BDNF

Brain-Derived Neurotrophic Factor (BDNF) is a pleiotropic neurotrophin and myokine upregulated by physical exercise that activates TrkB receptor signaling to promote cell survival, synaptic plasticity, and mitochondrial bioenergetics PMID 40869331, 2025; PMID 39456173PMID 36417200. It serves as a vital therapeutic target for neurodegenerative and metabolic conditions due to its ability to potentially facilitate neurogenesis, reduce neuroinflammation, and enhance lipid oxidation through the AMPK-PGC-1α and NF-κB pathways PMID 40869331PMID 40210118PMID 38699186PMID 34782555.

• Neuroplasticity and Survival: These pathways promote neuronal survival, dendritic remodeling, and synaptic plasticity. BDNF is essential for long-term potentiation (LTP), a key mechanism for learning and memory PMID 40869331PMID 39818278PMID 35283168.
• Mitochondrial Bioenergetics & Metabolism: In skeletal muscle, BDNF acts as an autocrine or paracrine factor that activates the AMPK-PGC-1α pathway PMID 40869331PMID 39335489PMID 38699186. This activation enhances mitochondrial biogenesis, improves respiratory coupling efficiency, and promotes fat and lipid oxidation (FAO) PMID 39136551PMID 39852400PMID 36417200.
• Anti-inflammatory and Antioxidant: BDNF exhibits anti-inflammatory properties by promoting the conversion of macrophages from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype PMID 38699186. It also activates Nrf2 to reduce oxidative stress and inhibit ferroptosis [ PMID 39988270; PMID 37247469].

BDNF is classified as an exerkine (specifically a neurokine and myokine) because its expression and secretion are significantly upregulated in response to physical activity, facilitating crosstalk between organs.

• Exercise-Induced Secretion: Both acute and chronic exercise stimulate the production of BDNF in the brain and skeletal muscle PMID 40869331PMID 39136551; PMID 38337694.
• Muscle as a Secretory Organ: Skeletal muscle cells synthesize and release BDNF into circulation during contraction, allowing it to act in aparacrine or autocrine manner PMID 39852400PMID 39522716PMID 35304603.
• Systemic Crosstalk: BDNF facilitates communication between muscles and the brain (the muscle–brain axis). While there is some debate regarding its permeability, several reviews indicate that muscle-derived BDNF or exercise-induced circulating BDNF can cross the blood–brain barrier (BBB) to exert central neuroprotective effects PMID 39456173PMID 36118704. Conversely, other reviews suggest the brain is the primary source of circulating BDNF during exercise or that muscle-derived BDNF acts locally [14 - Huiling & Peizhen, 2025; PMID 39136551].

• Alzheimer’s Disease (AD) & Cognitive Decline: BDNF is critical for mitigating memory impairment and synaptic failure: it reduces Amyloid-β (Aβ) production (shifting APP degradation to the non-amyloidogenic pathway) and reduces Tau phosphorylation PMID 38249295PMID 34782555. Exercise-induced BDNF prevents neurodegeneration and improves learning alongside memory formation PMID 39818278PMID 36118704.
• Parkinson’s Disease (PD): Reduced BDNF levels are associated with PD progression; additionally, BDNF supports the survival of dopaminergic neurons PMID 39456173.
• Multiple Sclerosis (MS): BDNF promotes remyelination and oligodendrocyte survival, making it a key factor for neural repair in demyelinating diseases. Exercise serves as a powerful activator for BDNF production in MS patients, supporting neuroprotection PMID 41038351.
• Sarcopenia and Muscle Health: As a myokine, BDNF promotes satellite cell proliferation and differentiation, aiding in muscle regeneration and potentially combating sarcopenia and cachexia (muscle wasting) PMID 40869331PMID 40801027.
• Cardiovascular Disease: BDNF/TrkB signaling is required for normal cardiac contraction and relaxation. It exerts cytoprotective effects on cardiomyocytes (reducing apoptosis) and promotes angiogenesis after myocardial infarction PMID 40210118.
• Metabolic Disorders (T2D): By enhancing glucose utilization in peripheral tissues, BDNF may help alleviate insulin resistance and improve metabolic profiles in Type 2 Diabetes PMID 40943107.

1. Neuropsychiatric Disorders: Depression and Anxiety

• Rapid-Acting Antidepressants: Ketamine and its enantiomers (esketamine) exert antidepressant effects by activating Sigma-1 receptors, which subsequently increases BDNF levels PMID 39326783PMID 38097715.
• Gut-Brain Axis: Probiotics, such as Lactobacillus strains and Akkermansia muciniphila, and short-chain fatty acids (SCFAs) have been shown to alleviate cognitive decline and depressive behaviors by upregulatingBDNF PMID 41297563PMID 39342324PMID 40301246.
• Post-Stroke Depression (PSD): Therapies like Electroacupuncture and natural compounds (e.g., Morroniside, Echinacoside) mitigate PSD by activating the BDNF/TrkB signaling axis PMID 33880028PMID 38006805PMID 38547621.

2. Neurodegenerative Diseases

• Alzheimer’s Disease (AD):
• Gene Therapy: Hippocampus-targeted delivery of BDNF using engineered adeno-associated viruses (e.g., AAVT42) has successfully rescued cognitive impairments and prevented neuronal loss in multiple AD mouse models PMID 41480410.
• Small Molecules: Compounds like 7,8-dihydroxyflavone (7,8-DHF), a TrkB agonist, and Ginsenoside RK3 promote neurogenesis and reverse synaptic deficits by activating the BDNF-TrkB or CREB/BDNF pathways PMID 37225683PMID 37981117.
• Nanocarriers: Novel brain-penetrable nanocarriers have been designed to deliver BDNF directly to the brain, reducing apoptosis and improving learning PMID 40847688.
• Parkinson’s Disease (PD):
• Neuronal Protection: BDNF protects dopaminergic neurons in the substantia nigra. Recent studies show that nicotine (via PI3K/AKT/Nrf2 signaling) can upregulate BDNF to improve antioxidant defenses PMID 41077168.
• Stem Cells: Human umbilical cord mesenchymal stem cells (MSCs) modified to overexpress BDNF have shown promise in improving motor function and reducing neuroinflammation in PD rats PMID 36228967.
• Huntington’s Disease (HD): Transplantation of human striatal progenitor cells engineered to overexpress BDNF rescued motor and cognitive deficits in HD mice, highlighting the potential of cell-based BDNF delivery PMID 39995448.

3. Traumatic Brain Injury (TBI) and Stroke

• Stroke Recovery: Transcranial Direct Current Stimulation (tDCS) improves motor function and plasticity post-stroke by activating BDNF/TrkB signaling PMID 39662631. Intranasal delivery of BDNF-loaded exosomes derived from MSCs has been shown to target ischemic regions and promote neural repair PMID 36958402.
• TBI Repair: The BDNF mimetic R-13 attenuates TBI pathogenesis by improving mitochondrial bioenergetics and synaptic function PMID 37286142. Additionally, Probucol promotes neuroregeneration and ameliorates functional deficits via the BDNF/TrkB pathway PMID 37263748.

4. Novel Delivery Systems

• Intranasal Delivery: This non-invasive route is being perfected using exosomes and nanoparticles (e.g., quercetin-based nanogels) to deliver BDNF directly to the brain, bypassing the BBB to treat conditions like depression and ischemia PMID 40883738PMID 37848975.
• Focused Ultrasound: Low-frequency focused ultrasound combined with microbubbles can non-invasively open the BBB to deliver BDNF plasmids, showing efficacy in treating autism models PMID 36117626.
• Implants: Osmotic core-shell polymeric implants have been developed for sustained delivery of BDNF-modulating agents via a minimally invasive nasal depot PMID 34252799.

5. Lifestyle and Non-Pharmacological Interventions

• Exercise: Physical activity (aerobic and resistance) consistently elevates BDNF levels, which is linked to improved cognition in aging and neuroprotection in rat models PMID 41206250PMID 41420669PMID 35743182.
• Heat Therapy: Emerging evidence suggests that heat therapy can increase brain BDNF and HSP70 content, offering a non-pharmacological strategy for neuroprotection PMID 41042852.
• Diet: Intermittent fasting and dietary compounds like resveratrol and Vitamin B-12 modulate BDNF expression to improve memory and reduce anxiety PMID 40591178PMID 41380913PMID 36243244.