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Exercise enhances learning and memory, not only through improved cardiometabolic but also through body-brain interactions mediated by secreted factors. Given the prominent role of skeletal muscle during exercise, muscle-derived factors, myokines, are believed to mediate the exercise-induced cognitive enhancements. Here, we demonstrate that intramuscular Serpina1e is upregulated following exercise in male mice. Systemic delivery of recombinant Serpina1e or intramuscular overexpression of Serpina1e reproduces exercise-induced memory enhancements in sedentary male mice. Conversely, muscle-specific depletion of Serpina1e abolishes hippocampal memory enhancement, indicating a requirement of muscle-derived Serpina1e for these cognitive benefits. Mechanistically, elevated plasma Serpina1e stimulates neurogenesis, brain-derived neurotrophic factor (BDNF) expression, and neurite growth in the hippocampus by crossing the blood-cerebrospinal fluid (CSF) and blood-brain barrier. Our findings identify Serpina1e as a key mediator of skeletal muscle-brain interaction that enables the beneficial effects of exercise on cognitive function. Show less

Valproic acid (VPA) is recognized for its neurotrophic properties and is widely used in psychiatric and peripheral disorders, while dextromethorphan (DM) has demonstrated anti-inflammatory and neuroprotective effects. This study examined whether adjunctive DM provides additional benefits on cognitive or immunomodulatory beyond standard VPA treatment in bipolar disorder (BD). BD aged 20-65 received open-label VPA (500-2500 mg/day; target blood level 50-100 μg/dl) for one week and were then randomized to VPA plus placebo (BDVPA) or VPA plus extended-release DM (BDVPA + DM; 30 or 60 mg/day) for twelve weeks. Neuropsychological measures (Continuous Performance Test, CPT; Wechsler Memory Scale-Revised, WMS-R), symptom severity, cytokines, and BDNF were assessed at baseline and post-treatment. A total of 109 participants (mean age 31.04 years, SD = 10.04) were enrolled; 96 completed cognitive testing and blood sampling (66 BD 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

Extended periods of microgravity during orbital flights can impair astronauts' cognitive abilities, including learning and memory, posing a persistent health concern in the field of aerospace medicine. The study examined the pharmacological effects of agmatine and its influence on simulated neurobehavioral changes in rats under microgravity conditions. Rats were exposed to simulated microgravity (SMG) conditions using the hindlimb unloading (HU) model for 28 days and evaluated for behavioural alterations using the open field test, elevated plus maze, and forced swim test, and cognitive deficits using the novel object recognition test and Morris water maze. Further, brain agmatine levels, neurochemical and structural alterations in the hippocampus, and prefrontal cortex were examined. Chronic agmatine treatment dose-dependently (40 and 80mg/kg) and its endogenous modulation by l-arginine, and aminoguanidine prevented behavioral and cognitive deficits by improving exploratory behaviour, reducing anxiety-depressive-like symptoms, and enhancing cognitive performance. Our findings reported a significant reduction in agmatine levels in the hippocampus and prefrontal cortex in SMG conditions. Agmatine administration and its modulation normalized neurotransmitter imbalances, especially by restoring the reduced levels of gamma-aminobutyric acid, dopamine, and serotonin, along with a reduction of elevated levels of glutamate in SMG conditions. Moreover, agmatine decreased reactive oxygen species production, enhanced hippocampal antioxidant enzyme activities, suppressed pro-inflammatory cytokines (TNF-α, IL-6), and improved IL-10 and brain-derived neurotrophic factor levels in HU rats. Moreover, agmatine and its endogenous modulation preserved neuronal cells of the hippocampus and prefrontal cortex. In conclusion, the present study suggests that agmatine administration and modulation of endogenous agmatine levels effectively mitigate SMG-induced neurological dysregulation through neuroprotection and neuromodulation. Understanding the neurobiological mechanisms underlying these effects opens up new possibilities for creating novel interventions targeting agmatinergic signaling in spaceflight conditions and associated complications. Show less