Protective effect of a novel Rho kinase inhibitor WAR–5 in experimental autoimmune encephalomyelitis by modulating inflammatory response and neurotrophic factors

Abstract

The Rho-kinase (ROCK) inhibitor Fasudil has proven beneficial in experimental autoimmune encephalomyelitis (EAE). Given the small safety window of Fasudil, we are looking for novel ROCK inhibitors, which have similar or stronger effect on EAE with greater safety. In this study, we report that WAR–5, a Y-27632 derivative, alleviates the clinical symptoms, attenuates myelin damage and reduces CNS inflammatory responses in EAE C57BL/6 mice at an extent similar to Fasudil, while exhibits less vasodilator and adverse reaction in vivo. WAR–5 inhibits ROCK activity, and selectively suppresses the expression of ROCK II in spleen, brain and spinal cord of EAE mice, especially in spinal cord, accompanied by decreased expression of Nogo. WAR-5 also regulates the imbalance of Th1/Th17 T cells and regulatory T cells, inhibits inflammatory microenvironment induced with NF–κB-IL-1β pathway. Importantly, WAR–5 converts M1 toward M2 microglia/macrophages that are positively correlated with BDNF and NT-3 production. Taken together, WAR–5 exhibits therapeutic potential in EAE by more selectively inhibits ROCK II, with a greater safety than Fasudil, and is worthy of further clinical study to clarify its clinical value.