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Brain-derived neurotrophic factor (BDNF) is a neurotrophin that has pleiotropic effects on neuronal morphology and synaptic plasticity that underlie hippocampal circuit development and cognition. Recent advances established that BDNF function is controlled and diversified by molecular and cellular mechanisms including trafficking and subcellular compartmentalization of different mRNA species, pre- vs. postsynaptic release of BDNF, control of BDNF signaling by tropomyosin receptor kinase B (TrkB) receptor interactors and conversion of pro-BDNF to mature BDNF and BDNF-propeptide. Defects in these regulatory mechanisms affect dendritic spine formation and morphology of pyramidal neurons as well as synaptic integration of newborn granule cells (GCs) into preexisting circuits of mature hippocampus, compromising the cognitive function. Here, we review recent findings describing novel dynamic mechanisms that diversify and locally control the function of BDNF in hippocampal neurons.

Among neurotrophins, including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4/5), BDNF has been extensively studied for its physiological role in cell survival and synaptic regulation in the central nervous system’s (CNS’s) neurons. BDNF binds to TrkB (a tyrosine kinase) with high affinity, and the resulting downstream intracellular signaling cascades play crucial roles in determining cell fate, including neuronal differentiation and maturation of the CNS neurons. It has been well demonstrated that the downregulation/dysregulation of the BDNF/TrkB system is implicated in the pathogenesis of neurologic and psychiatric disorders, such as Alzheimer’s disease (AD) and depression. Interestingly, the effects of BDNF mimetic compounds including flavonoids, small molecules which can activate TrkB-mediated signaling, have been extensively investigated as potential therapeutic strategies for brain diseases, given that p75NTR, a common neurotrophin receptor, also contributes to cell death under a variety of pathological conditions such as neurodegeneration. Since the downregulation of the BDNF/TrkB system is associated with the pathophysiology of neurodegenerative diseases and psychiatric disorders, understanding how alterations in the BDNF/TrkB system contribute to disease progression could provide valuable insight for the prevention of these brain diseases. The present review shows recent advances in the molecular mechanisms underlying the BDNF/TrkB system in neuronal survival and plasticity, providing critical insights into the potential therapeutic impact of BDNF mimetics in the pathophysiology of brain diseases.

Background: In the learned helplessness (LH) paradigm, approximately 35% of rats are resilient to inescapable stress. Methods: The roles of brain-derived neurotrophic factor (BDNF) and dendritic spine density in the brain regions of LH (susceptible) and non-LH rats (resilient) were examined. Western blot analysis and Golgi staining were performed. Results: BDNF levels in the medial prefrontal cortex, CA3, and dentate gyrus (DG) were significantly lower in the LH group than in the control and non-LH groups, whereas BDNF levels in the nucleus accumbens (NAc) in the LH group but not the non-LH group were significantly higher than those in the control group. Furthermore, spine density in the prelimbic cortex, CA3, and DG was significantly lower in the LH group than in the control and non-LH groups, although spine density in the NAc was significantly higher in the LH group than in the control and non-LH groups. Conclusions: The results suggest that regional differences in BDNF levels and spine density in rat brain may contribute to resilience to inescapable stress.

Depression is a serious mental disorder that affects individuals across diverse demographic and socioeconomic groups. Its pathophysiology is multifactorial and incompletely understood, and currently available pharmacological treatments remain limited in efficacy and scope. This article examines the involvement of the gamma-aminobutyric acid (GABA)ergic system in the pathogenesis of depression and reviews the pharmacological effects, therapeutic efficacy, and recent research developments related to various GABAA receptor modulators in the treatment of depressive disorders, including benzodiazepines, intravenous anesthetics, and neurosteroids. These agents may exert antidepressant and anxiolytic effects through modulation and restoration of GABAergic neurotransmission. In addition, certain agents, such as etomidate and allopregnanolone, have been reported to enhance synaptic plasticity and attenuate neuroinflammatory processes, thereby contributing to the reduction of depressive symptoms through multiple neurobiological mechanisms.Depression is a serious mental disorder that affects individuals across diverse demographic and socioeconomic groups. Its pathophysiology is multifactorial and incompletely understood, and currently available pharmacological treatments remain limited in efficacy and scope. This article examines the involvement of the gamma-aminobutyric acid (GABA)ergic system in the pathogenesis of depression and reviews the pharmacological effects, therapeutic efficacy, and recent research developments related to various GABAA receptor modulators in the treatment of depressive disorders, including benzodiazepines, intravenous anesthetics, and neurosteroids. These agents may exert antidepressant and anxiolytic effects through modulation and restoration of GABAergic neurotransmission. In addition, certain agents, such as etomidate and allopregnanolone, have been reported to enhance synaptic plasticity and attenuate neuroinflammatory processes, thereby contributing to the reduction of depressive symptoms through multiple neurobiological mechanisms.

Chronic pain is sustained, in part, through the intricate process of central sensitization (CS), marked by maladaptive neuroplasticity and neuronal hyperexcitability within central pain pathways. Accumulating evidence suggests that CS is also driven by neuroinflammation in the peripheral and central nervous system. In any chronic disease, the search for perpetuating factors is crucial in identifying therapeutic targets and developing primary preventive strategies. The brain-derived neurotrophic factor (BDNF) emerges as a critical regulator of synaptic plasticity, serving as both a neurotransmitter and neuromodulator. Mounting evidence supports BDNF’s pro-nociceptive role, spanning from its pain-sensitizing capacity across multiple levels of nociceptive pathways to its intricate involvement in CS and neuroinflammation. Moreover, consistently elevated BDNF levels are observed in various chronic pain disorders. To comprehensively understand the profound impact of BDNF in chronic pain, we delve into its key characteristics, focusing on its role in underlying molecular mechanisms contributing to chronic pain. Additionally, we also explore the potential utility of BDNF as an objective biomarker for chronic pain. This discussion encompasses emerging therapeutic approaches aimed at modulating BDNF expression, offering insights into addressing the intricate complexities of chronic pain.

Brain-Derived Neurotrophic Factor (BDNF) and its rs6265 single nucleotide polymorphism (SNP) play an important role in post-stroke recovery. We investigated the correlation between BDNF rs6265 SNP and recovery outcome, measured by the modified Barthel index, in 49 patients with stroke hospitalized in our rehabilitation center at baseline (T0) and after 30 sessions of rehabilitation treatment (T1); moreover, we analyzed the methylation level of the CpG site created or abolished into BDNF rs6265 SNP. In total, 11 patients (22.4%) were heterozygous GA, and 32 (65.3%) and 6 (12.2%) patients were homozygous GG and AA, respectively. The univariate analysis showed a significant relationship between the BDNF rs6265 SNP and the modified Barthel index cut-off (χ2(1, N = 48) = 3.86, p = 0.049), considering patients divided for carrying (A+) or not carrying (A−) the A allele. A higher percentage of A− patients obtained a favorable outcome, as showed by the logistic regression model corrected by age and time since the stroke onset, compared with the A+ patients (OR: 5.59). At baseline (T0), the percentage of BDNF methylation was significantly different between GG (44.6 ± 1.1%), GA (39.5 ± 2.8%) and AA (28.5 ± 1.7%) alleles (p < 0.001). After rehabilitation (T1), only patients A− showed a significant increase in methylation percentages (mean change = 1.3, CI: 0.4–2.2, p = 0.007). This preliminary study deserves more investigation to confirm if BDNF rs6265 SNP and its methylation could be used as a biological marker of recovery in patients with stroke undergoing rehabilitation treatment.

Parkinson's disease (PD) is a neurodegenerative disorder of the brain and is manifested by motor and non‐motor symptoms because of degenerative changes in dopaminergic neurons of the substantia nigra. PD neuropathology is associated with mitochondrial dysfunction, oxidative damage and apoptosis. Thus, the modulation of mitochondrial dysfunction, oxidative damage and apoptosis by growth factors could be a novel boulevard in the management of PD. Brain‐derived neurotrophic factor (BDNF) and its receptor tropomyosin receptor kinase type B (TrkB) are chiefly involved in PD neuropathology. BDNF promotes the survival of dopaminergic neurons in the substantia nigra and enhances the functional activity of striatal neurons. Deficiency of the TrkB receptor triggers degeneration of dopaminergic neurons and accumulation of α‐Syn in the substantia nigra. As well, BDNF/TrkB signalling is reduced in the early phase of PD neuropathology. Targeting of BDNF/TrkB signalling by specific activators may attenuate PD neuropathology. Thus, this review aimed to discuss the potential role of BDNF/TrkB activators against PD. In conclusion, BDNF/TrkB signalling is decreased in PD and linked with disease severity and long‐term complications. Activation of BDNF/TrkB by specific activators may attenuate PD neuropathology.

Background Chronic inflammatory pain (CIP) frequently coincides with depression among patients. The onset and development of pain and depression are associated with altered neural synaptic plasticity. Electroacupuncture (EA) can effectively relieve CIP and depression. However, the underlying mechanisms have not been fully illustrated. Objective To explore whether EA can relieve CIP and depression by regulating hippocampal synaptic plasticity, and the present study offers foundational evidence for the efficacy of EA in treating CIP‐related depression (CIPD). Methods Rats were divided into four groups: 0.9% normal saline group, complete Freund's adjuvant (CFA) group, CFA + duloxetine group, and CFA + EA group. Pain hypersensitivity was detected by mechanical withdrawal threshold and thermal paw withdrawal latency, and the depression level was gauged using the open field test, the sucrose preference test, and the forced swimming test. The morphology of the hippocampal neurons was observed using Nissl staining. The protein expression levels of synuclein (Syn), postsynaptic density protein‐95 (PSD‐95), brain‐derived neurotrophic factors (BDNFs), tyrosine‐protein kinase B (TrKB), p‐TrkB, cAMP response element binding protein (CREB), and p‐CREB were measured by western blotting and immunofluorescence staining. BDNF and TrkB mRNA expression were detected using quantitative real‐time polymerase chain reaction (PCR) (qRT‐PCR). The content of 5‐hydroxytryptamine (5‐HT) and γ‐aminobutyric acid (GABA) was detected using enzyme‐linked immunosorbent assay, and the glutamic acid (Glu) content was determined using the ultraviolet colorimetry method. The hippocampal neuron ultrastructure was observed using transmission electron microscopy. Results EA could alleviate CIP and related depressive behaviors as well as protect the hippocampal neuronal structure from damage and regulate 5‐HT/GABA/Glu levels in the hippocampus. Additionally, EA could significantly increase the expression of synapse‐associated proteins such as PSD‐95 and Syn by activating the BDNF/TrKB/CREB signaling pathway. Conclusion EA improves pain and depressive behaviors in CIPD rats, and the mechanism may be related to synaptic plasticity mediated by the BDNF/TrKB/CREB signaling pathway. CFA injection can induce pain sensitivity and depression‐like behavior in adult male SD rats. Electroacupuncture has demonstrated antidepressant and analgesic properties, which can be attributed to its ability to enhance hippocampal synaptic plasticity by mitigating neuronal damage, modulating neurotransmitters, regulating synaptic proteins, and activating the BDNF/TrkB/CREB signaling pathway.

Major depressive disorder (MDD) is considered a serious public health issue and adversely affects individuals' quality of life. Repetitive transcranial magnetic stimulation (rTMS) is a crucial strategy for treating MDD. This pilot study aims to investigate the relationship between serum IL-33/ST2 and BDNF levels and treatment improvement in MDD patients receiving rTMS therapy. This prospective study enrolled 36 patients diagnosed with MDD (under the DSM-5 diagnostic criteria) between July 2023 and July 2024. All patients underwent standard 10 Hz high-frequency rTMS for the left dorsolateral prefrontal cortex (DLPFC) for 4 weeks (totaling 20 sessions). Fasting venous blood was collected before treatment and at the end of treatment. Serum levels of IL-33, sST2, 5-HT, IL-6, and BDNF were measured using ELISA. Clinical efficacy was assessed using the Hamilton Depression Rating Scale-17 items (HAMD-17), with a reduction rate ≥50% defined as treatment response. Statistical analyses included correlation analysis, intergroup comparisons, and ROC curves, and analyses of pre-to-post-biomarker changes ( ) in relation to both response status and symptom reduction. A total of 36 MDD patients received rTMS treatment for 4 weeks. Among them, 20 patients (55.6%) responded significantly. At baseline, serum IL-33 levels were positively correlated with HAMD-17 scores (r = 0.41, FDR-adjusted 0.02), whereas sST2 levels were negatively correlated (r = -0.68, FDR-adjusted 0.001). After rTMS treatment, those responders exhibited significantly lower serum IL-33 levels (FDR-adjusted 0.007) but higher BDNF levels (FDR-adjusted 0.005) compared to those non-responders. Those responders also had significantly greater increases in BDNF (ΔBDNF, FDR-adjusted 0.0004) and sST2 (ΔsST2, FDR-adjusted 0.021) compared to non-responders. ΔBDNF levels ( = 0.499, FDR-adjusted 0.0049) were positively while ΔIL-33 levels (r = -0.477, FDR-adjusted 0.0054) were negatively correlated with symptom improvement. ROC analysis revealed that baseline 5-HT levels could predict treatment response (AUC = 0.834, 0.001), and post-treatment IL-33 (AUC = 0.916, 0.001) and BDNF (AUC = 0.916, 0.001) levels were significantly associated with rTMS treatment response. Effective rTMS treatment in MDD patients is associated with decreased serum IL-33 levels and increased BDNF levels. The IL-33/ST2 and BDNF pathways may be involved in the antidepressant mechanism of rTMS.

Brain-derived neurotrophic factor (BDNF) is a key mediator of neuroplasticity and responsive to acute physical exercise, providing a link between exercise and brain health. Lactate, a metabolite related to exercise, has been proposed as a potential mediator of the BDNF exercise response; however, lactate’s role in isolation has not yet been determined. To investigate this, 18 young, healthy volunteers (50% female) were recruited to donate blood and muscle before, during, and after a 1-h venous infusion of sodium lactate (125 μmol × kg FFM –1 × min –1 ) or isotonic saline. Muscle and blood samples were collected during 120 min of recovery from the infusion. Samples were analyzed for pro-BDNF and mBDNF using enzyme-linked immunosorbent assay and immunoblotting. The participants reached a peak plasma lactate level of 5.9 ± 0.37 mmol × L –1 in the lactate trial ( p = 0.0002 vs. Pre). Plasma pro-BDNF levels increased 15 min post lactate infusion and stayed elevated throughout the recovery (55%–68%, p < 0.0286 vs. Saline) while plasma and serum levels of mBDNF showed no significant change ( p > 0.05 vs. Saline). Muscle pro-BDNF levels were also unaltered by the lactate infusion ( p > 0.05 vs. Saline); however, the expression of pro-BDNF correlated with the proportion of type I muscle fiber area (fCSA%) of the participants ( n = 18, r = 0.6746, p = 0.0021). Muscle levels of the mBDNF isoform were non-detectable. In conclusion, these results suggest that lactate in isolation affects circulatory pro-BDNF, but not mBDNF levels. This implies that lactate may partly mediate the exercise response of pro-BDNF in humans.