Exercise and hypoxia independently stimulate platelet liberation of brain‐derived neurotrophic factor and platelet factor 4

Brain-derived neurotrophic factor (BDNF) is an essential mediator of exercise-induced neuroplasticity. The majority of BDNF in circulation (∼99%) is stored bound to platelets. Platelet activation by exercise stimulates the release of their contents, representing a dynamic, bioavailable pool of BDNF. Hypoxia also independently activates platelets; therefore the combination of these stressors provides a unique model to examine the role of platelets in liberating BDNF and to quantify its flux across the brain during exercise. Twelve healthy adults (six women; 28 ± 4 years) performed exercise to exhaustion at sea level (340 m) and after 6-8 days at high altitude (3800 m) in a repeated-measures cross-over design. Simultaneous radial arterial and internal jugular venous blood samples were collected within the last 2 min of maximal exercise to quantify BDNF across the brain, alongside platelet concentration and platelet factor 4 (PF4), another neurogenic factor and a biomarker of platelet activation. At sea level, maximal exercise doubled free BDNF (P < 0.001) with no difference between arterial and venous circulations (P = 0.849). At high altitude, there was a pronounced veno-arterial difference indicating net release of BDNF (P = 0.003), and in addition, exercise caused a similar doubling in free BDNF (P < 0.001). Platelet concentration decreased by a third across the brain with exercise at high altitude (P = 0.002), but not sea level, and PF4 release was strongly correlated with BDNF release (r = 0.61, P < 0.001). Platelet activation across the human brain during exercise and hypoxia liberates BDNF and PF4 and may contribute to the neurotrophic effect of exercise. KEY POINTS: Brain-derived neurotrophic factor (BDNF) is a protein involved in synaptic plasticity and neuronal growth, and it may mediate some of the neuroprotective effects of exercise. The majority of BDNF in circulation is stored bound to platelets, released as free BDNF into the plasma by platelet activation (e.g. by exercise or hypoxia). At sea level, maximal exercise doubled free BDNF to a similar extent between arterial and venous circulations. At high altitude, at rest, a net release of BDNF from the brain was observed (veno-arterial difference), with a similar doubling in free BDNF with maximal exercise. Platelet factor 4, a metric of platelet activation, was correlated with BDNF release, indicating that platelet activation offers an explanation for the increased liberation of BDNF during exercise and hypoxia.