A_2AR antagonist treatment for multiple sclerosis: Current progress and future prospects

Emerging evidence suggests that both selective and non-selective Adenosine A_2A receptor (A_2AR) antagonists could effectively protect mice from experimental autoimmune encephalomyelitis (EAE), which is the most commonly used animal model for multiple sclerosis (MS) research. Meanwhile, the recent FDA approval of Nourianz® (istradefylline) in 2019 as an add-on treatment to levodopa in Parkinson's disease (PD) with “OFF” episodes, along with its proven clinical safety, has prompted us to explore the potential of A_2AR antagonists in treating multiple sclerosis (MS) through clinical trials. However, despite promising findings in experimental autoimmune encephalomyelitis (EAE), the complex and contradictory role of A_2AR signaling in EAE pathology has raised concerns about the feasibility of using A_2AR antagonists as a therapeutic approach for MS. This review addresses the potential effect of A_2AR antagonists on EAE/MS in both the peripheral immune system (PIS) and the central nervous system (CNS). In brief, A_2AR antagonists had a moderate effect on the proliferation and inflammatory response, while exhibiting a potent anti-inflammatory effect in the CNS through their impact on microglia, astrocytes, and the endothelial cells/epithelium of the blood–brain barrier. Consequently, A_2AR signaling remains an essential immunomodulator in EAE/MS, suggesting that A_2AR antagonists hold promise as a drug class for treating MS.