A2AR antagonist treatment for multiple sclerosis: Current progress and future prospects

Chenxing Qi; Yijia Feng; Yiwei Jiang; Wangchao Chen; Serhii Vakal; Jiang-Fan Chen; Wu Zheng

doi:10.1016/bs.irn.2023.05.012

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

Int Rev Neurobiol. 2023:170:185-223. doi: 10.1016/bs.irn.2023.05.012. Epub 2023 Jun 5.

Authors

Chenxing Qi¹, Yijia Feng², Yiwei Jiang³, Wangchao Chen⁴, Serhii Vakal⁵, Jiang-Fan Chen¹, Wu Zheng⁶

Affiliations

¹ State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, P.R. China; Oujiang Laboratory (Zhejiang Laboratory for Regenerative Medicine, Vision and Brain Health), School of Ophthalmology & Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou, P.R. China.
² Key Laboratory of Alzheimer's Disease of Zhejiang Province, Institute of Aging, Wenzhou Medical University, Wenzhou, Zhejiang, P.R. China.
³ Alberta Institute, Wenzhou Medical University, Wenzhou, P.R. China.
⁴ State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, P.R. China.
⁵ Structural Bioinformatics Laboratory, Biochemistry, Faculty of Science and Engineering, Åbo Akademi University, Turku, Finland.
⁶ State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, P.R. China; Oujiang Laboratory (Zhejiang Laboratory for Regenerative Medicine, Vision and Brain Health), School of Ophthalmology & Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou, P.R. China. Electronic address: zhengwu@wmu.edu.cn.

PMID: 37741692
DOI: 10.1016/bs.irn.2023.05.012

Abstract

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.

Keywords: A(2A)R antagonist; Adenosine A(2A) receptor; Experimental autoimmune encephalomyelitis; Multiple sclerosis.

Publication types

Research Support, Non-U.S. Gov't
Review

MeSH terms

Adenosine A2 Receptor Antagonists* / therapeutic use
Animals
Astrocytes
Central Nervous System
Encephalomyelitis, Autoimmune, Experimental* / drug therapy
Endothelial Cells
Mice
Multiple Sclerosis* / drug therapy

Substances

Adenosine A2 Receptor Antagonists