The therapeutic potential of Rho kinase inhibitor fasudil derivative FaD-1 in experimental autoimmune encephalomyelitis.

Abstract

Although therapeutic potential of fasudil in EAE is promising, action mechanism and clinical limitations are still not fully understood and resolved. In this study, we observed the therapeutic potential of a novel Rho kinase (ROCK) inhibitor FaD-1, a fasudil derivative, and explored possible mechanism in MOG35-55-induced EAE. Experimental autoimmune encephalomyelitis (EAE) was induced by myelin oligodendrocyte glycoprotein (MOG35-55) immunization. The pathology of spinal cord was measured by immunohistochemistry and neurological impairment was evaluated using clinical scores. FaD-1, as a novel ROCK inhibitor, inhibited the expression of ROCK II that is mainly expressed in the CNS. We show here that FaD-1 ameliorates the neurological defects and the severity of MOG-induced EAE in mice, accompanied by the protection of demyelination and the inhibition of neuroinflammation in spinal cord of EAE. In addition, FaD-1 dampened TLR2 and TLR4 signaling as well as Th1 (IFN-γ) and Th17 (IL-17) responses in spinal cord of EAE. FaD-1 also prevented the expression of iNOS and production of inflammatory cytokine IL-1β, IL-6, and TNF-α which are specific markers for M1 inflammatory microglia/macrophages. This study highlights the therapeutic potential of FaD-1 as a ROCK inhibitor for the treatment of human autoimmune diseases with both inflammatory and autoimmune components.

• Authors: Yong-Fei Zhao, Xiang Zhang, Zhi-Bin Ding, Xing-Wang Yang, Hui Zhang, Jie-Zhong Yu, Yan-Hua Li, Chun-Yun Liu, Qing Zhang, Hong-Zhen Zhang, Cun-Gen Ma, Bao-Guo Xiao
• Journal: Journal of molecular neuroscience : MN (J Mol Neurosci) Vol. 55 Issue 3 Pg. 725-32 (Mar 2015) ISSN: 1559-1166 [Electronic] United States
• PMID: 25223373 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Interleukins
• Protein Kinase Inhibitors
• Toll-Like Receptor 2
• Toll-Like Receptor 4
• Tumor Necrosis Factor-alpha
• Interferon-gamma
• 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
• Nitric Oxide Synthase Type II
• rho-Associated Kinases
• fasudil

Topics

• 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine (analogs & derivatives, pharmacology, therapeutic use)
• Animals
• Cells, Cultured
• Encephalomyelitis, Autoimmune, Experimental (drug therapy)
• Female
• Interferon-gamma (genetics, metabolism)
• Interleukins (genetics, metabolism)
• Mice
• Mice, Inbred C57BL
• Nitric Oxide Synthase Type II (genetics, metabolism)
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Spinal Cord (drug effects, metabolism, pathology)
• Toll-Like Receptor 2 (metabolism)
• Toll-Like Receptor 4 (metabolism)
• Tumor Necrosis Factor-alpha (genetics, metabolism)
• rho-Associated Kinases (antagonists & inhibitors)