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In the core of a stroke, cell death occurs within minutes. In the penumbra, activity quickly drops, but cells typically remain viable for several hours. Improving neuronal survival in the penumbra is crucial for enhancing recovery in patients with stroke. Earlier work showed that mild activation may improve recovery, but the mechanisms are unclear. Brain-derived neurotrophic factor (BDNF) is well recognized for its neuroprotective functions via activation of tyrosine receptor kinase B (TrkB) receptors, and its release is activity-dependent. This study explored the role of BDNF/TrkB signaling in neuronal survival under hypoxic conditions, using cultures of dissociated cortical rat neurons. When exposed to hypoxia, activity quickly drops and cells become apoptotic after ∼12 h, similar to observations in the ischemic penumbra. Inhibition of the TrkB receptor in healthy, normoxic cultures led to a fivefold increase in apoptosis, confirming the importance of BDNF/TrkB signaling for cell viability in these preparations. The addition of BDNF to hypoxic cultures significantly improved neuronal survival, comparable with the effects of mild activation. These findings suggest that the beneficial effect of mild stimulation to prevent apoptosis in hypoxic cultures is mediated by BDNF/TrkB signaling, offering insights for potential therapeutic strategies aimed at promoting neuronal recovery after a stroke. Show less

To investigate the protective effects of dexmedetomidine on cerebral ischemia-reperfusion injury through the activation of the brain-derived neurotrophic factor (BDNF)/tyrosine kinase receptor B (TrkB) signaling pathway. This study utilized hippocampal neuronal oxygen-glucose deprivation/reoxygenation (OGD/R) models and rat middle cerebral artery occlusion models, with dexmedetomidine intervention. Compared with the sham-operated group, the model group rats exhibited a significant increase in Zea-Longa scores, a marked prolongation of the escape latency, a notable reduction in the number of platform crossings, a significant increase in the percentage of cerebral infarct size, and a marked decrease in the expression of BDNF, TrkB, and Bcl-2 proteins and mRNA (P < 0.05). The dexmedetomidine group showed significantly better outcomes in all above parameters compared to the model group. Compared with the control group, the OGD/R group exhibited a reduction in hippocampal neuronal cell viability, a significant increase in apoptosis rate, elevated expression of Bax and C-caspase-3 proteins, a marked decrease in Bcl-2 protein levels, and a significant reduction in the expression of BDNF and TrkB proteins and mRNA (P < 0.05). Dexmedetomidine exerts significant neuroprotective effects by activating the BDNF/TrkB signaling pathway, thereby alleviating ischemic brain injury. Show less

Neural circuit formation through synaptogenesis plays a crucial role in learning, memory, and the recovery of neural function following brain dysfunction. We previously reported that administering the low-dose cardiac glycoside digoxin, which activates brain Na/K-ATPase, promotes dendritic spine formation and improves motor learning. On the other hand, brain-derived neurotrophic factor (BDNF) is also involved in axon elongation, branching, attraction, and the maturation of dendritic spines. Since trans-2-decenoic acid ethyl ester (DAEE), an ester of medium-chain fatty acid with ten carbons, activates the signaling pathway downstream of BDNF-TrkB, co-administration of digoxin and DAEE could further improve motor learning. This study compared the effects of digoxin, DAEE, or both on motor learning performance and locomotor activity in mice. Digoxin improved early performance in the rotarod test without changing locomotor activity, but did not affect final performance. DAEE increased activity in the open-field test but had no effect on the running wheel and did not influence motor learning in the rotarod test. On the other hand, the combination of digoxin and DAEE improved performance on the rotarod test later in the study. These data indicate that combining digoxin with DAEE delays the peak effects of motor learning compared to digoxin monotherapy, a temporal shift that may offer therapeutic advantages in rehabilitation outcomes. Show less

Brain-derived neurotrophic factor (BDNF) is a growth factor that has a central role in sustaining brain function. Besides the brain, BDNF is also expressed in immune cells. In preclinical models, anthocyanins (AC) consumption has been associated with benefits in BDNF homeostasis. This study investigated in healthy adults if the simultaneous consumption of a high-fat meal (HFM) with a cyanidin/delphinidin-rich extract (CDRE) could affect circulating BDNF, and Show less

Brain-derived neurotrophic factor (BDNF) is a protein crucial to the survival, growth, and differentiation of neurons in the brain and spinal cord. BDNF is monitored across many populations as an indicator of one's cardiometabolic disease (CMD) and mental health (MH) risk. Adults living with a traumatic spinal cord injury (tSCI) are at a higher risk of developing CMD and MH issues, with symptoms often going unrecognized. Establishing serum BDNF as a screening tool within the tSCI population has the potential to improve CMD and MH symptom recognition. This systematic review aims to: (1) explore the tSCI literature to determine whether an association exists between serum BDNF, MH, and CMD risk(s); and; (2) identify best-practice BDNF sampling techniques within the tSCI population. A comprehensive search strategy was developed in collaboration with a University Health Network Librarian. Six databases (MEDLINE, Embase, CENTRAL, APA PsycInfo, CINAHL Ultimate, and Web of Science Core Collection) were searched to identify English-language studies published from inception to July 2025. Studies which reported serum BDNF in the tSCI population in addition to either MH or CMD and have three or more human participants with acute or chronic tSCI were included. Duplicate abstracts were removed and the remaining titles and abstracts reviewed and selected for full-text screening. Study quality was assessed for potential risk of bias using Downs and Black Checklist (Clinical Trials), Newcastle-Ottawa Score (Case-Control Study), or Joanna Briggs Institute Checklist (Cross-sectional Study), prior to data extraction. The serum BDNF analytic methods were reviewed in detail. A total of 2,148 potential studies were identified via the searches, of which 631 duplicates were removed, 1,488 abstracts were excluded for inappropriate population, outcome measure, or study design, and 29 articles were selected for full-text screening, with four studies included in the final review. All studies sampled and analyzed serum BDNF. A total of 271 participants (AIS: A-D, NLI: C1-L5), predominantly male (n = 224), with acute (n = 165) and chronic (n = 51) injuries aged 14-75 as well as healthy controls (n = 55) were included. One study investigated the influence of an intervention and three studies were cross-sectional. No identified study included a description or indication of the prevalence for MH conditions or CMD risk factors. Based on the reviewed literature, links between serum BDNF and MH disorders or CMD risk have not yet been established for individuals with acute or chronic tSCI. The selected studies demonstrated no consistent sampling or analysis methods, with limited adherence to prior established standards in the general population, bringing into question the reliability, validity, and quality of the available outcome data. Show less

Bupivacaine (BUP), a widely used amide-type local anesthetic, exhibits neurotoxic effects. This study aimed to explore the functions of brain-derived neurotrophic factor (BDNF) and methyltransferase Like 3 (METTL3) in BUP-induced hippocampal neuronal damage. HT22 cells and SH-SY5Y cells were treated with various concentrations of BUP. METTL3 and BDNF were manipulated using either overexpression or knockdown approaches to assess their functional roles. Cell viability, apoptosis, mitochondrial membrane potential and oxidative stress markers (Lactate Dehydrogenase (LDH), Reactive Oxygen Species (ROS), Superoxide Dismutase (SOD), Malondialdehyde (MDA)) were evaluated using Cell Counting Kit-8 (CCK-8), flow cytometry, JC-1 staining and commercial kits. The expression of BDNF, METTL3, Caspase-9, Bax and Bcl-2 was analyzed by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blot. The N6-methyladenosine (m6A) modification of BDNF mRNA was assessed using Methylated RNA Immunoprecipitation (Me-RIP) and commercial kits. BUP treatment dose-dependently reduced viability, while increasing oxidative stress and apoptosis in our cellular model. BDNF expression was down-regulated in BUP-induced cells. Additionally, BUP stimulation suppressed both total m6A levels and METTL3 expression in cell models. Overexpression of BDNF ameliorated BUP-induced cell damage. METTL3 stabilized BDNF through m6A modification, and the depletion BDNF reversed the protective effect of overexpressing METTL3 on BUP-induced neurotoxicity. Together, our results indicated that METTL3 attenuated BUP-induced neurotoxicity by enhancing BDNF expression via m6A modification. Show less

Neuroplasticity dysregulation is implicated in the early pathophysiology of schizophrenia. Nogo-A, a myelin- and neuron-associated inhibitor of structural plasticity, has been less studied in first-episode schizophrenia (FES) than brain-derived neurotrophic factor (BDNF). This study examined short-term changes in serum Nogo-A and BDNF in drug-naïve patients with FES. Thirty-nine drug-naïve FES patients and 43 healthy controls (HC) were assessed. Serum Nogo-A and BDNF were measured at baseline in both groups and re-measured in FES after achieving ≥20 % reduction in Positive and Negative Syndrome Scale total score (PANSS). Baseline Nogo-A levels were higher in FES than HC (p = .022) and increased further after treatment (p < .001). Baseline BDNF did not differ between groups (p = .069) and showed no significant change after treatment (p = .094). PANSS total and subscale scores decreased significantly after treatment (all p < .001). Baseline Nogo-A modestly discriminated FES from HC (AUC = 0.648, 95 % CI = 0.53-0.77, sensitivity 66.7 %, specificity 60.5 %). In multivariable analysis, only smoking independently predicted FES (OR = 3.69, 95 % CI = 1.48-9.23, p = .005), whereas Nogo-A was not retained. Serum Nogo-A is elevated at illness onset in FES and increases during early treatment, suggesting that peripheral Nogo-A may be associated with early illness-related and/or treatment-related biological changes. Although Nogo-A does not show sufficient performance as a stand-alone diagnostic biomarker, these findings should be interpreted cautiously given the relatively small sample size and naturalistic treatment design. Nogo-A may warrant further investigation as part of broader multi-marker approaches in early schizophrenia. Show less

Brain-derived neurotrophic factor (BDNF) plays a pivotal role in neuronal development, synaptic plasticity, and cognitive function, and its dysregulation is implicated in various neurodegenerative and neuropsychiatric disorders. To noninvasively monitor dynamic changes in Bdnf expression in vivo, we developed a novel transgenic mouse line, Bdnf-AkaLuc transgenic (Tg) mice, in which the coding region of BDNF was replaced in a BAC transgene with a mutant luciferase, AkaLuc. This luciferase is optimized for the synthetic substrate AkaLumine, which emits near-infrared bioluminescence suitable for deep-tissue imaging. This engineered bioluminescence imaging (BLI) system, termed AkaBLI, enables robust and highly sensitive detection of bioluminescence in the brains of living mice, significantly outperforming our previous Bdnf-Luciferase Tg model. Using this system, we successfully visualized activity-dependent Bdnf mRNA induction in response to pilocarpine-induced status epilepticus. To overcome the limitations of repeated imaging, we identified optimal BLI intervals and established a hairless Bdnf-AkaLuc Tg line, facilitating long-term longitudinal monitoring. Furthermore, by crossing Bdnf-AkaLuc Tg mice with 5xFAD Alzheimer's disease model mice, we successfully visualized reductions in Bdnf expression in the brains of living 5xFAD mice. Our study introduces a powerful tool for noninvasive, continuous visualization of Bdnf regulation under both physiological and disease-related conditions. This imaging approach holds potential for advancing our understanding of BDNF-related brain function and for evaluating therapeutic strategies targeting BDNF in neurological disorders. Show less

Premature ejaculation (PE) accompanied by anxiety or depression is a complex clinical condition at the intersection of male reproductive dysfunction and emotional disorders. Increasing evidence suggests that serotonin (5-HT) and brain-derived neurotrophic factor (BDNF) play central and interrelated roles in its pathogenesis. In this review we examine the bidirectional functions of 5-HT and BDNF in both the reproductive and nervous systems, highlighting their importance in regulating ejaculation, emotional stability, and synaptic plasticity. A comprehensive literature search (2010-2025) was conducted across multiple databases using relevant Medical Subject Headings (MeSH) terms, including pertinent original research and review articles, to synthesize the roles and regulatory pathways of 5-HT and BDNF in PE with comorbid anxiety or depression. We summarize the shared and distinct roles of 5-HT and BDNF in maintaining physiological balance across these systems and focus on their involvement in the major pathological processes underlying PE with anxiety or depression, including neurotransmitter imbalance, neuroendocrine dysregulation, inflammation, and oxidative stress. Furthermore, we outline the related signaling pathways through which 5-HT and BDNF exert their effects and interact. We also evaluate current pharmacological and non-pharmacological interventions targeting these molecules, demonstrating their potential to improve both ejaculatory control and emotional symptoms, and critically appraise selective serotonin reuptake inhibitor (SSRI)-related risks and highlighted the need for individualized dosing and monitoring. Emerging evidence suggests that Traditional Chinese Medicine formulations can extend intravaginal ejaculatory latency and mitigate mood symptoms and may serve as stand-alone or adjunctive options to reduce reliance on selective serotonin reuptake inhibitors (SSRIs). Overall, 5-HT and BDNF are not only deeply involved in the biological mechanisms of PE with comorbid psychological disorders, but also represent promising biomarkers and therapeutic targets, and their integrative neuro-reproductive regulatory functions provide new insights into the diagnosis and treatment of this multifaceted condition. Show less

Researchers have postulated a link between higher levels of brain-derived neurotrophic factor (BDNF) and more favorable outcomes in patients with normal pressure hydrocephalus (NPH). However, there is no clear evidence regarding the causal association between neurotrophins and NPH. To delve deeper into this potential connection, scientists employed a rigorous method known as bidirectional Mendelian randomization (MR). This technique was utilized to explore the causal impact of various neurotrophins-such as BDNF, nerve growth factor (NGF), neurotrophin-3 (NT-3), NT-4, ciliary neurotrophic factor (CNTF), and glial cell line-derived neurotrophic factor (GDNF)-on the development or progression of NPH. To investigate the causal relationship between five neurotrophin subtypes and NPH, we designed a two-sample Mendelian randomization (MR) study using comprehensive genome-wide association study (GWAS) data. Our primary approach involved the inverse-variance weighted (IVW) method. We also conducted reverse causality analysis to ensure robustness. Furthermore, we implemented complementary methods like the weighted median (WM), weighted mode, and MR-Egger to strengthen our findings. Sensitivity analyses, including MR-Egger, MR-PRESSO, leave-one-out, and Cochran's Q tests, were employed to validate results, explore heterogeneity and pleiotropy, and pinpoint potential biases. MR analysis of genetic prediction showed no statistical association of neurotrophins on NPH. However, a reverse analysis indicated a causal association between NPH and two neurotrophins: CNTF and GDNF. Specifically, individuals with NPH had a lower risk of CNTF (odds ratio: 0.7963, with a 95% confidence interval of 0.6537 to 0.9701, p = 0.0237) and a slightly reduced risk of GDNF (odds ratio: 0.9576, with a 95% confidence interval of 0.9226 to 0.9940, p = 0.0230). MR-Egger regression showed that pleiotropy did not affect the analysis. In addition, MR-PRESSO detected no outliers, and a leave-one-out analysis verified the robustness of the results. NPH was negatively and causally associated with CNTF and GDNF. Additional research is crucial to uncover the underlying mechanisms and devise strategies, including nutritional guidelines, to prevent NPH. Show less

Acute physical exercise (PE) is known to influence the expression of many neurobiological markers and cognitive functions, but the time course and domain-specificity of such effects remain under debate. This study investigated whether a single bout of maximal incremental exercise can increase serum brain-derived neurotrophic factor (BDNF) levels, improving cognitive performance in healthy adults. Twenty-eight physically active males underwent a maximal incremental cycling test. BDNF serum concentrations were measured at three timepoints: before exercise, 15 min after, and 24 h post-exercise. Cognitive performance in verbal and visuo-spatial memory and convergent creative thinking was assessed before and 24 h post-exercise. Results showed a significant increase in serum BDNF 24 h after exercise, while no significant change was observed 15 min post-exercise. Cognitive assessments revealed improvements in verbal immediate recall and visuo-spatial working memory, but not in long-term verbal memory, visuo-spatial short-term memory, and convergent creative thinking. No significant correlations emerged between BDNF changes and cognitive performance changes. The dissociation between BDNF and behavior points to complex and likely time-dependent mechanisms underlying exercise-induced cognitive enhancements. These results support the effectiveness of acute PE as stimulus for BDNF neurotrophin production and as a non-pharmacological tool to boost specific cognitive functions, with implications for optimizing learning and cognitive performance in healthy populations. Show less

Huntington's disease (HD) is a progressive neurodegenerative disorder characterized by motor, cognitive, and psychiatric impairments, partly due to disruptions in neurotrophin signaling. Brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and neurotrophin-3 (NT-3) play critical roles in neuronal survival, synaptic plasticity, and neuroprotection, yet their alterations across biofluids and brain regions in HD remain unclear. This study systematically reviewed and meta-analyzed human and rodent studies to quantify neurotrophin changes and explore moderating factors. Comprehensive searches of PubMed, Scopus, Web of Science, Embase, Google Scholar, and clinical trial registries were conducted up to December 2025. Studies reporting measurable BDNF, NGF, or NT-3 levels in HD patients or animal models were included. Data were extracted on neurotrophin type, sample source, subject characteristics, and measurement methods. Standardized mean differences were calculated using random-effects models, and meta-regression was applied to evaluate the effects of species, sex, sampling region, and analytical techniques. The results showed a significant decrease in neurotrophin levels in both peripheral biofluids and central brain regions in HD. The results for moderator analyses showed that species and sex significantly affected the magnitude of changes in ELISA-based studies, whereas molecular methods consistently detected reductions irrespective of these factors. No significant publication bias was identified. These findings highlight significant neurotrophic deficits in HD, highlight the importance of biological and methodological considerations in interpreting neurotrophin data, and suggest that peripheral neurotrophin measurements may serve as accessible biomarkers for disease progression. Show less

Acute hepatitis is a major pathological process underlying acute liver injury (ALI) and acute liver failure (ALF), both of which are associated with high mortality. Yet, no effective treatment is currently available, underscoring the pressing need for novel therapeutic targets. By integrating multiple transcriptomic datasets, this study finds that the expression of brain-derived neurotrophic factor (BDNF) is consistently downregulated in hepatocytes across various ALI/ALF models. Mechanistically, this downregulation is attributed to transcriptional repression of BDNF by RE1-silencing transcription factor. Restoration of endogenous BDNF or exogenous administration of recombinant BDNF significantly alleviates LPS/DGal-induced ALI/ALF. Correlation analysis and proteomic profiling reveal that BDNF exerts potent anti-inflammatory effects by directly binding to and antagonizing Toll-like receptor 4 (TLR4) on macrophages. Structural analysis identifies amino acids 233-244 of BDNF as the key functional domain responsible for this effect. A synthetic 12-mer peptide derived from this region, termed BDP12, retains TLR4-antagonizing ability, demonstrating strong anti-inflammatory efficacy and a favorable safety profile in cultured macrophages and mouse ALI/ALF models. In conclusion, this study identifies hepatocyte-derived BDNF as an endogenous antagonist of TLR4 and a critical immune checkpoint in acute hepatitis. BDNF and its mimetic peptide BDP12 represent promising therapeutic candidates for treating acute hepatitis-mediated ALI/ALF. Show less

Stroke induces severe neurological impairment, however, there is limited understanding of the mechanisms underlying post-stroke recovery. Nuclear factor erythroid 2-related factor 2 (NRF2) and brain-derived neurotrophic factor (BDNF) have been implicated in tissue responses to ischemic injury; however, their temporal interactions in middle cerebral artery occlusion (MCAO) models are not fully understood. Male C57BL/6 mice (7-8 weeks) were subjected to transient MCAO (tMCAO). Motor behavior, cerebral blood flow, and temporal changes in NRF2, heme oxygenase-1 (HO-1), and BDNF expression were assessed over 14 days. Cerebral blood flow in the ischemic cortex remained significantly reduced for up to 14 days after MCAO. Motor deficits were most severe on day 3 and showed gradual recovery by day 7. NRF2 expression peaked on day 3, whereas HO-1 and BDNF expression increased on days 7 and 14, coinciding with improved motor performance and increased neuronal preservation. These findings indicate that activation of the NRF2/HO-1 pathway is temporally associated with increased expression of endogenous BDNF and recovery of motor function following ischemic injury in male mice. Show less

We investigated the association between maternal overactive bladder (OAB) and voiding dysfunction (VD) in their children, and evaluated urinary nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) levels as potential biomarkers for early identification of VD. This prospective cross-sectional study included 196 participants: mothers with OAB (n = 39), their children with VD (n = 36), their children without VD (n = 41), healthy mothers (n = 40), and healthy children of healthy mothers (n = 40). Maternal OAB was diagnosed using the OAB-V8 questionnaire, while VD in children was assessed using the Dysfunctional Voiding Symptom Score (DVSS). Urinary NGF and BDNF levels were measured via ELISA. Receiver operating characteristic (ROC) analyses were performed to assess the diagnostic accuracy of these biomarkers. NGF and BDNF levels were significantly higher in mothers with OAB compared to controls (p < 0.001 for both). Children of OAB mothers with VD demonstrated markedly elevated DVSS scores, NGF, and BDNF levels compared to both healthy children of OAB mothers and children of healthy mothers (all p < 0.001). ROC analysis showed strong diagnostic performance for NGF (AUC = 0.828, cut-off 267.7 pg/ml, 75 % sensitivity, 99 % specificity) and acceptable performance for BDNF (AUC = 0.754, cut-off 3.06 ng/ml, 64 % sensitivity, 93 % specificity). Urinary NGF and BDNF levels were significantly elevated in mothers with OAB and their affected children. NGF demonstrated superior diagnostic accuracy for identifying VD in children, while BDNF may provide complementary value. These findings support the role of neurotrophin-related mechanisms in intergenerational transmission of lower urinary tract dysfunction. Show less

Cognitive flexibility is a core executive function vital for adaptation and adjustment to new information. The brain-derived neurotrophic factor (BDNF) single nucleotide polymorphism, val66met, has been suggested to modulate cognitive flexibility but it remains unclear how confounding variables such as stress and sex influence this relationship. Environmental enrichment (EE) may protect against stress-induced effects. The aim of this study was to test whether BDNF val66met alters reversal learning, a key component of cognitive flexibility, when tested under stressful water maze conditions. We used a Sprague Dawley val66met rat model where pregnant val/met dams were moved to either low or high EE environments. Dams and offspring stayed in these environments until weaning, after which the offspring was moved to standard, moderate enrichment housing. Adult male and female val/val, val/met and met/met offspring then underwent a water maze reversal learning protocol. All groups rapidly learned the new location of the platform. Mediation analysis showed the relationship between val66met and cognitive flexibility was mediated by differential use of spatial strategies. Sequential clustering analysis demonstrated that val66met interacted with sex to predict cognitive flexibility performance with lower flexibility in met/met males and val/met females compared to other genotypes. EE was not a strong promotor of cognitive flexibility. Water maze testing increased corticosterone levels, confirming the stressful nature of the test. This study demonstrates the importance of considering stress and sex when investigating the role of BDNF val66met in cognitive flexibility. Show less

Schizophrenia is a severe mental disorder whose molecular mechanisms remain poorly understood. Investigating brain-derived neurotrophic factor (BDNF)-dependent signaling pathways and their contribution to schizophrenia pathogenesis is a promising research direction in schizophrenia research. BDNF activates multiple intracellular cascades, among which the MAPK/ERK pathway plays a central role. In this study, expression levels of key regulatory proteins of the MAPK/ERK signaling pathway (ERK1/2, STAT3, STAT5, NF-κB, IGF1R, IRS1, IR, TSC2, and CREB1) were examined in lysates of peripheral blood mononuclear cells (PBMCs) from schizophrenia patients using multiplex analysis. The study group included 58 patients diagnosed with schizophrenia (F20); the control group included 60 healthy individuals. The results revealed significantly increased expression of ERK1/2 and STAT3, along with decreased NF-κB levels, in PBMCs from schizophrenia patients compared to controls. Moreover, patients with leading positive symptoms exhibited elevated expression of CREB1 and ERK1/2. These findings suggest that dysregulation of the MAPK/ERK signaling may play a significant role in the pathogenesis schizophrenia. BDNF-dependent signaling pathways may therefore represent promising targets for diagnostics and therapy of this disorder. Show less

Brain-derived neurotrophic factor (BDNF) is a key regulator of neuroplasticity, synaptic integrity and cognitive function and its dysregulation has been implicated across major psychiatric disorders. However, its transdiagnostic association with cognitive performance remains incompletely understood. In this cross-sectional study, 160 participants were examined, including individuals with schizophrenia (SCZ), bipolar disorder (BD), major depressive disorder (MDD) and healthy controls (HC) (n = 40 per group). Serum BDNF concentrations were measured using enzyme-linked immunosorbent assay (ELISA). Cognitive performance was assessed using the Montreal Cognitive Assessment (MoCA), Trail Making Tests (TMT-A/B) and Digit Span (Forward/Backward). Significant group differences were observed for both serum BDNF levels and cognitive performance. Serum BDNF concentrations were lowest in SCZ (18.2 ± 4.6 ng/mL) and MDD (19.5 ± 5.1 ng/mL), intermediate in BD (23.7 ± 5.9 ng/mL) and highest in HC (26.3 ± 6.2 ng/mL) (F(3156) = 15.47, p < 0.001). Cognitive impairment followed a parallel gradient, with SCZ exhibiting the most severe deficits (p < 0.001). Across the full cohort, serum BDNF showed moderate positive associations with global cognition (MoCA: r = 0.42, p < 0.001) and working memory (Digit Span Backward: r = 0.38, p < 0.001) and a negative association with executive dysfunction as indexed by TMT-B completion time (r = -0.46, p < 0.001). These findings indicate that serum BDNF is modestly but consistently associated with cognitive performance across major psychiatric disorders, supporting its role as a transdiagnostic neurobiological correlate of impaired neuroplasticity rather than a disorder-specific or deterministic biomarker. Show less

The formulation of therapeutic proteins such as Brain-Derived Neurotrophic Factor (BDNF) remains difficult because of their inherent instability and limited bioavailability, especially in central nervous system delivery. In this study, we propose an integrated computational-experimental workflow for the rational selection of excipients to optimize BDNF-loaded cubosomal formulations. Structure-based computational analyses-including SiteMap evaluation, molecular docking, and molecular dynamics (MD) simulations-were used to characterize potential binding sites, and assess the molecular compatibility of lipids, stabilizers, and hydrotropes with BDNF. Among the screened excipients, phytantriol showed the most favorable polar and hydrophobic interactions with the protein, while Tween 80 and PEG 200 were identified as the preferred stabilizer and hydrotrope, respectively. The MD trajectories revealed that protein-excipient contacts were transient yet overall stabilizing, helping the protein maintain its conformational integrity under simulated conditions. Experimental confirmation using Attenuated Total Reflectance-Fourier Transform Infrared (ATR-FTIR) spectroscopy supported these observations by demonstrating that BDNF's secondary structure was preserved in the presence of the selected excipients. This study provides molecular-level insight into excipient-protein interactions and demonstrates a predictive strategy for guiding the design of stable neurotrophin formulations. Show less

Brain-derived neurotrophic factor (BDNF) plays a critical role in neuronal development and synaptic plasticity across various maturation stages. However, the extent to which BDNF modulates the neuronal transcriptome to mediate these effects, and the gene clusters most responsive at each culture stage, remain poorly understood. To address this, we investigated the time-dependent effects of BDNF on the transcriptomes of cultured cortical neurons at different culture durations. We found that the magnitude of the transcriptomic response to a 6-h BDNF treatment, relative to untreated controls, increased with longer culture duration. Furthermore, a BDNF-induced shift towards a more mature-like transcriptional state was observed specifically in neurons cultured for shorter durations, suggesting a response dependent on the length of time in culture. Specifically, matrix metalloproteinase 3 (MMP3) was robustly induced by BDNF. Single-nucleus RNA sequencing (snRNA-seq) revealed that this induction was primarily localized to Lhx6-positive inhibitory neurons. Additionally, BDNF regulated the expression of various ligand and receptor genes through a combination of cell type-specific and non-specific mechanisms. These findings provide a comprehensive view of BDNF-mediated transcriptional regulation over the course of cortical neuron culture. Show less

A single nucleotide polymorphism in the brain derived neurotrophic factor (BDNF)-encoding gene leads to diminished BDNF signaling resulting from Val66Met and has been linked to obesity. Previous imaging studies regarding the impact of BDNF Val66Met on the central serotonin system, which is involved in behavior, cognition and control of satiety, have not focused on body weight or food-intake related behavior. We revisited a cohort of thirty non-depressed individuals with obesity and 15 normal-weight controls. 29 obese and 13 controls underwent [ Show less

To compare the effects of Mexidol, Cerebrolysin, and Cortexin on the levels of brain-derived neurotrophic factor (BDNF), tumor necrosis factor-alpha (TNF The study was performed on male Wistar rats. Right MCA occlusion-reperfusion was modeled using the method of J. Koizumi (1986). The occlusion duration was 60 minutes (1 hour). At the onset of reperfusion, animals were administered a single intravenous injection of either saline (control), or Mexidol (ethylmethylhydroxypyridine succinate) intravenously at a dose of 50 mg/kg, or Cerebrolysin intraperitoneally at a dose of 215 mg/kg, or Cortexin intraperitoneally at a dose of 1 mg/kg. Twenty-four hours after the start of reperfusion, the brain lesion volume was analyzed after staining with a 1% solution of 2.3,5-triphenyltetrazolium chloride. Western blotting was used to assess the levels of BDNF, TNF In the MCA occlusion-reperfusion model, the necrosis volume in the affected hemisphere of control animals was 38.16±5.98%. Mexidol reduced the necrosis volume to 20.48±2.33% ( Thus, when administered at the onset of reperfusion following MCA occlusion, Mexidol exerts the most pronounced cerebroprotective effect, stimulating neurogenesis and suppressing the development of neuroinflammation and apoptosis. Show less

We examined whether seven consecutive days of warm-water immersion could elevate resting and exercise-induced levels of brain-derived neurotrophic factor (BDNF), irisin and klotho in older adults. These biomarkers support cognitive and metabolic health, but their levels decline with age. Passive heat exposure, like warm-water immersion, may offer a promising alternative to exercise for enhancing cellular-level physiological resilience in populations where exercise is limited. Twelve habitually active older men (median [IQR] age: 68 [64-73] years; Show less

Age-related Macular Degeneration (AMD) is a leading cause of vision loss. There is no cure for AMD. Current treatments focus on preventing disease progression and preserving vision. In recent years, the role of brain-derived neurotrophic factor (BDNF) in AMD has attracted increasing attention. BDNF is widely involved in the physiology and pathophysiology of the retina. These include the development of photoreceptors during early development and synaptic communication between photoreceptors and retinal neurons. Under pathological conditions, BDNF affects the functions of multiple cell types in the retina including photoreceptors, ganglion cells, Müller cells, microglia cells, amacrine cells, and the retinal pigment epithelium (RPE). Importantly, BDNF does not act alone. Its function relates with other neurotrophic factors such as basic fibroblast growth factor (bFGF), ciliary neurotrophic factor (CNTF), and glial cell derived neurotrophic factor (GDNF). Meanwhile, the dynamic interaction between BDNF, its precursor protein proBDNF and the BDNF receptor TrkB not only affects the survival of retinal cells in AMD but may also guide the treatment strategy. Various approaches have been taken to deliver BDNF in animal models for managing AMD. Despite the exciting progress, challenges remain in implementing BDNF therapy as an effective treatment. In this review, we summarize the current research progress of BDNF in AMD and highlight the issues that need to be addressed before translation into clinical practice. 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

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

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