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Siponimod is an approved drug for secondary progressive multiple sclerosis (SPMS), and may exert neuroprotective effects beyond its established immunomodulatory properties. Brain-derived neurotrophic factor (BDNF) is a key molecule supporting neuronal survival and plasticity, and its secretion by immune cells may contribute to neuroregeneration in MS. We studied the impact of long-term siponimod therapy on the secretion of BDNF and other neurotrophic factors by immune cells in MS patients. Twenty patients diagnosed with relapsing-remitting MS (RRMS) or SPMS and receiving siponimod were assessed at baseline, 6 months, and 18 months. Peripheral blood mononuclear cells, CD3 A significant increase in BDNF secretion was observed in PBMCs and T cells after 18 months of siponimod treatment. The other neurotrophins remained below detectable thresholds. Correlation of RRMS vs. SPMS analyses (age, sex, disease duration, baseline Expanded Disability Status Scale, and disease course), and multivariable regression modelling revealed no significant associations between them and treatment-induced changes in BDNF. These findings suggest that prolonged siponimod therapy enhances BDNF secretion by immune cells, demonstrating a heretofore unreported neuroprotective mechanism contributing to siponimod's clinical efficacy in reducing disability progression in MS. Our study found that long-term treatment with siponimod, a drug for multiple sclerosis MS, led to a significant increase in the release of a BDNF by immune cells. This effect was seen after 18 months and was not influenced by patients' age, disease type, or disability level. The findings suggest that siponimod may support neuroprotection and repair in MS through a newly identified mechanism beyond its known immune effects. Show less

The repair mechanisms following sciatic nerve injury involve complex signaling interactions between neurons and microglia. Recent studies have demonstrated that neurons activate microglia by releasing chemokines, glutamate, and neurotrophic factors. In turn, microglia regulate neuronal survival and regeneration via phagocytosis, phenotypic switching, and secretion of growth factors. However, the spatiotemporal diversity of signaling pathways, metabolic regulation of the microenvironment, and barriers to clinical application remain inadequately addressed. This review provides a comprehensive analysis of morphological and functional changes in neuronal cell bodies and of the activation and regulatory mechanisms of microglia after sciatic nerve injury. It highlights the dynamic interaction network encompassing the ATP-P2X7 signaling pathway, the CX3CL1- CX3CR1 pathway, the CCL2-CCR2 chemokine axis, the BDNF-TrkB pathway, and inflammatory mediators, offering novel insights into precision therapeutic strategies targeting neuron-glial interactions. Show less

Prenatal stress may lead to cognitive and behavioral dysfunction in the offspring. Large evidence has shown the deleterious effects of maternal stress on cognitive and behavioral functions of the offspring; however, the effect of paternal stress has not been well documented. In the present study, we aimed to investigate the effect of paternal stress (chronic electrical footshocks, post-traumatic stress disorder or PTSD-like model) on cognitive and behavioral functions, and brain-derived neurotrophic factor (BDNF) hippocampal level in both male and female offspring during adolescence. The father rat (stress-exposed) was exposed to three consecutive shocks in a fear conditioning apparatus for ten times during four weeks, in an uncertain and unpredictable schedule. Saline (0.5 mL) or lithium chloride (50 mg/kg) was intraperitoneally injected to male and female offspring during 21-41 postnatal day (PND). The results showed that paternal stress decreased locomotor activity in female offspring, and increased anxiety-like behavior in both male and female offspring, with more effect on females. Paternal stress also decreased pain subthreshold only in female offspring and impaired passive avoidance and spatial memory in both male and female offspring. Paternal stress also decreased BDNF expression level only in female offspring. However, lithium reversed most of the behavioral dysfunctions in rats' offspring with a history of paternal stress. We concluded that paternal stress significantly impairs cognitive and behavioral function in the offspring during adolescence, with more effect on females. Also, chronic lithium treatment may reverse the deleterious effects of paternal stress. Show less

Studies have reported that the prevalence of aggression is higher in individuals with schizophrenia compared to the general population. Various factors, including genetic variations, contribute to the emergence of aggression in patients with schizophrenia. Among these, the monoamine oxidase A (MAOA) and brain-derived neurotrophic factor (BDNF) genes are considered key genetic factors potentially influencing aggressive behavior in schizophrenia. This study investigated the association of BDNF rs6265 and MAOA rs1465108 polymorphisms with aggression in schizophrenia. A total of 150 patients diagnosed with schizophrenia were included in the study. The MAOA rs1465108 and BDNF rs6265 polymorphisms were analyzed using the Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) method. Aggression was evaluated using the Buss-Perry Aggression Questionnaire. Suicide risk, childhood trauma, and impulsivity which were related to aggression were evaluated using the Suicide Probability Scale, the Childhood Trauma Questionnaire, and the Barratt Impulsiveness Scale, respectively. Negative and positive symptoms of schizophrenia were assessed using the Scale for the Assessment of Negative Symptoms (SANS) and the Scale for the Assessment of Positive Symptoms (SAPS), respectively. No direct genotype associations were observed between aggression and the BDNF rs6265 and MAOA rs1465108 polymorphisms. However, impulsivity, SAPS, and SANS scores were significantly associated with aggression. These findings highlight that aggression in schizophrenia is primarily shaped by environmental and clinical factors rather than by BDNF or MAOA variants. Show less

Local intraspinal or intramuscular administration of brain-derived or glial cell line-derived neurotrophic factors (BDNF, GDNF) is known to protect neural tissue after traumatic spinal cord injury (SCI). In this study, we investigated whether oral supplementation with antioxidant carnosine, a natural dipeptide, could stimulate endogenous production of these neuroprotective molecules within the neural and muscle microenvironment 6 weeks after SCI. We assessed the effects of 6-week carnosine treatment in female Zucker rats, administered either before (CB-I) or after injury (CA-I). The impact of thoracic SCI and carnosine treatment was evaluated in in/active microenvironments of fore limb and hind limb muscles, along with their corresponding innervation regions. To better understand how carnosine treatment affects the neural microenvironment, we analysed mRNA expression levels of neurotrophic factors and their receptors. We also examined molecules that may indicate which cell types are involved in producing or responding to BDNF or GDNF in the spinal cord. Six weeks after thoracic SCI, we observed better locomotor recovery in CA-I compared to CB-I treated rats. In the hind limb, posttraumatic carnosine treatment prevented SCI-induced reductions in BDNF and GDNF protein levels. Additionally, this treatment blocked the SCI-induced reduction of GDNF protein levels and the oligodendrocyte-specific gene Olig2 in the lumbar and cervical spinal cord segments. Interestingly, the postinjury treatment elevated the gene expression in BDNF receptor- and astrocyte-specific genes in the cervical segments. The finding that carnosine may prevent BDNF and GDNF declines in denervated hind limb muscles positions this dipeptide as a promising candidate for inclusion in future combination therapies. Show less

Recent evidence suggests that reduced peripheral levels of brain-derived neurotrophic factor (BDNF) may be involved in the pathophysiology of bipolar disorder (BD), although its relevance in young populations remains uncertain. This systematic review synthesized studies that evaluated serum BDNF levels in children and adolescents with BD, examining its potential as a risk marker. Following PRISMA 2020 guidelines and a protocol registered in PROSPERO, searches were conducted in the Cochrane, MEDLINE, SciELO, and Scopus databases. Studies including participants aged 0-19 years diagnosed with BD according to DSM criteria were included. Studies with mixed samples (adults, children and adolescents) without separate age-group analyses were excluded. After screening and eligibility assessment, seven studies were included. Five of them included a control group, from which a meta-analysis was performed. Moderate methodological heterogeneity was observed and corrected after sensitivity analysis, reinforcing the robustness of the findings, although no statistically significant difference in serum BDNF levels was found between patients with bipolar disorder and controls. Current evidence does not support BDNF as a diagnostic biomarker for pediatric BD. Future studies with greater sample power and methodological standardization are needed to clarify its role in the risk and course of early-onset bipolar disorder. Show less

Major Depressive Disorder (MDD) is a multifactorial psychiatric disease influenced by a combination of genetic and environmental factors. Among the genes linked to MDD, the Melanocortin 1 Receptor (MC1R), Catechol-O-Methyltransferase (COMT), Brain-Derived Neurotrophic Factor (BDNF), and the serotonin transporter (5-HTT) are of particular interest due to their critical roles in stress regulation and neural function. Despite their biological significance, the contribution of specific polymorphisms within these genes to MDD risk remains understudied. This retrospective observational case-control study included 87 Colombian patients diagnosed with MDD according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). The control group comprised Latino/admixed individuals without, sourced from the gnomAD v2.1.1 database. The complete coding region of the MC1R gene and three polymorphisms: 5-HTTLPR Insertion/Deletion 44 bp, BDNF-c.196G>A, and COMT-c.472G>A were genotyped using PCR and Sanger sequencing. The polymorphisms rs885479 and rs4680 were identified as protective factors against MDD, while the polymorphisms rs796296176, rs779504604, rs1805005 were associated with an increased risk of developing MDD (OR:22.87, OR:51.26, OR: 1.97, respectively). Several of the analyzed polymorphisms (rs796296176, rs779504604, rs1805005) increase the risk for MDD. Notably, we provide novel evidence of these polymorphisms in MC1R as a risk to MDD. Show less

Peripheral nerve injuries often lead to significant functional impairment. While autografts remain the gold standard for repairing critical-sized nerve defects, donor site morbidity and limited graft availability have prompted the exploration of alternative strategies. Although studies investigating nerve regeneration using nerve conduits and biological agents are present in the literature, research investigating the effect of neurotrophic factors enriched secretome with biocompatible 3D conduits combination is insufficient. The aim of this study is to evaluate the regenerative potential of 3D biodegradable chitosan-PCL nerve conduit combined with BDNF-enriched secretome in peripheral nerve defects. In this study, biodegradable three-dimensional (3D) nerve conduits composed of polycaprolactone (PCL) and chitosan (75:25 wt/wt) were fabricated and used to bridge 10 mm sciatic nerve defects in rats. The conduits were evaluated alone or in combination with the secretome derived from Wharton's Jelly mesenchymal stem cells (WJ-MSC), either in the native form or enriched with brain-derived neurotrophic factor (BDNF). Thirty-two adult male Wistar Albino rats (mean weight 300-400 g) were randomized into four groups: Autograft (Group 1), conduit only (Group 2), conduit and WJ-MSC derived secretome (Group 3), and conduit combined with BDNF-enriched WJ-MSC derived secretome (Group 4). Functional recovery was assessed using the sciatic functional index (SFI), electromyography (EMG), and gastrocnemius muscle wet weight. Morphological and histological evaluations were performed at 12 weeks postoperatively. At the end of 12 weeks, Group 4 (-49.48 ± 2.82) exhibited significantly improved SFI values compared to Group 2 (-66.62 ± 5.31) and Group 3 (-60.60 ± 5.34) (p < 0.05). Electromyographic analysis revealed higher compound muscle action potential amplitutes in Group 4 (19.72 ± 3.62 mV) than Group 2 and Group 3 (p < 0.05), with values compared to the autograft group. Gasrtrocnemius muscle wet weight ratios were also significantly higher in Group 4 (69.09% ± 9.88%) than in Groups 2 and 3. Histological analyses showed enhanced axonal regeneration, reduced inflammation, and better myelination in Group 4. Scanning electron microscopy confirmed the conduit structural integrity and stability over the 12-week period. The combination of a 3D biodegradable chitosan-PCL conduit with BDNF-enriched WJ-MSC-derived secretome significantly enhanced peripheral nerve regeneration in a rat model. This strategy shows strong potential as an alternative to autografts for treating critical-sized nerve defects. Show less

To identify associations of polymorphic variants of the genes of Two hundred thirty-five patients with AfD and 62 patients with AR and comorbid AlD aged 18 to 65 years were examined. The severity of AfD was assessed using the Structured Interview Guide for the Hamilton Depression Rating Scale, Seasonal Affective Disorder Version (SIGH-SAD) and the Clinical Global Impression (CGI), and the level of anxiety was assessed using the Hamilton Anxiety Rating Scale (HARS) at baseline and on Day 28 of psychopharmacotherapy. Polymorphic variants rs6265, rs7124442, rs11030104, and rs7103411 of the In AfD patients, rs3924999* The polymorphic variants rs3924999 of the Show less

Parkinson's disease (PD) is a progressive neurological disorder characterized by the loss of dopaminergic neurons in the substantia nigra and is associated with neuroinflammation, apoptosis, oxidative stress, and motor impairment. Imipramine, a tricyclic antidepressant, has a wide range of biological effects such as anti-inflammatory, anti-apoptotic, and free radical scavenging activities. The present study was designed to investigate the neuroprotective effect of imipramine in a rat model of PD induced by 6-hydroxydopamine (6-OHDA). Male Wistar rats were treated with daily intraperitoneal administration of imipramine (20 mg/kg, for 14 days) starting 72 h after 6-OHDA injection (20 μg/rat; 4 μl in the right medial forebrain bundle (MFB)). The motor performance was assessed using the rotarod, beam, pole, and apomorphine-induced rotation tests. The protein levels of neurotrophic factors (BDNF, GDNF, and NT3) and factors involved in oxidative stress (MDA, CAT, SOD, GST, and GSH) were measured in the striatum by ELISA technique. The neuronal survival was also evaluated by Nissl staining. Our results showed that 6-OHDA caused motor impairments and neuronal cell death. It also significantly reduced the protein levels of neurotrophic factors and induced an oxidative stress response in the striatum of rats. Whereas, imipramine treatment effectively reduced 6-OHDA-induced motor deficits and neuronal cell death. This improvement was accompanied by an increase in neurotrophic factors, especially GDNF, as well as a reduction in oxidative stress through increased SOD levels. These findings provide direct evidence that imipramine treatment contributes to improve of neuronal cell death and motor deficits, perhaps by increasing the striatal levels of SOD and GDNF, which play a key role in the survival of dopaminergic neurons. Further studies are also needed to elucidate the precise underlying molecular mechanisms of neuroprotective effects of imipramine. Show less

Psilocybin-containing mushrooms, commonly known as magic mushrooms, strongly affect mood, cognition, and behavior. Psilocybe azurescens is a species of psilocybin mushrooms that contains the main active compounds psilocybin and psilocin. Psilocybin mushrooms have been used since ancient times to improve the quality of life. However, their adverse effects have been less studied. This study aimed to investigate, for the first time, the effect of oral consumption of P. azurescens on social behavior, anxiety- and depressive-like behaviors in rats. The underlying mechanisms of these behaviors were also studied. Male Wistar rats received three doses of P. azurescens (10, 100, and 250 mg/kg) by gavage every other day for 14 days. Social interaction, anxiety- and depressive-like behaviors were assessed using the three-chamber, elevated plus maze, and forced swimming tests, respectively. Protein levels of neurotrophic (BDNF and GDNF), neuroinflammatory (IL-6 and TNFα), and oxidative stress (ROS and SOD) factors were measured in the hippocampus, prefrontal cortex (PFC), and amygdala by ELISA technique. The results showed that P. azurescens significantly increased anxiety- and depressive-like behaviors and disrupted social interaction behavior in rats. These effects were accompanied by increased neuroinflammation and oxidative stress and decreased neurotrophic factors in the hippocampus, PFC, and amygdala. This study suggests that the high doses of P. azurescens can cause mood disorders by increasing inflammatory responses and oxidative stress and decreasing the expression of neurotrophic factors. Show less

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with progressive loss of motor neurons. Insufficiency of neurotrophic factors is suspected to underlie the disease, but direct evidence remains scarce. In this study, we discover that brain-derived neurotrophic factor (BDNF) val/met mutation, which results in a decrease in BDNF secretion, reduces survival time of ALS patients in two separate cohorts. Using a knockin mouse model of the ALS causal gene FUS Show less

ObjectivesThis study aimed to compare the effects of different exercise interventions on brain-derived neurotrophic factor (BDNF) levels in patients with neurodegenerative diseases and to explore regulatory factors.MethodsSearched PubMed, Scopus, Web of Science Core Collection, CNKI and Cochrane Library databases up to March 15, 2025. Bayesian network meta-analysis was conducted using R software, and meta-regression analyzed the moderating effects of training period and frequency.Results42 randomized controlled trials covering 1482 patients were included. The Surface Under the Cumulative Ranking (SUCRA) indicated that stretching training (SUCRA = 78.92) and high-intensity interval training (SUCRA = 69.73) were ranked higher than other exercise modalities and exhibited more favorable effect on BDNF enhancement, although neither demonstrated statistically significant superiority over the blank control. In contrast, combined training (SUCRA = 35.58), aerobic training (SUCRA = 35.17), and resistance training (SUCRA = 12.98) showed relatively lower potential for BDNF enhancement (blank control SUCRA = 67.62). Meta-regression analysis showed that the effect of combined training was significantly and positively correlated with intervention period ( Show less