Journal Club: exercise and hypoxia differentially influence platelet activation of brain‐derived neurotrophic factor and platelet factor 4

The neurotrophic benefits of exercise are well established, with regular physical activity known to enhance neuronal plasticity, synaptic maintenance and cognitive resilience. Brain-derived neurotrophic factor (BDNF) is a central protein in this process, supporting neuronal survival, differentiation and synaptic growth. Circulating BDNF levels increase with both acute and chronic exercise and are closely linked to improved memory, learning and neuroprotection. Despite these associations the physiological origins of exercise-induced BDNF remain unclear. BDNF is produced within both the brain and the peripheral tissues; however ∼99% of the circulating BDNF is stored in platelets within α granules, whereas the other 1% of BDNF exists in a free, plasma-saturable form (Radka et al., 1996). These stark differences in storage raise a fundamental question: are the increases in circulating BDNF observed during exercise primarily the result of new synthesis within the brain, or do they reflect platelet activation and release into the bloodstream (Brigadski & Leßmann, 2020)? To address this uncertainty Thomas et al. (2025) published a study in the Journal of Physiology where they examined whether platelet activation contributes to the liberation of BDNF during physiological stress. The authors investigated two conditions known to independently stimulate platelet activity: exercise and hypoxia. They reasoned that if platelet activation drives the release of BDNF, then conditions that heighten platelet activation should produce synergistic increases in circulating BDNF concentrations. Platelets are increasingly recognized as active participants in physiological signalling. They act as circulating reservoirs for bioactive molecules such as cytokines and neurotrophins that can influence vascular and neural functions. When activated by mechanical or chemical stimuli, platelets undergo degranulation, releasing their stored contents into circulation. This process can be triggered rapidly by physiological stressors, including exercise and hypoxia, and represents a means by which peripheral stimuli can influence systemic and neural adaptations (Numakawa et al., 2018). During exercise elevations in blood flow and sympathetic activity promote platelet activation and the release of stored molecules such as BDNF. Although exercise-induced platelet activation is well established, it remains unclear whether hypoxia alone induces the release of BDNF from platelets. Previous studies have shown that platelets are activated under hypoxic conditions, leading to the release of stored contents, but the involvement of BDNF in this response has not been confirmed (Delaney et al., 2021). Platelet factor 4 (PF4) was used as an index of platelet activation. PF4 is a chemokine known to be robustly released during platelet activation and has been consistently observed to increase in hypoxic conditions. Because PF4 and BDNF are stored within the same platelet α granules, augmented changes in PF4 concentrations would provide strong evidence that BDNF release occurs with platelet activation. Particularly PF4 carries its own biological relevance: emerging evidence links it to neurotrophic signalling and neurogenesis, suggesting that its behaviour under exercise and hypoxia may offer additional insight into how the brain responds to these stressors. Assessing PF4 alongside BDNF therefore provides a novel view of platelet involvement, exploring synergistic contributions to neurobiological adaptation. The authors hypothesized that the brain is the primary source of circulating BDNF and that its release is enhanced by platelet activation across the cerebral circulation. This hypothesis was based on three key considerations. First if the brain were the main source of circulating BDNF, free BDNF concentrations would be greatest in the jugular venous circulation, representing blood exiting the brain, and would increase further during exercise as cerebral blood flow increased. Second because platelets are known to be activated by hypoxia, and this activation is amplified when hypoxia is combined with exercise in a dose-dependent manner, the authors anticipated that hypoxia would independently elevate free BDNF at rest and to an even greater extent during exercise. Third if platelet activation contributes to this process, increases in BDNF release across the brain should correspond with similar elevations in PF4 concentrations, because both molecules are co-stored and co-released from platelet α granules. These expectations led the researchers to predict the additive effects of exercise and hypoxia on BDNF and PF4 release, reflecting an integrated platelet-mediated neurotrophic response. Twelve healthy men and women performed incremental cycling exercise to exhaustion at sea level and after 6–8 days of acclimatization to high altitude (3800 m). The study used a repeated-measures cross-over design with simultaneous sampling of radial arterial and internal jugular venous blood. Radial arterial blood served as a surrogate for systemic arterial blood supplying the brain, whereas internal jugular venous blood reflected blood draining the brain. This approach allowed the investigators to estimate cerebral uptake and release patterns of neurotrophic factors. BDNF was measured in three forms: total BDNF from serum, free BDNF from platelet-poor plasma and platelet-saturated BDNF to account for the storage pool. PF4 was used as an index of platelet activation, and platelet counts assessed changes in platelet aggregation and degranulation. At sea level maximal exercise approximately doubled free BDNF concentrations in both arterial and venous blood, yet no veno-arterial difference was observed. This indicates that although circulating BDNF increased substantially, net cerebral release or uptake could not be detected. Such a pattern is consistent with a predominantly peripheral source of BDNF, potentially mediated by platelet activation. Still the possibility that the brain contributed BDNF cannot be excluded because cerebral release may have occurred outside the two sampling windows (end exercise and 5 min postexercise) and therefore gone undetected. Total platelet BDNF content remained stable during exercise, suggesting that one explanation for the increased plasma BDNF is redistribution from platelet stores rather than new synthesis. PF4 concentrations also doubled, indicating platelet activation, although this association alone does not establish causality and may represent only one component of a broader physiological response. Particularly both BDNF and PF4 returned to baseline within 5 min of recovery, highlighting the transient nature of these changes. Collectively the findings support the need for finer temporal sampling or alternative methodological approaches to clarify their contributions. At high altitude a different pattern emerged. Venous BDNF concentrations were significantly greater than arterial concentrations even at rest, revealing a net release of BDNF from the brain under hypoxic conditions. The magnitude of this veno-arterial difference was maintained during exercise, and the exercise-induced doubling of free BDNF persisted. These findings are consistent with the idea that platelets are activated by hypoxia to release stored contents and that this activation becomes more pronounced when hypoxia is combined with exercise. The authors proposed that such hypoxia-induced BDNF release may play a role in the adaptive process known as hypoxic preconditioning, in which repeated or brief exposure to hypoxia or ischaemia protects the brain from subsequent injury. Platelet activation provides a plausible explanation for the observed increase in BDNF during hypoxia, although delayed upregulation of BDNF gene expression under chronic exposure may also contribute. Importantly this study provides compelling human evidence that hypoxia alone can elicit cerebral BDNF release, bridging mechanistic observations in animal models with human physiology. PF4 followed a similar trajectory, increasing with both exercise and hypoxia and remaining consistently higher in venous than arterial blood at altitude. The strong correlation between PF4 and BDNF release supports the conclusion that platelet activation contributes concurrent liberation of these molecules. Platelet counts across the brain decreased by ∼25% during high-altitude exercise, consistent with aggregation and degranulation. These findings support that exercise and hypoxia independently stimulate platelet activation and that their combination produces additive effects, amplifying the release of both BDNF and PF4. Collectively this study demonstrates that the acute increase in circulating BDNF during exercise is most consistently explained by platelet-mediated release. This interpretation is supported by the increases in PF4, the unchanged total platelet BDNF content and the amplified response under hypoxia, which together point to a shared degranulation pathway activated by physiological stress. Although the findings suggest a platelet-derived origin, the absence of a veno-arterial gradient at sea level does not fully rule out cerebral release, because any neural contribution may have occurred outside the sampling window. Thus platelet activation appears to be the driver of the observed BDNF increase, with the possibility of a transient cerebral component, which remains unresolved. Although the transient surge in free BDNF quickly returned to baseline after exercise, raising questions about its lasting physiological impact, the work of Thomas and colleagues represents a meaningful step towards understanding how platelet biology and environmental stress shape neurotrophic signalling. The paired measurement of BDNF and PF4 was particularly valuable because PF4 offered a clearer index of platelet activation and strengthened the mechanistic interpretation beyond what BDNF alone could provide. This combined biochemical approach underscores platelets as active participants in neurotrophic communication and reveals a brief, stress-responsive signal rather than a sustained elevation. These findings lay the groundwork for future studies that use higher temporal resolution and additional neural markers to distinguish platelet-derived contributions from true cerebral release and to clarify how vascular health and environmental stressors support neuroplasticity and cognitive resilience across the lifespan. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. No competing interests declared. Sole author. None. The author thanks Dr Daniel Craighead, University of Minnesota–Twin Cities, for his valuable feedback and guidance on this article.