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Erythroid-related nuclear factor 2 (NRF2) and the antioxidant-responsive-elements (ARE) signaling pathway are the master regulators of cell antioxidant defenses, playing a key role in maintaining cellular homeostasis, a scenario in which proper mitochondrial function is essential. Increasing evidence indicates that the regular practice of physical exercise increases cellular antioxidant defenses by activating NRF2 signaling. This manuscript reviewed classic and ongoing research on the beneficial effects of exercise on the antioxidant system in both the brain and skeletal muscle.

Fatigue reflects a typical limitation of endurance to physical exertion, but it is also a symptom at rest in many neurodegenerative diseases, which impair common activities in patients with multiple sclerosis, Parkinson's disease, and Alzheimer's disease. In this case, the symptom is known as central fatigue. The pharmacological and environmental approach of central fatigue is not effective because the pathophysiology is unclear. Raised neuronal adenosine A 2A receptor (A 2A R) density is associated with the pathology and clinical condition of these neurodegenerative diseases. The nonselective adenosine receptor antagonist caffeine has been shown to be a good therapeutic option for these cases. Caffeine is also the main ergogenic resource used by athletes. In this mini-review, we propose that central fatigue can be mediated by A 2A R in the central nervous system and that caffeine may be a good therapeutic option for central fatigue or neurodegenerative patients.