Abstract
Excessive exercise can lead to physical fatigue and disruption of the antioxidant system, resulting in neurological damage and cognitive decline. Cordycepin, the main component of Cordyceps militaris, has anti-inflammatory, antioxidant and neuroprotective effects. In this study, the anti-fatigue effect and potential mechanism of action of cordycepin were investigated using a forced exercise mouse model. The results showed that oral administration of cordycepin enhanced exercise endurance, increased liver and muscle glycogen content, and simultaneously decreased serum levels of lactic acid, lactate dehydrogenase, creatine kinase, and blood urea nitrogen (p < 0.05). In addition, cordycepin had antioxidant effects, increasing superoxide dismutase activity and decreasing serum malondialdehyde (MDA) levels (p < 0.01). In vitro experiments further demonstrated the antioxidant and anti-fatigue effects of cordycepin. Behavioral tests showed that the learning and memory ability of mice in the excessive exercise model group decreased to 40% compared with the control group. Cordycepin alleviated the learning and memory deficits in the over-exercised mice, significantly reduced the levels of fatigue metabolites and oxidative stress in vivo (p < 0.05), and altered the levels of neurotransmitters levels (p < 0.05). Furthermore, cordycepin modulated Keap1/Nrf2/HO-1-mediated oxidative stress and enhanced BDNF levels (p < 0.05). These findings suggest that cordycepin can alleviate excessive exercise-induced fatigue by modulating the Keap1/Nrf2/HO-1 signaling pathway and BDNF expression, providing strong supporting evidence for the development of cordycepin-functional foods or anti-fatigue drugs.