GLP-1RAs consistently enhanced BDNF expression and signalling in models of diabetes, neurodegeneration and neurotoxicity, with diabetic models included for their relevance to GLP-1RA pharmacology and shared neuroinflammatory pathway. Reported increases in BDNF expression ranged from 76 % to 377 %, correlating with improved synaptic plasticity, cognition and neuronal survival. In vitro, GLP-1 and exendin-4 increased BDNF expression and axonal transport even under Aβ oligomer exposure. While most neuroprotection aligned with BDNF upregulation, some effects occurred independently through alternative pathways. GLP-1RAs upregulate BDNF in preclinical models, supporting its role as a key mediator of neuroprotection. Despite some BDNF-independent actions, the consistent restoration of neurotrophic support positions BDNF as a central pathway for disease modification. Show less

Maternal immune activation (MIA) is a key environmental risk factor for neurodevelopmental disorders such as schizophrenia. MicroRNAs are critical regulators of brain development, yet their role in MIA-induced pathology remains unclear. We found that miR-322-5p was significantly upregulated in the prefrontal cortex of MIA-exposed offspring and directly targeted the 3' untranslated region of brain-derived neurotrophic factor (BDNF), inhibiting its expression. This upregulation impaired BDNF/TrkB/AKT signaling and reduced the synaptic protein PSD95, leading to hypoactivity, cognitive deficits, social impairments, and disrupted sensorimotor gating. Inhibition of miR-322-5p or overexpression of BDNF in the prefrontal cortex restored signaling and reversed both behavioral and molecular abnormalities. These results identify miR-322-5p as a key mediator of MIA-induced neuropathology via repression of BDNF signaling and suggest its potential as a therapeutic target in neurodevelopmental disorders. Show less

Brain-derived neurotrophic factor (BDNF) plays an important role in the survival of dopaminergic neurons. Clinical studies have suggested that serum BDNF levels are reduced in patients with Parkinson's disease (PD). However, no study has investigated peripheral BDNF levels and BDNF Val66Met polymorphism in the prodromal stage of PD and their relationship with disease conversion. In total, 120 patients with video-polysomnography confirmed isolated REM sleep behavior disorder (iRBD) and 120 healthy controls (HCs) were enrolled. Genetic analyses were performed, and plasma levels of BDNF were measured. All patients with iRBD underwent comprehensive clinical testing, and 107 iRBD patients were prospectively followed up. Plasma BDNF levels were significantly lower in the iRBD group than in HCs (18,878.85 pg/mL vs. 24,649.85 pg/mL, p = 0.002), but no differences were observed in BDNF Val66Met carrier rates between the two groups. Plasma BDNF levels did not differ significantly between BDNF Val66Met carriers and noncarriers. Notably, higher plasma BDNF levels were associated with an increased risk of short-term disease conversion (hazard ratio = 3.418, 95% CI: 1.520-7.684, p = 0.003), whereas BDNF Val66Met carrier rates showed no such association. Our findings suggest that plasma BDNF is significantly associated with iRBD and may likely serve as a prognostic biomarker for the development of neurodegenerative disease. However, the BDNF Val66Met polymorphism may not be involved in the pathogenesis of iRBD as well as phenoconversion in the studied population. Show less

Bodin et al. (2025) provide valuable insights into neurodevelopmental vulnerability by examining radiofrequency electromagnetic fields (RF‑EMF) exposure during early life. Their integrative design, combining whole-body exposure with endpoints such as neonatal brain proteomics, BDNF expression, synaptogenesis, and oxidative stress, offers a comprehensive framework for developmental neurotoxicology. However, interpretation of proteomic clustering relies heavily on principal component analysis (PCA), a linear technique ill-suited for high-dimensional datasets dominated by non-linear dependencies and strong inter-feature correlations. PCA plots (Figure 3) illustrate group separation, yet variance explained (55%) and clustering stability remain underreported, raising concerns about robustness and biological interpretability, particularly given only ten differentially expressed proteins. To enhance inference, future studies should adopt biologically meaningful feature selection and advanced frameworks such as Feature Agglomeration and Highly Variable Feature Selection, alongside non-parametric correlation measures such as Spearman's rho and Kendall's tau. These strategies will improve reproducibility, uncover mechanistic patterns, and strengthen translational relevance for neurodevelopmental research. Show less

Brain-derived neurotrophic factor (BDNF) is a neurotrophin that, through the activation of its full length receptor, TrkB-FL, plays a pivotal role in neuroprotection, namely against neuronal toxicity mediated by amyloid-β peptide (Aβ). In astrocytes, the increase of calcium (Ca Show less

The strong relationship between Alzheimer's Disease (AD) and diabetes mellitus (DM) is described by the term "type 3 diabetes". Canagliflozin (CAN), a sodium-glucose co-transporter 2 inhibitor (SGLT2i), is an antidiabetic agent under investigation as a potential new treatment for AD due to its acetylcholinesterase (AChE) inhibitory properties. We aimed to examine the effect of CAN on the efficacy of the anti-acetylcholinesterase, rivastigmine (RIV), against aluminum chloride (AlCl Show less