Parkinson´s disease (PD) is one of the most common neurodegenerative diseases characterized by a loss of dopaminergic-neurons in the substantia nigra and accumulation of misfolded α-synuclein protein aggregates in Lewy bodies. Leading symptoms of PD are bradykinesia or akinesia with rest tremor, postural instability or rigor. Additionally, patients suffering from PD show a broad range of non-motor symptoms differing in early and late-stage symptoms, e.g., obstipation and dementia. Despite an unknown etiology of PD, many risk factors such as age, male gender, environmental factors, intestinal inflammation, and genetics are described [53,54]. Besides the known risk factors it is discussed that nutrition may be associated with increased (dairy products) or decreased (phytochemicals, Omega-3 fatty acids, tea) risk or progression in PD [55]. Multiple epidemiological studies could already demonstrate an inverse association between coffee drinking and PD and thereby suggest a link to caffeine, and consequently methylxanthines, as A2A receptor antagonists [56,57,58]. Recent studies have confirmed this association (for an overview see Table 3). Bakshi et al. found a significantly lower caffeine intake, determined through questionnaire, in idiopathic PD patients compared to control group from the Harvard Biomarkers Study cohort with 369 cases of PD and 197 healthy controls [59]. In a study from Fujimaki et al., the authors investigated serum from 108 patients with PD by liquid chromatography-mass spectrometry (LC-MS) compared to 31 age-matched healthy control participants and found significantly lowered serum levels of not only caffeine, but also its downstream products like theophylline, theobromine and paraxanthine [60]. Crotty et al. demonstrated similar results in a recent metabolomics study showing a significantly lower plasma and CSF concentration of caffeine (71% lower) and its degradation products, e.g., paraxanthine and theophylline (57%, 56% lower), in PD patients versus control group measured via LC-MS. Subgroup analysis of carriers of the LRRK2 mutation, a mutation in the leucine-rich repeat kinase 2 gene (known for an increased risk for sporadic PD) [61], revealed an even greater decrease of plasma caffeine level by 76% for PD LRRK2 mutation carriers compared to healthy LRRK2 carriers [62]. Ohmichi et al. found similar results for the methylxanthine analogue theophylline and confirmed a significantly lower plasma concentration in patients with PD versus an age-matched control group [63]. A recent meta-analysis by Hong et al., which included 13 studies in total, showed that for healthy individuals, caffeine consumption results in a significantly lower risk of developing PD specific symptoms (HR = 0.797, 95% CI: 0.748–0.849, p < 0.001, I2: ~ 15.41%, 9/13 studies). Furthermore, a significant deceleration of PD progression among early-stage PD individuals with higher caffeine consumption was found (HR = 0.834, 95% CI = 0.707–0.984, p = 0.03, I²: ~39.7%, 4/13 studies) [64]. Another interesting recent study, carried out by Maclagan et al., used a computational approach to rank 620 drugs with the ability to inhibit α-synuclein aggregation. They examined associations between the top 15 drugs in case-control validation study by using health administrative databases. Their logistic regression models found that patients exposed to methylxanthines, especially the synthetic pentoxifylline (PTX) and the natural occurring theophylline, were associated with decreased odds of occurrence of PD. Additionally longer durations of PTX administration revealed a trend towards dose-response [65]. One modified methylxanthine, istradefylline (ISD), has been used to decrease daily “off episodes”, a state where symptoms recur when the effect of L-DOPA weakens, in PD patients. ISD was approved first in Japan in May 2013 and by the FDA in the US in 2019 [66]. A meta-analysis including six studies revealed that treatment with ISD 40 mg/day decreased the duration of “off episodes” and enhanced the motor symptoms of PD patients. Similar effects could be found for 20 mg/day. ISD treatment revealed no significant effect on adverse effects. In summary the meta-analysis showed that ISD 20 mg and 40 mg both improved the unified Parkinson’s disease rating scale III (UPDRS) [67].

Older studies have already demonstrated neuroprotective effects of caffeine in PD mouse models [68]. In line with these previous encouraging results, Luan et al. demonstrated that chronic caffeine treatment reduced the effect of intra-striatal injected human A53T α-Synuclein fibrils in mice [69]. Caffeine was administered seven days before the injection and applied for 120 days at concentrations of ~0.4–2 mg/L. They found significantly decreased inclusion of α-Synuclein in the striatum of the caffeine treated mice. Furthermore, apoptosis, microglial activation and astrogliosis were significantly reduced [69]. A similar study used 52 rats with a control group, a PD model group—generated by injecting 1.5 mg/kg rotenone intraperitoneally (i.p.) for 45 days—and two caffeine groups. One of the caffeine groups was injected with 30 mg/kg caffeine i.p. in addition to the administered rotenone for 45 days, whereas the other group was treated with caffeine after the induction of PD via rotenone. The study revealed that co-treatment and post-treatment with caffeine in the intoxicated rats enhanced the dysfunction of rotenone-induced motor symptoms by recovering dopamine levels in the midbrain and striatum. In addition, caffeine improved the antioxidant effect by reducing rotenone-induced lipid peroxidation and superoxide dismutase activity in the striatum and midbrain. Furthermore, the data revealed reduced rotenone-induced TNF-α activity in the caffeine groups indicating an anti-inflammatory effect of caffeine. Caffeine protection and treatment restored open field test parameters, forelimb hanging test and traction test to nearly control group values. Histopathological investigation revealed a degeneration of neurons and presence of Lewy bodies in the rotenone-induced PD group, which was prevented in both caffeine groups with a more prominent effect in the caffeine protected group [70]. Pardo et al. demonstrated in another animal study that the naturally occurring methylxanthine theophylline can reverse motor symptoms in rats. In this study theophylline reversed locomotion, catalepsy and tremulous jaw movement (resembling parkinsonian tremor) induced by pimozide, a D2 dopamine antagonist [71]. In conclusion, these studies show a link for caffeine and other methylxanthines acting as A2A receptor antagonists with a decreased risk for PD and modification of progression, indicating new adenosine receptor ligands might be encouraging targets in treating PD. In a study by Rohilla et al. newly synthesized xanthine derivates as selective AR antagonists were analyzed. Evaluation of the antiparkinsonian effect in the study was carried out by inducing catatonia in rats with perphenazine. Most xanthines significantly lowered the catatonic score compared to control. The most potent antiparkinsonian effect was found for the methylxanthine RB-531 (8-[3-(3-Chloropropxy)]-1,3-dipropyl-7-methylxanthine), showing a similar response as the standard treatment L-DOPA [72]. The abovementioned studies and their outcomes are summarized in Figure 2 and Table 4.