G Protein-Coupled Receptor 17 Inhibition as a Prospective Treatment for Multiple Sclerosis: A Research Protocol

Abstract

Introduction: Multiple sclerosis (MS) is a chronic inflammatory neurodegenerative disease. MS is the most prevalent neurological disability that often leads to severe cognitive or physical incapacitations in young adults. As MS is currently an incurable disease, more effective treatments need to be investigated. The disease is associated with axonal degenerations and the development of demyelinated plaques, due to episodic autoimmune destruction of oligodendrocytes. Usually, demyelination is followed by remyelination as the brain attempts to reconstruct the myelin sheaths. Oligodendrocyte precursor cells are essential for remyelination as these cells proliferate and differentiate into mature oligodendrocytes. An important regulator of oligodendrocyte development is G protein-coupled receptor 17 (GPR17), whose inhibition has been suggested in previous studies to the promote oligodendrocyte differentiation and remyelination. As such, a potential therapy for MS patients is through decreasing GPR17 expression via inhibition of one of its ligands, LTC4. Methods: We aim to promote remyelination in MS patients using the LTC4 synthase inhibitor AZD9898 to indirectly partially inhibit GPR17 in proteolipid protein-induced experimental autoimmune encephalomyelitis (PLP-induced EAE) MS mice models. There will be 6 experimental groups and 8 control groups. All experimental groups will receive a three mg dose of AZD9898. After approximately zero, one, five and ten days, the mice will be sacrificed, and magnetic resonance imaging will be conducted. The myelin water fraction will then be determined to visualize in vivo myelination of the central nervous system through myelin water imaging. Western blotting will be used to verify AZD9898’s indirect inhibition of GPR17. The resulting data will be analyzed with the Kolomogorov–Smirnov test, Pearson’s correlation coefficient (linear) and two-tailed paired t-tests and ImageJ software. Anticipated Results: It is expected that AZD9898 administration in PLP-induced EAE mice models will result in an increased myelin water fraction, indicating remyelination, alongside decreased GPR17 expression. Discussion: These results will provide a potential treatment for MS by illustrating how AZD9898 is effective at indirectly inhibiting GPR17 in mice models, and thus promoting remyelination. Conclusion: This study will provide insight on the treatment of demyelinating diseases by demonstrating how pharmacological inhibition of GPR17 ligand LTC4 can promote remyelination in MS patients.