Caffeine and Parkinson’s Disease: Multiple Benefits and Emerging Mechanisms

Abstract

Parkinson’s disease (PD) is the second most common neurodegenerative disorder, characterized by dopaminergic neurodegeneration, motor impairment and non-motor symptoms. Epidemiological and experimental investigations into potential risk factors have firmly established that dietary factor caffeine, the most-widely consumed psychoactive substance, may exerts not only neuroprotective but a motor and non-motor (cognitive) benefits in PD. These multi-benefits of caffeine in PD are supported by convergence of epidemiological and animal evidence. At least six large prospective epidemiological studies have firmly established a relationship between increased caffeine consumption and decreased risk of developing PD. In addition, animal studies have also demonstrated that caffeine confers neuroprotection against dopaminergic neurodegeneration using PD models of mitochondrial toxins (MPTP, 6-OHDA, and rotenone) and expression of α-synuclein (α-Syn). While caffeine has complex pharmacological profiles, studies with genetic knockout mice have clearly revealed that caffeine’s action is largely mediated by the brain adenosine A2A receptor (A2AR) and confer neuroprotection by modulating neuroinflammation and excitotoxicity and mitochondrial function. Interestingly, recent studies have highlighted emerging new mechanisms including caffeine modulation of α-Syn degradation with enhanced autophagy and caffeine modulation of gut microbiota and gut-brain axis in PD models. Importantly, since the first clinical trial in 2003, United States FDA has finally approved clinical use of the A2AR antagonist istradefylline for the treatment of PD with OFF-time in Sept. 2019. To realize therapeutic potential of caffeine in PD, genetic study of caffeine and risk genes in human population may identify useful pharmacogenetic markers for predicting individual responses to caffeine in PD clinical trials and thus offer a unique opportunity for “personalized medicine” in PD.

Elucidating the Neuroprotective Role of PPARs in Parkinson’s Disease: A Neoteric and Prospective Target

“…Numerous researchers have explored the action of caffeine (a most extensively utilized psychoactive agent) intake on the evolution of PD and discovered that individuals consuming coffee are less prone to the condition [ 214 , 215 , 216 ]. Caffeine belongs to the class of purinergic P1 adenosine (ADO) A 2A receptor inhibitors, which are considered to exert a beneficial action on patients experiencing PD [ 217 ], and has been proven to exhibit a neuroprotective role in experimental mouse models experiencing PD [ 218 ].…”

Targeting Melanoma-Initiating Cells by Caffeine: In Silico and In Vitro Approaches

“…Finally, a crucial role of the gut microbiota in the immunomodulation of melanoma patients has recently been demonstrated, with important implications for cancer treatment [56,57]. This opens up a further fascinating point of view for correlating the in vivo effects of Caff, whose modulation of gut microbiota has been reported [58,59], possibly by acting on TYR and melanin production.…”

Neuropeptide S Receptor as an Innovative Therapeutic Target for Parkinson Disease

“…The adenosinergic system could be another mechanism by which NPS mediates antiparkinsonian effects. In fact, adenosine A 2A receptor antagonists, including caffeine, are reported to be innovative therapeutic strategies for the treatment of behavioral symptoms and neurodegeneration of PD [ 78 , 79 ]. A parallel between caffeine and NPS effects has already been drawn in the literature.…”