Selective GPR17 antagonism enhances structural and functional recovery in animal models of demyelination.

Myelination, driven by differentiation of oligodendrocyte precursor cells, is critical for metabolic and structural support and efficient axonal signal transmission in neurons. Loss of myelin is a hallmark of multiple sclerosis and other devastating demyelinating disorders. As demyelination persists, neurons become increasingly vulnerable, leading to neurodegeneration and chronic disability. Restoring myelin through endogenous repair mechanisms offers a promising therapeutic approach to mitigate progressive neuronal loss. One key regulator of myelination is the G protein-coupled receptor 17, GPR17, whose chronic upregulation in oligodendrocyte precursor cells is commonly seen with myelin injury. In line with single-nucleus transcriptomic data showing predominant expression of GPR17 in committed oligodendrocyte precursor cells, our postmortem immunohistochemical analyses of MS patient tissue revealed a significant upregulation of GPR17+/BCAS1+ oligodendrocyte precursor cells adjacent to and in demyelinated lesions. Importantly, remyelinated lesions lacked GPR17 immunoreactivity, consistent with a model in which sustained GPR17 expression is associated with demyelination and impaired oligodendrocyte precursor cell differentiation. To test the impact of pharmacological GPR17 inhibition on remyelination, we evaluated the effects of a novel, selective GPR17 antagonist in cuprizone-induced murine demyelination models. This toxin-induced approach has been widely used to study mechanisms of de- and remyelination, in the absence of the full inflammatory complexity of demyelinating diseases such as multiple sclerosis. We show that oral treatment results in robust functional recovery consistent with remyelination, as evidenced by improved spatial memory and recovery of visual evoked potential latency delays. GPR17 antagonism also accelerated structural remyelination in the corpus callosum and optic nerve. Together, these findings support a role for pharmacological GPR17 antagonism in promoting remyelination and highlight this G protein-coupled receptor as a promising therapeutic target for demyelinating disorders.