Adenosinergic Pathway in Parkinson's Disease: Recent Advances and Therapeutic Perspective

Parkinson's disease (PD) is a neurodegenerative disease characterized pathologically by α-synuclein (α-syn) aggregation. In PD, the current mainstay of symptomatic treatment is levodopa (L-DOPA)-based dopamine (DA) replacement therapy. However, the development of dyskinesia and/or motor fluctuations which is relevant to levodopa is restricting its long-term utility. Given that the ability of which is to modulate the striato-thalamo-cortical loops and function to modulate basal ganglia output, the adenosinergic pathway (AP) is qualified as a potential promising non-DA target. As an indispensable component of energy production pathways, AP modulates cellular metabolism and gene regulation in both neurons and neuroglia cells through the recognition and degradation of extracellular adenosine. In addition, AP is geared to the initiation, evolution, and resolution of inflammation as well. Besides the above-mentioned crosstalk between the adenosine and dopamine signaling pathways, the functions of adenosine receptors (A₁R, A_2AR, A_2BR, and A₃R) and metabolism enzymes in modulating PD pathological process have been extensively investigated in recent decades. Here we reviewed the emerging findings focused on the function of adenosine receptors, adenosine formation, and metabolism in the brain and discussed its potential roles in PD pathological process. We also recapitulated clinical studies and the preclinical evidence for the medical strategies targeting the Ado signaling pathway to improve motor dysfunction and alleviate pathogenic process in PD. We hope that further clinical studies should consider this pathway in their monotherapy and combination therapy, which would open new vistas to more targeted therapeutic approaches.