Emerging nondopaminergic medications for parkinson’s disease: Focusing on a_2a receptor antagonists and glp1 receptor agonists

Parkinson’s disease (PD) is a severe neurodegenerative disease characterized by classic motor features associated with the loss of dopaminergic neurons and appearance of Lewy bodies in the substantia nigra. Due to the complexity of PD, a definitive diagnosis in the early stages and effective management of symptoms in later stages are difficult to achieve in clinical practice. Previous research has shown that colocalization of A_2A receptors (A_2AR) and dopamine D₂ receptors (D₂R) may induce an antagonistic interaction between adenosine and dopamine. Clinical trials have found that the A_2AR antagonist istradefylline decreases dyskinesia in PD and could be used as an adjuvant to levodopa treatment. Meanwhile, the incretin hormone glucagon-like peptide 1 (GLP1) mainly facilitates glucose homeostasis and insulin signaling. Preclinical experiments and clinical trials of GLP1 receptor (GLP1R) agonists show that they may be effective in alleviating neuroinflammation and sustaining cellular functions in the central nervous system of patients with PD. In this review, we summarize up-to-date findings on the usefulness of A_2AR antagonists and GLP1R agonists in PD management. We explain the molecular mechanisms of these medications and their interactions with other neurotransmitter receptors. Furthermore, we discuss the efficacy and limitations of A_2AR antagonists and GLP1R agonists in clinical practice.