Caffeine, a natural methylxanthine nutraceutical, exerts dopaminergic neuroprotection

Neurochem Int. 2021 Sep:148:105066. doi: 10.1016/j.neuint.2021.105066. Epub 2021 May 15.


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.

Keywords: Adenosine A(2A) receptor; Caffeine; Dopamine; Neurodegenerative disease; Neuroprotection; Parkinson's disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antioxidants / pharmacology
  • Behavior, Animal / drug effects
  • Caffeine / pharmacology*
  • Dietary Supplements*
  • Dopaminergic Neurons / drug effects*
  • MPTP Poisoning / drug therapy*
  • MPTP Poisoning / pathology
  • MPTP Poisoning / psychology
  • Mice
  • Mice, Inbred C57BL
  • Neuroinflammatory Diseases / drug therapy
  • Neuroprotective Agents / pharmacology*
  • Substantia Nigra / metabolism
  • Substantia Nigra / pathology


  • Antioxidants
  • Neuroprotective Agents
  • Caffeine