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This study investigated the neuroprotective effects and mechanisms of cycloastragenol (CAG) on oxidative stress and neurological function in cerebral ischemia-reperfusion injury (CIRI) and oxygen-glucose deprivation/reoxygenation (OGD/R) models. In vivo, rats were given oral CAG daily for 28 days before CIRI induction. Cerebral infarction and hippocampal injury were assessed using TTC, Nissl, and HE staining. Neurological scores, morris water maze, grip strength tests, and brain water content were used to evaluate functional outcomes. Oxidative stress was determined by biochemical assays, DHE staining, and transmission electron microscopy, while Western blotting was performed to measure neuroprotective proteins. In vitro, primary neurons were treated with CAG and subjected to OGD/R. Cell viability was tested by CCK-8 assay, apoptosis and mitochondrial membrane potential were analyzed by flow cytometry, ROS levels were quantified, and MDA, SOD, and GSH were measured biochemically. Western blot further evaluated BDNF and NeuN expression to confirm in vivo findings. In vivo, CAG reduced infarct volume and edema, improved neurological deficits, preserved the structural integrity of neurons in the hippocampal CA1 region. CAG also promoted motor function recovery, markedly reduced MDA levels, increased SOD and GSH activity, and upregulated BDNF and NeuN expression. In vitro, CAG enhanced cell viability in the OGD/R model, reduced apoptosis, restored mitochondrial membrane potential, and significantly suppressed oxidative stress induced by ischemia-reperfusion. CAG effectively alleviated injury caused by cerebral and cellular ischemia-reperfusion by maintaining redox homeostasis, inhibiting oxidative stress, and promoting the expression of neuroprotective proteins, demonstrating promising neuroprotective potential. Show less

Neuro-related disorders will be rising globally. Current treatments have numerous limitations that can impair patients' quality of life. One of the key therapeutic approaches is promoting neuroplasticity. Neuroplasticity plays a vital role in memory, learning, and recovery of function after neural damage. Acetaminophen (Paracetamol; APAP) has been suggested as a neuroprotective treatment through modulation of neuroplasticity dose-duration dependently. This systematic review was conducted across major databases such as PubMed/MEDLINE, Google Scholar, Scopus, and Web of Science, between 2002 and October 2025, and from an initial pool of 537 articles, we selected only English-language studies with complete methodology and full results reporting the effects of acetaminophen on neuroplasticity. Preclinical evidence suggests that short-term, low-dose acetaminophen can have neuroprotective effects. Acetaminophen is metabolized in the brain to AM404, which activates TRPV1, inhibit COX-1/COX-2, and modulates the endocannabinoid system, reducing inflammation and oxidative stress. They also engage BDNF neurotrophic signalling, creating a mechanistic basis for potential neuroplasticity modulation. While low-dose, short-term acetaminophen shows neuroprotective effects in preclinical models, long-term or high-dose use may lead to neurotoxicity. Although preclinical evidence suggests that acetaminophen may influence neuroplasticity in a dose- and time-dependent manner, substantial heterogeneity in dosing protocols limits definitive conclusions. Therefore, further standardized preclinical and clinical studies with larger sample sizes and longer follow-up are required to define safe and effective exposure windows in humans. 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

Electrical stimulation (ES) is emerging as a non-pharmacological neuromodulation strategy, but its direct impact on human dopaminergic neurons and its relationship to rapid-acting antidepressant mechanisms remain unclear. This study aimed to investigate whether brief biphasic low-frequency low-intensity (LF-LI) ES can induce structural and molecular plasticity in human induced pluripotent stem cell (iPSC)-derived mesencephalic dopaminergic neurons, identify the underlying signaling mechanisms, and evaluate its potential to rescue cortisol-induced impairments as in-vitro endocrine model of depression. iPSC-derived dopaminergic neurons were exposed to LF-LI ES using a custom culture-compatible stimulator, and structural plasticity was quantified three days later by computer-assisted morphometry. Pharmacological blockers, quantitative PCR and Western blot analyses were employed to assess calcium influx, brain-derived neurotrophic factor (BDNF)-TrkB-extracellular signal-regulated kinase (ERK)-mTOR signaling, and dopamine D3 auto-receptor roles in mediating LF-LI ES effects. A single 1h LF-LI ES session at 4 mA induced robust increases in maximal dendrite length, primary dendrite number, and soma area, comparable to 1 μM ketamine. LF-LI ES rapidly enhanced ERK and p70-S6K phosphorylation and required L-type voltage-gated calcium channels, TrkB and mTOR, as their inhibition prevented structural remodeling. LF-LI ES increased dopamine D3 auto-receptors mRNA, and its antagonism attenuated LF-LI ES-induced plasticity. In cortisol-treated neurons, LF-LI ES fully reversed dendritic hypotrophy and soma shrinkage. In conclusion, brief LF-LI ES elicits long-lasting, ketamine-like structural and molecular plasticity in human dopaminergic neurons and rescues stress hormone-induced impairments, supporting LF-LI ES-based neuromodulation approaches targeting dopaminergic circuits in major depressive disorder and treatment-resistant depression. Show less

To compare two 16-week high-load, velocity-intentional resistance training programs-elastic bands (HL-VIRT-EB) vs. water-based (HL-VIRT-AQ)-combined with creatine or placebo supplementation on neuroplasticity, oxidative stress, inflammation, strength, physical function, cognition, and quality of life in older adults. In a randomized controlled trial, 103 community-dwelling older adults (57 women, 46 men; 68.2 ± 4.6 y) were assigned to HL-VIRT-EB + Creatine, HL-VIRT-EB + Placebo, HL-VIRT-AQ + Creatine, HL-VIRT-AQ + Placebo, Control+Creatine, or Control+Placebo. Training was performed 3×/week (60 min). Creatine was consumed daily (3 g). Outcomes included brain-derived neurotrophic factor, F2-isoprostanes (F2-iso), glutathione peroxidase (GPx), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), isokinetic strength (knee/elbow, 60°·s Both training modalities produced significant improvements in neurocognitive biomarkers, oxidative/inflammatory profiles, strength, functional performance and quality of life (p < 0.05). HL-VIRT-AQ yielded greater reductions in F2-iso and TNF-α and larger gains in functional tests compared to HL-VIRT-EB (d = 0.12-1.18), which elicited superior upper-limb strength gains. Creatine provided additional benefits, increasing GPx, reducing IL-6/TNF-α and improving strength and function when combined with exercise modalities. Creatine alone reduced F2-iso and TNF-α and improved perceived health versus placebo. High-load, velocity-intentional resistance training-on land or in water-effectively improves neurocognition, oxidative balance, inflammation, strength, function, and quality of life in older adults. Aquatic training is particularly effective for attenuating oxidative stress and inflammation. Creatine supplementation confers complementary, modality-specific benefits and supports their use in combination to high-speed resistance exercise to promote healthy aging. NCT06620666 (ClinicalTrials.gov). Show less

The progressive neurodegenerative disease known as Parkinson's Disease (PD) is represented by deficits in both motor and non-motor functions. Levodopa and dopamine agonists are examples of pharmaceutical treatments that mainly reduce symptoms without having any discernible neuroprotective effects. The potential of exercise-based physical therapy to improve neuroplasticity and slow disease progression has drawn increasing attention. To provide awareness of their complementary roles in enhancing outcomes for people with PD, this narrative review examines the combined neuroprotective effects of pharmaceutical medicines and physical therapy. The aim of the review was to evaluate the effects of both physical and pharmaceutical therapies in the management of Parkinson's disease to enhance motor recovery and retard disease progression. The evidence from previous research is compiled in this review, which focuses on preclinical and clinical trials examining the neuroprotective benefits of medication and exercise-based physical therapy. We searched databases such as PubMed, Scopus, Embase, the Cochrane Library, and Web of Science to identify relevant peer-reviewed articles. The review discusses therapeutic synergies, underlying mechanisms, and how these affect clinical practice. Aerobic, resistance, and balance training are examples of exercise-based physiotherapy that reduce oxidative stress, increase brain-derived neurotrophic factor (BDNF) levels, and promote neuroplasticity. These effects enhance the ability of pharmacological drugs to relieve symptoms. Research indicates that, compared to stand-alone treatments, combined therapies produce superior outcomes in motor function, non-motor symptom management, and overall quality of life. The review also highlights important mechanisms of interaction between various medicines, including neuroprotective signaling pathways and improved dopamine utilization. Combined therapy in Parkinson's disease enhances neuroprotection by boosting BDNF and other neurotrophic factors, reducing oxidative stress and inflammation, and promoting neurogenesis. Exercise and medications work synergistically to improve neuronal survival, cognition, and motor function. However, challenges include poor patient adherence, limited access to structured programs, limited clinical integration, and the need to tailor treatment to disease stage. A possible method for improving neuroprotection in PD is the combination of pharmaceutical therapies and exercise-based physical therapy. Further research is needed to optimize therapy regimens and develop individualized approaches to enhance patient outcomes and slow disease progression. This combined method offers a multifaceted and comprehensive approach to managing Parkinson's disease. Show less

Serotonergic psychedelics have attracted considerable interest as promising therapeutic agents. However, the molecular mechanisms linking their acute hallucinogenic-like effects to longer-lasting neuroplastic responses remain incompletely understood, partly because of the scarcity of native neural models suitable for mechanistic studies. Here, we developed a neural stem cell-derived in vitro model capable of differentiating into neuronal and glial lineages and, after characterization, used it to investigate the molecular pharmacology of serotonergic psychedelics. A panel comprising tryptamines, phenethylamines and ergolines, including psychedelic compounds and selected non-psychedelic analogues, was evaluated alongside ketamine and TrkB agonists. Endpoints included dendritogenesis, synaptogenesis, immediate-early gene induction, BDNF expression and lactate production. TrkB silencing abolished dendritogenic responses to serotonergic psychedelics, ketamine and TrkB agonists, whereas 5-HT Show less

Melatonin, a key regulator of circadian rhythms and sleep-wake cycles, is implicated in the pathophysiology of major depressive disorder (MDD). Emerging evidence supports its anti-inflammatory, cytoprotective, and neuroprotective roles, including promotion of neuroplasticity. This study aims to investigate alterations in serum melatonin, interleukin-6 (IL-6), and brain-derived neurotrophic factor (BDNF) levels in first-episode MDD patients, and explores their clinical correlations. A total of 74 first-episode patients diagnosed with MDD and 72 healthy controls were enrolled in this study. The severity of depressive symptoms was assessed using the 24-item Hamilton Depression Rating Scale (HAMD-24). All blood samples were collected in the morning, and serum levels of melatonin, IL-6, and BDNF were quantified via enzyme-linked immunosorbent assay (ELISA). Baseline serum concentrations of melatonin, IL-6, and BDNF were compared between the MDD group and the control group. Additionally, the discriminative ability of these biomarkers (melatonin, IL-6, and BDNF) in distinguishing MDD patients from healthy controls was evaluated using receiver operating characteristic (ROC) curve analysis. Pearson correlation analysis or Spearman's rank correlation analysis was performed to explore the relationships between serum melatonin levels and clinical disease severity, as well as with IL-6 and BDNF levels, in patients with MDD. Compared with the control group, the MDD group showed significantly higher serum levels of melatonin (Z = -3.861, P < 0.001) and IL-6 (Z = -4.240, P < 0.001), but significantly lower serum BDNF levels (t = 9.537, P < 0.001). Moreover, the combined panel of BDNF, IL-6, and melatonin achieved high accuracy in distinguishing MDD patients from healthy controls, with an area under the curve (AUC) of 0.905. Additionally, no significant correlations were found between serum melatonin levels and clinical disease severity (assessed by HAMD-24 scores), IL-6 levels, or BDNF levels in MDD patients (all P > 0.05). These findings suggest that dysregulation of melatonin, IL-6, and BDNF may contribute to the pathophysiology of first-episode MDD, with their combined measurement offering strong diagnostic potential. Show less

Heart failure (HF) is a complex systemic syndrome with major neuropsychiatric consequences. Cognitive impairment (e.g., dementia) and depression are common among HF patients, worsening prognosis, increasing hospital admissions, and impairing quality of life. Despite their prevalence, the neurobiological basis of these comorbidities is not yet fully understood. This review uniquely discusses converging neuroendocrine, inflammatory, and neuroplastic mechanisms linking HF, depression, and dementia inside an integrative heart-brain axis highlighting brain-derived neurotrophic factor (BDNF) as an important modulator of synaptic plasticity, neurogenesis, and stress resilience. Understanding the interactions between HF-induced hypothalamic-pituitary-adrenal axis activation, systemic inflammation, and impaired BDNF signaling may contribute to the development of novel multimodal therapeutic strategies targeting neurotrophic pathways and improving cognitive and mental health outcomes in HF. Show less

Serotonergic psychedelics are re-emerging as therapeutic candidates across psychiatry, particularly for treatment-resistant depression. Their rapid and sustained antidepressant effects, alongside evidence for neuroplastic, dopaminergic, and glutamatergic modulation, have prompted interest in whether they could address depressive and negative symptoms in schizophrenia spectrum disorders (SSDs). This narrative review summarizes mechanistic, preclinical, and early clinical findings relevant to psychedelic use in SSDs. Schizophrenia and major depressive disorder share disturbances in dopamine, glutamate, and neuroplasticity, and both involve large-scale network abnormalities. Schizophrenia is associated with widespread dysconnectivity, mesocortical hypodopaminergia, and striatal hyperdopaminergia linked to NMDA receptor hypofunction. Depression is characterized by fronto-limbic and default mode network hyperconnectivity, mesolimbic hypodopaminergia, and reduced cortical glutamatergic tone. Depressive symptoms within SSDs may reflect an intermediate phenotype combining depressive-like hyperconnectivity with schizophrenia-related global dysconnectivity, suggesting that psychedelics' capacity to transiently increase network flexibility and recalibrate maladaptive connectivity may be clinically relevant. Preclinical studies show increased dendritic spine density, enhanced BDNF expression, restored reward sensitivity, and modulation of network dynamics after psychedelic administration. Clinically, uncontrolled exposure appears associated with increased psychosis-related presentations, whereas limited case reports suggest controlled administration may be tolerated in carefully selected, clinically stable individuals with SSDs. To date, only one early-phase trial (MDMA in schizophrenia) is ongoing, and no randomized trials have evaluated psilocybin or LSD in SSDs. Overall, psychedelics are biologically and mechanistically plausible but remain unproven for depressive and negative symptoms in SSDs, which partially overlap. Carefully designed, safety-focused early-phase studies in clinically stable patients are therefore a prerequisite for broader clinical application. 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

Classic psychedelics, such as psilocybin, lysergic acid diethylamide (LSD), and N,N-dimethyltryptamine (DMT), have emerged as potent modulators of neuroplasticity and metaplasticity in the adult brain, offering novel therapeutic strategies for neuropsychiatric disorders. Recent findings reveal that beyond their transient psychotropic effects, these compounds activate serotonin 5-HT Show less

Neuroplasticity refers to the ability of the brain to modify synaptic connections and reorganize neural circuits, underpinning cognitive function, emotional regulation, and recovery from injury. Recent advances have redefined adult neuroplasticity as more dynamic and therapeutically accessible than previously thought, spurring investigation into pharmacological interventions that can augment these adaptive processes. This review dissects current evidence for drug strategies targeting synaptic modulators (NMDA, AMPA, and GABA receptors), neuropeptide systems (including BDNF, oxytocin, vasopressin), and psychedelic compounds (psilocybin, LSD, ketamine), integrating insights from cellular, preclinical, and clinical studies. We detail how these agents modulate molecular pathways governing synaptic transmission, dendritic remodeling, and gene expression linked to neuronal growth and resilience. Highlighted findings include the rapid-acting antidepressant effects of NMDA antagonists, the structural and functional reorganization induced by classic psychedelics via 5-HT2A receptor activation, and the neurorestorative roles of neuropeptides in synaptic and network adaptation. Alongside these advances, we critically address safety, ethical considerations, and the risk of maladaptive plasticity, underscoring the importance of dosing, patient selection, and controlled therapeutic environments. Non-hallucinogenic neuroplastogens and combinatorial approaches that are still emerging offer new avenues to fine-tune plasticity with an improved safety profile. The collective evidence positions neuroplasticity-targeting pharmacology as a promising and complex frontier for the treatment of neuropsychiatric and neurodegenerative disorders in adulthood. Show less

Childhood growth-restriction can lead to lasting developmental changes, increasing susceptibility to chronic diseases and neurodegenerative conditions in adulthood. High-intensity interval training (HIIT) elevates brain-derived neurotrophic factor (Bdnf) levels more effectively than moderate intensity continuous exercise, supporting neuroplasticity. Building on these findings, this study aimed to determine whether HIIT could enhance neuroplasticity-related protein expression in the brains of PNGR mice. FVB mouse pups born to normal-protein and low-protein-fed dams were cross-fostered at postnatal day (PN) 1 to establish two groups: postnatally growth-restricted mice (PNGR) and control mice (CON). At PN 21, all pups were weaned onto a normal protein diet and assigned to either a high-intensity interval training group (TRD) or a sedentary group (SED). At PN 45, a maximal exercise performance test was conducted to determine HIIT intensities. Based on these results, mice performed treadmill HIIT 5 days per week for 4 weeks, with alternating intervals of 8 minutes at 85% and 2 minutes at 50% of maximal exercise capacity, totaling 60 minutes per session. At PN 73, all mice were euthanized, and cerebrum tissue was collected for western blot analysis of Bdnf, Tropomyosin receptor kinase B (TrkB), Growth-associated protein 43 (Gap-43), and synaptophysin protein expression. Despite significant body mass reductions observed in both CON and PNGR groups following HIIT, neuroplasticity-related protein expression did not increase in PNGR mice. The PNGR group exhibited consistently lower TrkB and reduced Bdnf and Gap-43 levels compared to CON mice, indicating a limited neuroplastic response to exercise. Contrary to expectations, HIIT did not elevate neuroplasticity markers in PNGR mice, highlighting the lasting impact of early-life growth restriction on brain plasticity and suggesting the need for alternative interventions. 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

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

The serotonin receptor 7 (5-HT7R) has been indicated as a key modulator of neuronal structure and function, playing critical roles in synaptic plasticity, dendritic spine formation, and cytoskeletal remodeling. 5-HT7R activation promotes neurite outgrowth, enhances long-term potentiation (LTP), stimulates local protein synthesis at synapses, and regulates mitochondrial functions, and the mTOR pathway. These properties make the 5-HT7R a compelling candidate for therapeutic intervention in neurodevelopmental disorders characterized by synaptic dysfunctions. Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by the loss of function of the maternal UBE3A gene, resulting in impairments of synaptic plasticity, dendritic spine density, protein synthesis, mitochondrial activity and mTOR signaling. Intriguingly, many of the processes altered in AS are the ones that are positively regulated by 5-HT7R activation. For instance, AS animal models exhibit reduced LTP and altered dendritic morphology and 5-HT7R stimulation enhances synaptic strength and spine formation in the brain of wild type rodents. Moreover, BDNF/TrkB function signaling is impaired and mitochondrial integrity is disrupted in AS and 5-HT7R agonists enhance the altered BDNF/TrkB signalling and restore mitochondrial dysfunctions in Rett syndrome (RTT) mice model. Interestingly, recent evidence demonstrates that pharmacological activation of 5-HT7Rs increases synaptic protein synthesis, restores LTP, enhances dendritic spine density, and improves cognitive function in an AS mouse model. These encouraging results open the way to future studies using neurons and brain organoids generated from iPSCs obtained from AS patients, which represent novel tools in preclinical research. Overall, 5-HT7R stimulation, by counteracting the molecular alterations associated with the loss of UBE3A, may represent a novel approach to restore neural function in the mature brain, leading to translational applications in AS patients, and possibly also in other synaptopathies. Clinical trial number: not applicable. 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

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

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

Human Immunodeficiency Virus (HIV) remains a global epidemic and is frequently associated with neurocognitive impairment, known as HIV-Associated Neurocognitive Disorder (HAND). Brain-Derived Neurotrophic Factor (BDNF), which regulates neuroplasticity, learning, and memory, may play a key role in this process. This study aimed to investigate the correlation between BDNF, CD4 levels, and cognitive function in patients with HIV. We conducted a cross-sectional study at Adam Malik General Hospital, Medan, Indonesia, from July 2024 to January 2025. Fifty-eight HIV-positive patients aged 18-60 years with CD4 ≥200 cells/mm³ and on antiretroviral therapy for at least 4 months were included. Blood samples were analyzed for serum BDNF (ELISA) and CD4 counts. Cognitive function was assessed using the Stroop Test, and correlations were examined with Spearman's test Result: Participants had a mean age of 38.77 ± 9.28 years; 79.3% were male. The mean BDNF level was 1.08 ± 0.59 ng/mL, the mean CD4 count was 512.60 ± 331.08 cells/mm³, and the mean Stroop Test score was 68.75 ± 24.60 seconds. A significant negative correlation was observed between BDNF and Stroop performance (r = -0.288, p = 0.028), indicating that higher BDNF was associated with better cognitive function. No significant correlation was found between CD4 and cognitive function (p = 0.336) Discussion: These findings suggest that reduced BDNF may contribute to cognitive impairment in HIV, whereas CD4 levels may not directly reflect neurocognitive status, particularly in patients with CD4 ≥200. BDNF levels are significantly correlated with cognitive function in HIV-positive patients, underscoring its potential role as a biomarker for HAND. Show less

Recent evidence highlights a fundamental link between masticatory function and brain health. Once regarded solely as a peripheral motor activity for food processing and occlusal balance, mastication is now recognized as a key factor in maintaining and enhancing cognitive function across the lifespan. This narrative review was conducted using relevant keywords through searches in PubMed, Scopus, and Web of Science, as well as manual searching of the bibliographies of journal articles. Basic research has shown that chewing stimulates neurogenesis in the hippocampus, resulting in increased neuronal and synaptic density, as well as the upregulation of brain-derived neurotrophic factor (BDNF), which leads to improvements in memory and cognition. This effect has been documented in both animal and clinical research, particularly among the elderly, and is supported by data from national health programs, which indicate that adequate prosthodontic rehabilitation can help preserve cognitive function. Etiopathogenetic insights suggest that loss of posterior teeth, rather than overall tooth count, is particularly detrimental, as these teeth are essential for effective mastication. Proposed mechanisms involve exercise-induced myokines, such as Cathepsin B, and chewing-induced neprilysin production, which may mediate hippocampal neuroprotection. Collectively, these findings support a paradigm shift: mastication should be promoted as a preventive strategy for both oral and neural health. Public health efforts and clinical practices should integrate education on maintaining posterior dentition, promoting diets with adequate texture, and supporting prosthetic rehabilitation to sustain neuromuscular activity, thereby protecting cognitive function from early development through old age. Show less

Chronic heart failure (CHF) impairs cognitive function. Xijiaqi Formula (XJQ), a traditional Chinese medicine (TCM) used clinically to treat CHF, demonstrates potential for improving cognition in CHF patients. However, its precise mechanism in treating post-CHF cognitive dysfunction remains unclear. This study systematically investigates XJQ's effects on post-CHF cognitive dysfunction and the underlying mechanisms. The components of XJQ were identified through liquid chromatography-mass spectrometry. CHF was induced in rats via ligation of the left anterior descending coronary artery, followed by six weeks of XJQ treatment. Cardiac function was evaluated through echocardiography and hemodynamic parameters, while cognitive function was assessed using Morris water maze (MWM) and open field tests (OFT). XJQ treatment enhanced both cardiac and cognitive functions in CHF rats. Network pharmacology identified 12 core active components of XJQ and indicated its effect on cognitive dysfunction involved regulating synapses, inflammation, and phosphodiesterase 4 (PDE4)-dependent cyclic adenosine monophosphate (cAMP) signaling. XJQ inhibited microglial and astrocyte activation, decreased proinflammatory cytokines, and mitigated neuronal damage. Notably, XJQ promoted synaptic repair and dendritic growth by downregulating PDE4 and upregulating cAMP, protein kinase A (PKA), cAMP-response element binding protein (CREB), brain-derived neurotrophic factor (BDNF), PSD95, and synapsin I levels. Molecular docking and Bio-layer interferometry assays confirmed direct binding of quercetin, kaempferol, isorhamnetin, and darutoside to PDE4. In conclusion, XJQ alleviates neuroinflammation and enhances synaptic plasticity to improve cognitive dysfunction in CHF rats via the PDE4/cAMP/PKA/CREB signaling pathway. These findings provide valuable insight into the heart-brain axis. Show less

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), originally developed for type 2 diabetes mellitus (T2DM) and obesity, show promising potential as a novel treatment for depression, particularly in patients with comorbid metabolic disorders. This narrative review examines the bidirectional relationship between obesity and depression, driven by shared mechanisms such as chronic low-grade inflammation, hypothalamic-pituitary-adrenal axis dysregulation, and impaired neuroplasticity. GLP-1 RAs, including liraglutide and exenatide, demonstrate neuroprotective effects by enhancing brain-derived neurotrophic factor expression and synaptic plasticity, alongside anti-inflammatory properties that reduce proinflammatory cytokines (e.g., tumor necrosis factor-alpha and interleukin-6). They also modulate serotonin turnover in mood-regulating brain regions, mirroring selective serotonin reuptake inhibitors. Preclinical studies in animal models reveal improved behavioral outcomes, while human observational studies and limited clinical trials, such as the LEAD-3 trial, report enhanced mood and quality of life in T2DM and obesity patients. However, challenges, including high treatment costs ($800-$1000/month), injectable administration, and needle-related anxiety, limit patient adherence, and clinical adoption. The lack of large-scale randomized controlled trials targeting depression as a primary outcome further hinders definitive conclusions. This review highlights GLP-1 RAs' potential to address both metabolic and depressive symptoms, offering a holistic approach to managing these interconnected conditions. Future research should focus on long-term efficacy, optimal dosing, and overcoming adherence barriers to establish GLP-1 RAs as a viable psychiatric treatment. Show less

Chronic pain, marked by nociceptive sensitization and maladaptive neuroplasticity, affects 30% of the global population with escalating socioeconomic burdens. Epidemiological data show a 2-3-fold increase in neuropsychiatric co-morbidities among individuals with chronic pain, where epigenetic dysregulation serves as a key mechanism linking ongoing pain to emotional disorders. This review systematically explores epigenetic signatures in supraspinal integration hubs, notably the limbic-paralimbic networks and prefrontal regulatory circuits. The identified epigenetic signatures encompass dysregulation of DNA methyltransferases (DNMTs), RNA modifications, histone post-translational modifications and locus-specific alterations, including aberrant methylation at the brain-derived neurotrophic factor (BDNF), opioid μ receptor and transient receptor potential ankyrin 1 (TRPA1) gene loci. Additionally, they involve dysfunction of the glucocorticoid receptor (GR)/corticotropin-releasing factor (CRF) axis via epigenetic modulation. Building on these findings, we evaluate therapeutic strategies addressing epigenetic dysregulation. While preclinical data demonstrate the efficacy of histone deacetylase (HDAC) and DNMT inhibitors, clinical translation faces significant barriers, including limited blood-brain barrier permeability. Notably, our analysis highlights the benefits of combining pharmacological interventions with non-invasive neuromodulation for enhanced co-morbidity management. Looking forward, this review proposes innovative approaches that leverage CRISPR-based chromatin editing platforms, biomimetic nanocarriers for neuron-specific delivery and closed-loop neuromodulation integrating real-time biomarker feedback, collectively establishing a precision medicine framework for pain or neuropsychiatric co-morbidities. Show less

Visceral pain is frequently accompanied by depression, a comorbidity involving central neuroinflammation and abnormal neuronal plasticity. The P2X7 receptor (P2X7R) plays a crucial role in neuroinflammation and pyroptosis, while Jujuboside A (JuA), a major saponin extracted from Ziziphus jujuba seeds, has been reported to exert significant antidepressant and analgesic effects. In this study, we systematically evaluated the regulatory effects of JuA on the P2X7R-brain-derived neurotrophic factor (BDNF) pathway and on pyroptosis and apoptosis using a rat model of colorectal distension (CRD) and primary neuron/astrocyte cultures. JuA markedly alleviated visceral hypersensitivity and depressive-like behaviors in CRD rats and reduced P2X7R expression in both the spinal cord (SC) and hippocampus (HPC). Further investigations in vitro revealed that JuA inhibited excessive P2X7R activation in SC astrocytes, thereby decreasing the expression of NLRP3, Caspase-1, GSDMD, IL-1β and TNF-α, indicating suppression of pyroptosis. Similarly, JuA exerted an anti-pyroptotic effect in HPC astrocytes and inhibited neuronal apoptosis by reducing Caspase-3 and Bax levels while increasing Bcl2 expression, leading to upregulation of HPC BDNF. Collectively, JuA targets P2X7R and suppresses downstream pyroptotic and apoptotic signaling in vitro, which may contribute to its neuroprotective effects. These findings provide experimental evidence supporting the potential of JuA as a therapeutic agent for comorbid visceral pain and depression. Show less

Extremely low-frequency electromagnetic field (ELF-EMF) therapy is gaining attention for its potential benefits in treating neurodegenerative conditions. However, the underlying molecular mechanisms responsible for the possible protective effects of ELF-EMF remain unclear. Our previous research revealed that ELF-EMF exposure can establish a new "set-point" for stress responses, with outcomes dependent on field intensity. Stress hormones have been shown to modulate hippocampal function and plasticity. Therefore, our study aimed to assess how ELF-EMF exposure affects the expression of transcripts related to hippocampal plasticity, including genes related to neurogenesis (BDNF, TrkB, GAP43), synaptic activity (PSD95, SYN1), and cell survival (Bcl-2, Bcl-xL, Bak1). Adult rats were exposed to ELF-EMF (50 Hz) at 1 mT and 7 mT intensities for three 7-day periods, 1 h/day, with 3-week break between each cycle. A subset of animals was sacrificed after each exposure to collect hippocampi. The relative expression of neural/synaptic genes and anti-/pro-survival factors was measured by real-time quantitative polymerase chain reaction. Our findings indicate that ELF-EMF exposure modulates mRNA expression of neural/synaptic genes and anti-/pro-survival factors. The direction and dynamics of changes depend on ELF-EMF intensity and the number of exposures. "Low-intensity" ELF-EMF (1 mT) increased pro-neuroplastic factors expression, while "high-intensity" ELF-EMF (7 mT) decreased them. In summary, "low-intensity" ELF-EMF enhances adaptive processes like neuroplasticity by eliciting a mild stress response, while "high-intensity" exposure disrupts homeostasis and brain function by inducing severe stress. Our findings indicate that the overall effects of ELF-EMF depend on the intricate interplay between stress reactions and long-term brain plasticity. Show less

The roots of Platycodon grandiflorus (Jacq.) A. DC. (Campanulaceae), known as Platycodi Radix (PR), have long been used as a traditional medicine for respiratory ailments and for relieving chest oppression, a symptom associated with qi stagnation and emotional imbalance resembling depressive states. However, the molecular mechanisms underlying this ethnopharmacological effect and neuroplastic signaling remain to be elucidated. This study aimed to investigate the antidepressant-like activities of PR and its triterpenoid saponins, platycodin D (PD) and platycodin D2 (PD2), and their underlying molecular mechanisms. In a chronic restraint stress (CRS) mouse model, antidepressant efficacy was evaluated using behavioral assessments, including open field tests and forced swimming tests. Hippocampal microarray and pathway enrichment analyses, as well as the compound combination-oriented natural product database unified terminology (COCONT) database, were used to explore signaling pathways and active components, respectively. The molecular mechanisms underlying brain-derived neurotrophic factor (BDNF) expression and secretion were investigated in N2a cells and hippocampal tissues. The activation of BDNF-related signaling pathways was examined using neurite outgrowth assays, quantitative PCR, immunoblotting, and immunofluorescence analysis. PR extract (PRE), PD, and PD2 significantly improved depressive-like behavioral deficits induced by CRS and restored the expression of hippocampal neuroplasticity markers, including BDNF, neurofilament light, and PSD95. These effects were accompanied by enhanced activities in ERK/cAMP-response element binding protein (CREB) and Akt/mechanistic target of rapamycin (mTOR) signaling pathways. These compounds promoted neurite outgrowth and triggered α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs)-dependent Ca PR and its triterpenoid saponins, PD and PD2, could alleviate stress-induced depressive symptoms and modulate BDNF-centered neuroplasticity signaling, supporting their potential relevance as phytotherapeutic candidates for depressive disorders. Show less

Preserving brain health is essential to maintaining quality of life and cognitive function with age. Exercise plays an essential role. Aerobic exercise such as running and cycling can enhance brain plasticity through increasing gray matter volume in the cerebellum and temporal lobe, as well as the density of connections in the brain's frontal and motor areas via upregulating brain-derived neurotrophic factor (BDNF) and serotonin systems. Anaerobic exercise, such as weightlifting, primarily increases gray matter volume in the basal ganglia and increases the density of connections in the posterior lobe of the cerebellum. In midlife, aerobic exercise can increase white matter integrity and cortical thickness in primary motor and somatosensory areas, while in older age it improves specific markers of cognitive function, such as episodic memory. With regards to neurodegenerative diseases, aerobic exercise has been linked to improved memory performance and reduced hippocampal atrophy in Alzheimer's disease. In Parkinson disease, aerobic exercise has shown to reduce brain atrophy, improve motor function and cognitive control, while anaerobic exercise improves motor performance and information processing. Overall, both aerobic and anaerobic exercises are integral and complementary to preserving brain health through effects on cognitive function and brain structure. Show less