Caffeine consumption and Parkinson’s disease: a mini-review of current evidence

In the absence of efficient disease-modifying treatments for Parkinson’s disease (PD), research has focused on identifying potential environmental factors whose modulation may prevent or slow the progression of this neurodegenerative disorder. Compelling epidemiological evidence suggests that caffeine consumption is inversely associated with the risk of developing PD. Further experimental findings demonstrated that caffeine, by particularly targeting adenosine A2A (A2AR) receptors, protected PD animal models against the loss of dopaminergic neurons. The antagonistic action of caffeine on adenosine receptors not only slowed PD-related neurodegeneration, but also improved motor and nonmotor symptoms of PD in animal models. Here, we review the potential action mechanisms by which caffeine might play a role in reducing the risk of PD. We also review current evidence of the benefits of caffeine consumption in motor and nonmotor symptoms of PD. Finally, we point out how these promising findings could lead to the identification of new approaches for effective treatment of PD.

Synthetic caffeine can also be added to food, beverages, and In this study, we provide a mini-review of the potential action mechanisms by which caffeine may reduce the risk of developing PD. We also provide current evidence of the benefits of caffeine consumption in motor and nonmotor symptoms of PD. Finally, we discuss how these findings may open novel avenues for advancing therapeutic strategies in PD.

Modulation of adenosine receptors in brain physiology and Parkinson's disease pathogenesis
Caffeine is a competitive, non-selective antagonist of adenosine receptors, which belongs to the G-protein-coupled receptor (GPCR) family 5 . Three classes have been used to classify these receptors: A 1 , A 2 , and A 3 5 . Adenosine A 1 (A 1 R) and A 2A (A 2A R) receptors are the commonest types of adenosine receptors found in the brain 6 , wherein both A 1 R and A 2A R are mostly located in synapses, particularly in the excitatory (glutamatergic) ones 6 . The A 1 R is highly expressed in the cortex, hippocampus, and cerebellum, whereas A 2A R is primarily found in the basal ganglia, although it can also be found at low levels in other brain regions, such as the hippocampus and cortex 6 . The consumption of 3 to 4 cups of coffee per day is sufficient to occupy nearly 50% of A 1 R and A 2A R for at least several hours 1 .
While A 2A R is mostly coupled to G s proteins, A 1 R is primarily coupled to G i/o proteins, whose activation leads to excitatory and inhibitory effects, respectively. For example, the activation of A 2A R by extracellular adenosine increases gamma-aminobutyric acid (GABA) uptake by astrocytes, which decreases tonic GABAergic inhibition and enhances excitatory tonus 6 . On the other hand, A 1 R activation inhibits GABA transport into astrocytes, thereby increasing extracellular concentrations of GABA and depressing excitatory drive 6 . In neurons, postsynaptic activation of A 1 R inhibits N-methyl-D-aspartate (NMDA) receptor-mediated currents 6 , and it may also lead to membrane hyperpolarization via G-protein-dependent activation of inwardly rectifying K + channels (GIRKs) 6 . Conversely, the presynaptic activation of A 1 R inhibits the release of several neurotransmitters (e.g., glutamate, GABA, acetylcholine, and monoamines) probably via G-protein-coupled inhibition of Ca 2+ channels at the nerve terminals 6 . In general, the most prominent inhibitory effect mediated by adenosine is at the level of excitatory synapses, whereas adenosinemediated inhibition of GABAergic transmission is less frequently observed. Therefore, the net effect of adenosine receptor activation is to decrease excitability throughout the brain 2 . This is consistent with findings of caffeine-induced Interestingly, a U-shaped association between coffee consumption and risk of PD was found in the female subgroup, wherein women who reported drinking 1 to 3 cups of coffee/day had the lowest risk of developing PD 9 . More recently, a meta-analysis involving 13 cohort studies showed that caffeine consumption was significantly associated with a lower risk of developing PD in the healthy cohort, as well as with a lower rate of PD progression in the PD cohort 10 . Since the consumption of decaffeinated coffee was not significantly linked to a lower risk of PD 9 , the inverse association between coffee drinking and PD was particularly attributable to caffeine itself rather than to other coffee components. weeks after the beginning of MPTP infusions 11 . Similar neuroprotective effects of caffeine were also observed in 6hydroxydopamine (6-OHDA)-lesioned rats 13 , as well as in rats chronically exposed to pesticides 14 .
The neuroprotective benefits of caffeine have also been observed in α-synuclein (α-Syn)-mediated pathology. A recent study showed that chronic caffeine consumption (at  The consumption of caffeine has also been hypothesized to enhance cognitive performance, especially in the elderly.

Benefits of Caffeine in nonmotor symptoms of
In animal models of PD, caffeine at the doses of 0.1 and 0.3 mg/kg reversed cognitive impairments in MPTP-lesioned rats compared to control rats 29 . Caffeine at doses up to 30.0 mg/kg also reversed deficits in social recognition memory of reserpine-treated rats compared to control rats 30 . This modulatory effect is likely dependent on A 2A R signaling, since the A 2A R antagonist ZM241385 but not the A 1 R antagonist DPCPX was also found to rescue reserpine-induced deficits in social recognition memory 30 . Importantly, beneficial effects of caffeine (as well as A 2A R antagonist ZM241385) cannot be explained by improvements in locomotor activity of MPTPand reserpine-treated rats since no behavioral changes were observed in these animals 29,30 .