# Protection From Demyelination by the Novel Adenosine Dual A2A /A2B Receptor Antagonist P626 in EAE and Cultured Oligodendrocyte Precursor Cells

## TL;DR

A new drug called P626 helps protect against myelin loss and improves symptoms in a mouse model of multiple sclerosis.

## Contribution

P626, a novel dual adenosine A2A/A2B receptor antagonist, shows remyelinating and neuroprotective effects in EAE and cultured OPCs.

## Key findings

- P626 improved motor symptoms and reduced hypersensitivity in EAE mice without affecting body weight.
- P626 preserved myelin staining in spinal cord sections of treated mice.
- P626 prevented adenosine-induced reduction in key ion currents in cultured OPCs, supporting cell differentiation.

## Abstract

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 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, 14 days after MOG35–55 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 A2AR‐ and A2BR‐mediated reduction in sustained I

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and transient I

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currents, both essential for cell differentiation. In conclusion, P626 showed efficacy in reducing neurological symptoms and demyelination in an MS model.