Figure - available from: Journal of Clinical Medicine (JCM)
This content is subject to copyright.
Potential mechanisms of lactate-BDNF interaction following physical exercise. Physical exercise is associated with intensity-dependent increase of lactate levels. Lactate can cross the blood-brain barrier (BBB) via different monocarboxylate transporters (MCT‘s). Furthermore, lactate binding to the hydroxycarboxylic acid receptor (HCAR1) at the BBB can induce angiogenesis. In neurons, lactate exerts several neurotrophic and metabolic effects through transmembrane transport via MCT’s and direct binding to HCAR1. Firstly, lactate binding to HCAR1 on neurons inhibits the adenylate cyclase (AC) and thus decreases cAMP, resulting reduced BDNF expression and regulatory function in the control of blood flow, and synaptic functions. Secondly, lactate can induce the PGC1α/FNDC5/BDNF pathway through SIRT1 activation. Thirdly, lactate increases intracellular NADH, resulting in enhanced calcium levels and BDNF gene expression. Released BDNF can then enhance neuroplasticity via different neurobiological mechanisms (e.g., neurogenesis, synaptogenesis, growth of dendritic spines, long-term potentiation [LTP]).
Source publication
Accumulating evidence from animal and human studies supports the notion that physical exercise can enhance neuroplasticity and thus reduce the risk of several neurodegenerative diseases (e.g., dementia). However, the underlying neurobiological mechanisms of exercise induced neuroplasticity are still largely unknown. One potential mediator of exerci...
Similar publications
Adaptive capacity and the ability to sustain long-term changes as neural activity patterns are considered as the most critical and intriguing properties of the brain. This concept, called neuroplasticity, refers to the ability of the brain to adapt and change over time. Sometimes, reorganization or re-adaptation mediates crucial physiological event...
Citations
... Notably, lactate regulates the expression and function of neurotrophic factors, directly or indirectly, through its involvement in neuronal metabolic regulation, activation of specific signalling pathways, and influence on gene expression. Research has demonstrated that lactate can upregulate the expression of BDNF [49,55], a key factor in neurodevelopment and neuroplasticity. Lactate promotes neuronal growth and synaptic plasticity by modulating energy metabolism and redox balance while also supporting synaptic formation and the maintenance of neural network homeostasis. ...
... However, an environment with high lactate concentrations may activate inflammatory pathways and increase oxidative stress, potentially inhibiting NGF expression and function [56]. Additionally, lactate may indirectly support neurotrophic maintenance by promoting metabolic coupling between neurones and glial cells [55]. Studies have shown that lactate shuttled through astrocytes provides energy to neurons and regulates local neurotrophic factor levels, thereby influencing neuronal function and survival. ...
p>Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder characterized by impairments in social interaction, communication, and repetitive behavioral patterns. ASD is often accompanied by metabolic abnormalities, dysregulation of the immune system, and neuroinflammation. Glycolysis, a central pathway in energy metabolism, is vital for neurodevelopment and functioning. Recent studies have indicated that patients with ASD may experience disturbances in brain metabolism, particularly in the glycolytic pathway, with abnormal lactic acid production and utilization. Lactic acid serves not only as an energy source for cellular functions but also plays a significant role in cell signaling, gene expression regulation, and immune modulation. This review examines the mechanisms of glycolysis, especially the role of lactic acid in ASD; explores the relationship between lactic acid accumulation and neuroinflammation, neuroplasticity, and neurotrophic factors; and discusses the potential of lactic acid as a diagnostic and therapeutic target for ASD. Future research on modulating lactic acid metabolism may offer new strategies for the early diagnosis, precise treatment, and neural repair of ASD.</p
... Lactate intervention can improve brain-derived neurotrophic factor (BDNF) signaling, angiogenesis signaling (p/t-Aging and Disease • Volume 17, Number 2, April 2026 10 AKT/ENOS/VEGF), mitochondrial biomarker (SDHA), and metabolic signaling in the hippocampus of aged mice. Lactate may also be used as a therapeutic agent for neurodegenerative diseases in the elderly individuals [128,129]. EPB41L4A-AS1, a long non-coding RNA (lncRNA) downregulated during aging and in AD, regulate histone acetyltransferase 5-like 2 (GCN5L2) expression to enhance histone acetylation, crotonylation and lactylation near the transcription site of autophagyrelated genes, further enhancing astrocyte-mediated clearance of amyloid β peptide (Aβ) and delaying the progression of AD [130]. Some studies also found that lactylation of amyloid precursor protein (APP) decreased in Alzheimer's patients and Alzheimer's model mice and cells. ...
... However, this is in dispute with previous studies, and it may be caused by the research subjects were the fast-twitch fibers of mice [134,135]. The strategy of using lactate for the treatment of neurodegenerative diseases in the elderly remains controversial [128,129,131]. The research results indicate that the increase in lactate levels in the cerebrospinal fluid of elderly individuals can serve as a biological marker of aging, particularly in the brain. ...
... Fundamental motor skills, including basic motor functions, are crucial for neurological health and can influence neurotransmitter release and neuroplasticity via multiple pathways (Müller, Duderstadt, Lessmann, & Müller, 2020). Studies demonstrate that brain gym exercises that include simple movements can facilitate the release of neurotransmitters like dopamine and serotonin, which are essential for cognitive functions such as attention and memory (Chan, Jang, & Ho, 2022). ...
This study has been planned to identify the impact of brain gym (BG) exercises on the mind for children with mild levels of intellectual disability and to provide the more common use of BG exercises in rehabilitation programs. A total of 24 intellectually disabled students, 10 girls, and 14 boys, aged between 6 and 18 years, studying at Bağcılar Başak Special Education and Rehabilitation Center School were included in the study. To identify the intelligence level of the students, in order they have been applied Bender Gestalt Visual Perception Test and Wechlers Intelligence Test by expert psychologist. Then while individual private training session as 6 hours per month and with the observation of the physiotherapist 15-minute sessions three times a week have been given to the experiment group, the control group received only private training session 6 times a month. Also the exercises given to the experiment group have been required as homework. After 6 weeks of training the tests which had been applied at the beginning were applied to both groups again. Participants demonstrated significant improvements in Bender Gestalt Visual Perception Test reducing the error score after working (p
... Lactate increases intracellular cAMP levels and activates adenylate cyclase when it interacts with GPR81. Protein kinase A is further activated by cAMP, which results in the transcription and translation of BDNF [100]. The ability of lactate to increase BDNF may be connected to the GPR81 signaling pathway. ...
As the final product of glycolysis, lactate serves as an energy substrate, metabolite, and signaling molecule in various diseases and mediates lactylation, an epigenetic modification that occurs under both physiological and pathological conditions. Lactylation is a crucial mechanism by which lactate exerts its functions, participating in vital biological activities such as glycolysis-related cellular functions, macrophage polarization, and nervous system regulation. Lactylation links metabolic regulation to central nervous system (CNS) diseases, such as traumatic brain injury, Alzheimer’s disease, acute ischemic stroke, and schizophrenia, revealing the diverse functions of lactylation in the CNS. In the future, further exploration of lactylation-associated enzymes and proteins is needed to develop specific lactylation inhibitors or activators, which could provide new tools and strategies for the treatment of CNS diseases.
... Exercise training activates neurotrophic factors signalling pathways that reduce brain apoptosis, with BDNF being extensively studied in this context. Both high-and moderate-intensity exercise training have been shown to elevate BDNF levels in serum and brain tissue [27,63,64]. Increased BDNF can trigger protective signalling pathways [65], including inhibiting apoptosis through the hedgehog pathway and enhancing erythropoietin levels [66]. ...
Background
Ketamine abuse damages brain function and structure, increasing reactive oxygen species and apoptosis in the cerebral cortex, but moderate‐intensity continuous training (MICT) can enhance antioxidant defences and reduce apoptosis. Therefore, we aimed to answer whether MICT can reduce the side effects of chronic ketamine abuse.
Method
24 Wistar rats were split into control (CON), ketamine abuse (KET), exercise after ketamine withdrawal (KET + EX), and non‐intervention ketamine withdrawal (KET + WD) groups. Ketamine intervention groups received 50 mg/kg/day ketamine for 8 weeks; KET + EX underwent 5 MICT sessions/week at 60–75% VO2max for 8 weeks post‐withdrawal. Post‐sampling of cerebral cortex, we evaluated histological changes, apoptotic cell numbers, Bax, Bcl‐2, Caspase‐3 mRNA/protein, 8‐oxo‐2′‐deoxyguanosine (OXO) expression, glutathione peroxidase (GPX) and glutathione reductase (GR) mRNA and other oxidative stress and antioxidant markers levels. Effect sizes (ES) were used to assess group differences.
Results
MICT significantly reduced apoptotic cells (ES = 14.24, p < 0.0001), decreased Bax and caspase‐3 protein expression, and increased Bcl‐2 compared to the KET group (Bax: ES = 2.77, p = 0.005; caspase‐3: ES = 7.73, p < 0.0001; Bcl‐2: ES = 12.11, p < 0.001). It also lowered Bax and caspase‐3 mRNA (Bax: ES = 4, p = 0.014; caspase‐3: ES = 2.29, p = 0.024). MICT reduced OXO and increased GR and GPX mRNA and nitric oxide (NO) level (GR: ES = 2.02, p = 0.016; GPX: ES = 1.98, p = 0.035; OXO: ES = 11.39, p < 0.0001; NO: ES = 3.52, p = 0.003). Levels of malondialdehyde, myeloperoxidase, glutathione, superoxide dismutase, and catalase remained unchanged between groups.
Conclusion
MICT seems effective in reducing apoptosis and oxidative damage in the cerebral cortex of rats with long‐term ketamine abuse.
... 2025, 15, 252 7 of 28 formation of new neurons, which can aid in cognitive function. Exercise has been shown to increase BDNF levels, which are crucial for neuronal survival, growth, and differentiation [77]. The development of long-term versus short-term memory is determined by the duration of BDNF signaling, which also has a significant impact on neuronal survival and CREB phosphorylation kinetics. ...
Neurological disorders are defined by a deterioration or disruption of the nervous system’s structure and function. These diseases, which include multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and schizophrenia, are caused by intricate pathological processes that include excitotoxicity, neuroinflammation, oxidative stress, genetic mutations, and compromised neurotrophic signaling. Although current pharmaceutical treatments relieve symptoms, their long-term efficacy is limited due to adverse side effects and weak neuroprotective properties. However, when combined with other neuroprotective drugs or adjunct therapy, they may offer additional benefits and improve treatment outcomes. Phytochemicals have emerged as attractive therapeutic agents due to their ability to regulate essential neurotrophic pathways, especially the brain-derived neurotrophic factor (BDNF) signaling cascade. BDNF is an important target for neurodegenerative disease (ND) treatment since it regulates neuronal survival, synaptic plasticity, neurogenesis, and neuroprotection. This review emphasizes the molecular pathways through which various phytochemicals—such as flavonoids, terpenoids, alkaloids, and phenolic compounds—stimulate BDNF expression and modulate its downstream signaling pathways, including GSK-3β, MAPK/ERK, PI3K/Akt/mTOR, CREB, and Wnt/β-catenin. This paper also highlights how phytochemical combinations may interact to enhance BDNF activity, offering new therapeutic options for ND treatment. Despite their potential for neuroprotection, phytochemicals face challenges related to pharmacokinetics, blood–brain barrier (BBB) permeability, and absorption, highlighting the need for further research into combination therapies and improved formulations. Clinical assessment and mechanistic understanding of BDNF-targeted phytotherapy should be the main goals of future studies. The therapeutic efficacy of natural compounds in regulating neurotrophic signaling is highlighted in this review, providing a viable approach to the prevention and treatment of NDs.
... Additionally, long-term physical activity programs stimulate neurotrophic factors that promote neural blood vessel formation and neurogenesis [20]. At a physiological level, physical activity has been shown to enhance brain function through multiple mechanisms, including increased cerebral blood flow and neurotrophic factor release, which support cognitive function and learning processes [24,25]. ...
... Additionally, moderate-intensity exercise helps maintain a balance between physiological activation and cognitive demands, thereby promoting sustained concentration [30]. In contrast, vigorousintensity physical activity has been linked to more pronounced neurobiological changes and stimulates the production of lactate, which serves as an important energy source for neurons and has been associated with both neuroprotective and cognitive-enhancing effects [25]. Furthermore, moderate-and vigorous-intensity exercise contribute to improved oxygenation and nutrient delivery to the brain, which supports synaptic plasticity and executive function [24]. ...
This study analyzed the relationship between time spent on daily physical activity at different intensities (light, moderate, and vigorous) and learning strategies in adolescents. The sample included 147 Spanish adolescents (62% girls, 13.61 ± 1.95 years). Learning strategies were assessed using the Motivated Strategies for Learning Questionnaire (MSLQ), while physical activity intensity was recorded via the Xiaomi Mi Band 4 smartband, which measured heart rate (HR). HR was categorized into light (rest–50% max HR), moderate (50–70% max HR), and vigorous (70–85% max HR). Adolescents who engaged in moderate-intensity activities for 46–62 min daily showed the highest scores in elaboration, critical thinking, and metacognitive self-regulation, with girls also excelling in effort regulation (all p < 0.05). Among boys, 3–6 min of vigorous activity per day was linked to higher scores in elaboration, organization, critical thinking, peer learning, and rehearsal. Conversely, girls engaging in less than 3 min of vigorous activity obtained the highest scores in critical thinking and peer learning (all p < 0.05). It is recommended that students engage in 60 min of daily moderate-intensity physical activity. Additionally, short 5-min vigorous-intensity sessions should be encouraged in both boys and girls to enhance learning benefits and reduce social barriers to high-intensity exercise.
... Strategies that aim to influence these processes, such incorporating more omega-3 fatty acids into one's diet [133], flavonoids [134], and polyphenols [135], have demonstrated their potential to enhance neurogenesis and promote synaptic remodeling. Similarly, regular physical exercise, particularly aerobic and resistance training [136], has been shown to upregulate brain-derived neurotrophic factor (BDNF) and other neurotrophins that support neuronal survival and plasticity [137]. Emerging research also highlights the synergistic effects of combining targeted nutritional interventions with structured exercise protocols to optimize neuroplasticity [138,139]. ...
... Notably, the production of lactate is closely linked to the intensity of exercise; studies demonstrate that exercise-induced lactate acts as a signaling molecule to stimulate neurogenesis and enhance cognitive functions such as memory and executive processing. Although lactate was considered the "villain" in exercise physiology, recent research highlights its essential role in supporting cognitive processes, showing that it is crucial for optimal performance in tasks involving memory and executive functions [137]. ...
The interplay between nutrition, physical activity, and mental health has emerged as a frontier in bioengineering research, offering innovative pathways for enhancing cognitive function and psychological resilience. This review explores the neurobiological mechanisms underlying the synergistic effects of tailored nutritional strategies and exercise interventions on brain health and mental well-being. Key topics include the role of micronutrients and macronutrients in modulating neurogenesis and synaptic plasticity, the impact of exercise-induced myokines and neurotrophins on cognitive enhancement, and the integration of wearable bioelectronics for personalized monitoring and optimization. By bridging the disciplines of nutrition, psychology, and sports science with cutting-edge bioengineering, this review highlights translational opportunities for developing targeted interventions that advance mental health outcomes. These insights are particularly relevant for addressing global challenges such as stress, anxiety, and neurodegenerative diseases. The article concludes with a roadmap for future research, emphasizing the potential of bioengineered solutions to revolutionize preventive and therapeutic strategies in mental health care.
... Furthermore, exercise intensity is a pivotal factor for neuroplasticity induction and BDNF secretion. Lactic acid, produced during moderate-to-high-intensity exercise, has been implicated in this process, with peripheral lactate elevations post-exercise correlating with increased brain BDNF concentrations and, consequently, enhanced neuroplasticity [32]. The interplay between neurotrophic factors and serotonin has also been documented [33][34][35][36], with the role of serotonin in ADHD being substantiated by clinical investigations [37][38][39][40][41]. Serotonin modulates aggressive and hyperactive behaviors [42], regulates sleep patterns, and influences mood states [43]. ...
Attention-deficit/hyperactivity disorder (ADHD) is a prevalent neurodevelopmental condition in children, characterized by inattention, hyperactivity, and impulsivity. Recent studies have investigated the potential role of physical exercise as a complementary intervention to traditional ADHD treatments. This study aimed to compare the effects of moderate-intensity continuous training (MICT) and high-intensity interval training (HIIT) on ADHD symptoms and behavioral inhibition in children diagnosed with ADHD. In a randomized controlled trial, 60 male participants aged 7–10 years were allocated into three groups: control, MICT, and HIIT. The intervention lasted 12 weeks, with the MICT group performing 20 min of running at 70–75% of their individual VO2 max and the HIIT group performing alternating intervals of running at 100% and 50% of their VO2 max for 1 min each. The control group received no exercise intervention. Cognitive and symptomatic assessments were conducted using the Children’s Symptom Questionnaire (CIS-4) and go/no-go tasks before and 48 h post-intervention. Both MICT and HIIT demonstrated significant improvements in behavioral components, including attention deficit, hyperactivity, and impulsivity (all P < 0.0001). HIIT showed superior effects on attention deficit compared to MICT (P = 0.008). Both HIIT (P < 0.0001) and MICT (P = 0.028) improved correct responses (CR) in the Go task compared to the control group. HIIT also outperformed the control group in erroneous responses (ER) (P = 0.022) and correct reaction time (P = 0.027) in the Go task. In the No-Go task, HIIT showed superiority over the control group in both CR (P = 0.013) and ER components.
Conclusion: This study highlights the comparative efficacy of MICT and HIIT as nonpharmacological interventions for children with ADHD. HIIT, in particular, demonstrated superior benefits for attention deficits, suggesting its potential as a targeted adjunctive treatment. These findings may inform the development of exercise programs to enhance the quality of life and daily functioning of children with ADHD. What Is Known:
• Physical exercise has been explored as a complementary intervention for ADHD, with evidence suggesting its potential to improve symptoms such as inattention, hyperactivity, and impulsivity.
• Moderate-intensity continuous training (MICT) has shown positive effects on cognitive and behavioral outcomes in children with ADHD.
What Is New:
• High-intensity interval training (HIIT) demonstrated superior benefits over MICT in improving attention deficits in children with ADHD.
• Both HIIT and MICT significantly improved behavioral inhibition, with HIIT showing additional advantages in reducing erroneous responses and enhancing reaction times in cognitive tasks.
... It has been discovered that exercise raises BDNF levels, a protein that is essential for supporting neuronal survival, development, and differentiation. The capacity of synapses to become stronger or weaker over time is known as synaptic plasticity, and BDNF is known to improve it (Müller et al. 2020). Additionally, it shields already-existing neurons from harm or deterioration and encourages the development of new synapses. ...
Engaging in activity has proven to have beneficial effects on different facets of well-being, such as conditions related to the deterioration of the nervous system. Non-coding RNAs (ncRNAs) and exosomal ncRNAs associated with vesicles have been recognized as influencers of gene expression and cell signaling, potentially contributing to the positive impact of physical activity on neurodegenerative conditions. It is hypothesized that exercise-induced changes in ncRNA expression may regulate key processes involved in neuroprotection, including neuroinflammation, oxidative stress, protein aggregation, and synaptic function. Exercise has shown promise in preventing neurodegenerative diseases (NDs), and ncRNAs and exosomal ncRNAs are emerging as potential mediators of these benefits. In review, we explored how ncRNAs and exosomal ncRNAs play a role in enhancing the impacts of activity on neurodegenerative disorders for future treatments. Research studies, both preclinical and clinical, that have documented the use of various exercises and their effects on ncRNAs and exosomal ncRNAs for the treatment of NDs have been compiled and enlisted from the PubMed database, spanning the time period from the year 2000 up to the current time. Studies show that manipulating specific ncRNAs or harnessing exercise-induced changes in ncRNA expression and exosomal cargo could potentially be utilized as therapeutic strategies for preventing or treating NDs. In conclusion, studies suggest that various exercise modalities, including aerobic, resistance, and high-intensity interval training, can modulate the expression of ncRNAs and exosomal ncRNAs in the context of NDs. The altered ncRNA profiles may contribute to the neuroprotective and therapeutic effects observed with exercise interventions. However, more research is needed to fully understand the underlying mechanisms and to further explore the potential of exercise-induced ncRNA signatures as biomarkers and therapeutic targets for neurodegenerative disorders.
