Protection from demyelination by the novel adenosine dual A2A/A2B receptor antagonist P626 in EAE and cultured oligodendrocyte precursor cells

Multiple sclerosis (MS) is a chronic inflammatory disease characterized 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 A2A and A2B receptors (A2AR, A2BR), it inhibits OPC maturation. In the efforts of developing remyelinating and neuroprotective agents, this study evaluated the ability of a novel dual A2AR/A2BR antagonist, P626, in the experimental autoimmune encephalomyelitis (EAE) mouse model and cultured OPCs. EAE mice, fourteen days after MOG35–55 immunization, received intranasal administration of P626 for two weeks that 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 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 A2AR- and A2BR-mediated reduction in sustained IK and transient IA currents, both essential for cell differentiation. In conclusion, P626 showed efficacy in reducing neurological symptoms and demyelination in an MS model.