Pharmacological blockade of GPR17 promotes functional and structural remyelination in the murine cuprizone model

Abstract

Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system. Current therapies are very efficacious in reducing inflammatory MS relapses but do not prevent the progression of the disease. One of the drivers of disability progression has been linked to chronic demyelination which can lead to irreversible axonal damage and neuronal death. Remyelination, the generation of new myelin in the adult nervous system, is an endogenous repair mechanism that provides metabolic support to axons and restores axonal functions. A significant drive in development of MS therapeutics is to address this high unmet medical need and to identify drug targets that can promote remyelination by engaging oligodendrocyte precursor cells (OPC) to form new myelin. G protein-coupled receptor 17 (GPR17) has been identified as an important regulator in oligodendrocytes development and remyelination. Here, we demonstrate that blocking GPR17 using a novel proprietary orally acting small molecule (RWT001) enhances remyelination in an acute cuprizone model. Male C57Bl/6 mice were fed with a diet containing 0.3% cuprizone for 6 weeks to induce demyelination, followed by 9 days of daily p.o. treatment with RWT001 during normal diet feeding to induce remyelination. Non-invasive visual evoked potential (VEP) latency time was recorded to assess the myelin status of the optic nerve. Compared to baseline, the VEP latency was significantly delayed following 6 weeks of cuprizone treatment. Treatment with RWT001 significantly stimulated recovery of the VEP latency time as compared to the vehicle, indicating improved in vivo remyelination of the optic nerve during the treatment period. In agreement with the functional VEP data, histological analysis of markers of myelination showed increased remyelination in the corpus callosum following treatment with RWT001 as compared to the vehicle. Collectively, our study provided evidence that the small molecule compound RWT001, which selectively and potently inhibits the GPR17 receptor, accelerates functional remyelination in the cuprizone model and as such might contribute to the repair-inducing treatments for myelin-related disorders.