Protection From Demyelination by the Novel Adenosine Dual A_2A/A_2B Receptor Antagonist P626 in EAE and Cultured...

Multiple sclerosis (MS) is a chronic inflammatory disease characterised by myelin and axonal loss. Lack of remyelination is primarily attributed to the failure of oligodendrocyte progenitor cells (OPCs) to differentiate into mature oligodendrocytes. The neuromodulator adenosine can influence OPC differentiation, and by selectively stimulating A_2A and A_2B receptors (A_2AR, A_2BR), it inhibits OPC maturation. In the efforts of developing remyelinating and neuroprotective agents, this study evaluated the ability of a novel dual A_2AR/A_2BR antagonist, P626, in the experimental autoimmune encephalomyelitis (EAE) mouse model and cultured OPCs. EAE mice, 14 days after MOG_35-55 immunisation, received intranasal administration of P626 for 2 weeks, which improved motor symptoms, as evidenced by reduced clinical scores and enhanced performance on the rotarod test, and alleviated thermal and mechanical hypersensitivity without significantly affecting body weight. In spinal cord sections, P626 protected from the reduction of Luxol Fast Blue staining and increased myelin basic protein staining in immunohistochemical analysis. Patch-clamp experiments on cultured OPCs exposed to high extracellular adenosine concentrations demonstrated that P626 prevented the A_2AR- and A_2BR-mediated reduction in sustained I_K and transient I_A currents, both essential for cell differentiation. In conclusion, P626 showed efficacy in reducing neurological symptoms and demyelination in an MS model.