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.
Highlights
Parkinson’s disease (PD) is the second most common neurodegenerative disorder characterized by clinical presentation of motor impairment and non-motor symptoms
With the discovery of α-Syn as the main pathogenesis gene and the main component of Lewy body (Lashuel et al, 2013; Kalia and Kalia, 2015; Wong and Krainc, 2017), wide-spread distribution of α-Syn aggregates in the brain provide the pathological basis for non-motor symptoms of PD which are increasingly recognized as a key component of the disease (Chaudhuri et al, 2006; Postuma and Berg, 2016)
We described the potential mechanisms underlying caffeine’s protective effects, including modulation of neuroinflammation and of newly emerging mechanisms associated with autophagy and gut microbiota
Summary
Parkinson’s disease (PD) is the second most common neurodegenerative disorder characterized by clinical presentation of motor impairment and non-motor symptoms. With the discovery of α-Syn as the main pathogenesis gene and the main component of Lewy body (Lashuel et al, 2013; Kalia and Kalia, 2015; Wong and Krainc, 2017), wide-spread distribution of α-Syn aggregates in the brain provide the pathological basis for non-motor symptoms of PD (e.g., cognitive dysfunction, fatigue, balance impairment, sleep disturbance, autonomic dysfunction) which are increasingly recognized as a key component of the disease (Chaudhuri et al, 2006; Postuma and Berg, 2016). We discussed possible genetic polymorphisms of caffeineassociated genes in influencing caffeine drug responses and its clinical implications
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