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This comprehensive review examines the synergistic effects of physical exercise and polyphenolic compounds, such as flavonoids, curcumin, and resveratrol, on spatial learning and memory. The interplay between these interventions highlights their potential to enhance cognitive function by promoting neurogenesis, synaptic plasticity, and resilience against oxidative stress and inflammation. Mechanistic insights reveal that exercise and polyphenols activate complementary neuroprotective pathways, including the upregulation of BDNF and CREB, as well as the modulation of antioxidant defenses via Nrf2. Evidence from both animal and human studies demonstrates significant improvements in spatial memory and hippocampal function when these strategies are combined. Despite promising findings, challenges related to bioavailability, dosing, and long-term efficacy remain, underscoring the need for further investigation. This review emphasizes the potential clinical applications of these combined approaches for preventing cognitive decline and promoting brain health during aging and in neurodegenerative conditions. Show less

Prenatal stress (PS) significantly influences the neurodevelopment of offsprings, potentially resulting in deficits in learning and memory. Mangiferin (MGF) is a naturally occurring flavonoid compound found in many plants, exhibits various pharmacological effects. The study investigates the potential molecular mechanisms of MGF in improving learning and memory deficits in offspring exposed to PS. Animal model of PS offspring and ACR-induced PC12 cell model were used to investigate the effects of MGF. Synaptic plasticity-related proteins and the BDNF signaling pathway were studied, as well as MGF's potential to alleviate endoplasmic reticulum stress (ERS). MGF can mitigate learning and memory impairments and enhance the density of hippocampal neurons, as well as increase the expression of neuronal markers Neurogranin (Ng), DLG4 and activity marker c-fos in the offspring of PS mice. Meanwhile, MGF significantly increased BDNF signaling pathway and synaptic plasticity-related proteins in PS offspring. MGF also efficiently alleviated ERS. Additionally, MGF significantly up-regulated the reduced viability, DLG4 protein expression and synaptic plasticity-related proteins in ACR-induced PC12 cells. MGF can improve endoplasmic reticulum morphology and down regulated the expression of key molecular proteins in the endoplasmic reticulum signaling pathway. MGF could improve the cognitive and memory impairments in the PS offspring mice. The underlying mechanisms involved the alleviation of ERS and improvement of synaptic plasticity-related proteins. The study indicated that MGF holds promise as an effective intervention for ameliorating learning and memory deficits associated with PS, and it offers potential therapeutic effect for neurological disorders linked to ACR dysfunction. Show less

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

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

Acute exercise modulates circulating exerkines and affective states, yet it remains unclear whether mind-body exercise modalities, such as yoga, elicit responses observed in aerobic exercise. This study examined the acute effects of yoga, stretching, moderate-intensity aerobic exercise, and low-intensity aerobic exercise on exerkines and affect. Eighty-eight adults (52% female; mean age = 23.3 ± 5.79 years) were randomized to one of two study arms: aerobic exercise (moderate-intensity = 70-75% heart rate max and low-intensity = 40-50% heart rate max) or mind-body exercise (yoga and stretching). At two laboratory visits, participants completed 30-minutes of each condition within their assigned arm in a counterbalanced order. Venous blood collected immediately before and after exercise was analyzed for brain-derived neurotrophic factor (BDNF) and endocannabinoids (N-arachidonoylethanolamine [AEA], 2-arachidonoylglycerol [2-AG]). State anxiety and positive and negative affect were assessed pre- and post-exercise. Linear mixed-effects models tested pre-to-post changes and condition interactions. Moderate-intensity aerobic exercise increased circulating concentrations of AEA (b = 0.10, p = .005), while 2-AG and BDNF concentrations were unchanged across conditions. All four exercise conditions decreased state anxiety and negative affect, whereas only yoga, stretching, and moderate-intensity aerobic exercise increased positive affect. Pre-to-post AEA increases were correlated with changes in positive affect (b = 0.18, p = .041). In this randomized study-arm design, moderate-intensity aerobic exercise uniquely increased AEA, whereas affective improvements were observed across modalities. These findings implicate cardiovascular intensity in the endocannabinoid response to exercise, while diverse forms of acute exercise are associated with short-term affective benefits. Show less

Alzheimer's disease (AD) is characterized by progressive cognitive decline and memory dysfunction, with prominent roles in cholinergic deficits and synaptic plasticity impairments. Vitisin B, a resveratrol tetramer derived from Vitis vinifera, exhibits potent antioxidant and neuroprotective properties. However, its potential to influence cognitive function in AD models remains inadequately explored. In this study, we first tested vitisin B in an in vitro model using SH-SY5Y cells exposed to scopolamine-induced cytotoxicity, where vitisin B significantly enhanced cell viability and promoted cell survival. We evaluated its therapeutic potential in vivo using both systemic administration and direct delivery into the third ventricle of the brain in a scopolamine-induced AD mouse model. Across both administration routes, vitisin B exerted a broad pro-cognitive effect, restoring multiple domains of learning and memory disrupted by scopolamine. Vitisin B recovered spatial working memory in the Y-maze, normalized exploratory activity in the open field, improved recognition memory in the novel object recognition (NOR) test, and enhanced long-term memory retention in the passive avoidance assay. This treatment restored cognitive function, alleviated cholinergic deficits, increased hippocampal brain-derived neurotrophic factor (BDNF) levels, and enhanced synaptic plasticity. These results suggest that vitisin B exerts reliable cognitive and neuroprotective effects through both systemic and cerebral administration, highlighting its potential as a promising therapeutic compound for restoring cholinergic function and enhancing hippocampal synaptic plasticity in AD. Show less

Hyposalivation affects cognitive function. However, its impact on hippocampus-dependent memory remains unclear. Saliva contains brain-derived neurotrophic factor (BDNF), which is also synthesized in the hippocampus and can pass through the blood-brain barrier (BBB) to influence hippocampal plasticity. Therefore, we hypothesized that hyposalivation reduces peripheral BDNF availability, leading to decreased hippocampal BDNF levels and cognitive impairment. In this study, this relationship was investigated using an in vivo model of sialadenectomy-induced hyposalivation. A total of 24 8-week-old male ddY mice were divided into control and extraction (EXT) groups. The EXT group underwent submandibular and sublingual salivary gland extractions, whereas the control group underwent a sham operation. Saliva was collected at baseline (0 weeks) and at 2- and 3-weeks postoperatively. Cognitive function was assessed using the Y-maze, fear conditioning (FC), novel object recognition (NOR), and object location tests (OLT). Anxiety-like behavior was evaluated using the open field test (OFT) and elevated plus-maze (EPM) tests. Hippocampi were collected at 3 weeks post-operation for BDNF quantification using enzyme-linked immunosorbent assay, and its concentration in subregions of the hippocampus was determined by semi-quantitative analysis. Hyposalivation significantly impaired spatial working memory in the Y-maze test and contextual fear memory in the FC, both of which are hippocampus-dependent. NOR showed only a transient deficit at 24 h during the 2-week period (no significant difference in 3-week post-operation), whereas long-term spatial memory measured by the OLT exhibited a persistent 24-h impairment at both 2 and 3 weeks, indicating reduced long-term spatial memory rather than accelerated decay. No significant differences were observed in anxiety-like behavior. Although sialoadenectomy significantly reduced salivary secretion and total salivary BDNF output, the concentration of BDNF in saliva in both groups remained unchanged at 2- and 3-weeks post-operation. However, hippocampal BDNF levels were significantly lower in the EXT group than in the control group. These findings suggest that hyposalivation may selectively impair hippocampus-related spatial memory without affecting recognition memory or anxiety-related behaviors. Show less