Caffeine, a natural methylxanthine nutraceutical, exerts dopaminergic neuroprotection.

Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects more than 10 million people worldwide. Oxidative stress and mitochondrial dysfunction play a significant role in altering the homeostasis of energy production and free radical generation. Current PD therapies are focused on reducing the cardinal symptoms rather than preventing disease progression in the patients. Adenosine A2A receptor (A2A R) antagonist (Istradephylline) combined with levodopa shows a promising therapy for PD. In animal studies, caffeine administration showed to improve motor functions and neuroprotective effect in the neurons. Caffeine is probably the most extensively used psychoactive substance. In this current study, we investigated the neuroprotective effect of caffeine against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurodegeneration. Here, we demonstrate that caffeine improves behavioral and neurotransmitter recovery against MPTP-induced toxicity. Caffeine restores endogenous antioxidant levels and suppresses neuroinflammation. Our finding suggests that the blockage of A2AR is a promising disease-modifying therapy for PD. Target engagement strategies could be more beneficial in preventing disease progression rather than symptomatic reliefs in PD patients.