BBB-penetrant selective ROCK2 inhibitor ameliorates a murine model of multiple sclerosis by harnessing inflammation and demyelination 2632

Abstract Description Multiple sclerosis (MS) is a chronic and progressive autoimmune disease affecting the central nervous system. It is characterized by damage to neurons myelin protective sheath, which results in impaired nervous communication and consequently in deterioration of physical, cognitive and mental capacities. Rho-associated coiled-coil-containing protein kinase 2 (ROCK2) regulates key signaling pathways involved in pro-inflammatory immune response. Selective ROCK2 inhibition has been shown to dampen inflammation – notably autoimmune Th17 and innate immune responses, in various tissues and pathologies, but not in MS. Here, we show that therapeutic oral administration of novel BBB-penetrant selective ROCK2 inhibitor ameliorates limb paralysis and significantly reduces the clinical scores in an Experimental Autoimmune Encephalomyelitis (EAE) murine model of MS, consistent with efficient target engagement in the brain. ROCK2 inhibition improves the demyelination score, decreases inflammatory foci and Th17 cells while increasing Treg and microglia populations in the spinal cord. Ex vivo, ROCK2 targeting directly promotes both myelin expression and myelinating capacity in oligodendrocytes and upregulates phagocytosis of myelin residues by microglia, two crucial aspects for effective remyelination. These data underscore the therapeutic potential of selective ROCK2 inhibition in MS by concurrently rebalancing disease-associated inflammation and promoting remyelination. Topic Categories Neuroimmunology (NEUR)