Intranasal delivery of FSD-C10, a novel Rho kinase inhibitor, exhibits therapeutic potential in experimental autoimmune encephalomyelitis.

Abstract

Viewing multiple sclerosis (MS) as both neuroinflammation and neurodegeneration has major implications for therapy, with neuroprotection and neurorepair needed in addition to controlling neuroinflammation in the central nervous system (CNS). While Fasudil, an inhibitor of Rho kinase (ROCK), is known to suppress experimental autoimmune encephalomyelitis (EAE), an animal model of MS, it relies on multiple, short-term injections, with a narrow safety window. In this study, we explored the therapeutic effect of a novel ROCK inhibitor FSD-C10, a Fasudil derivative, on EAE. An important advantage of this derivative is that it can be used via non-injection routes; intranasal delivery is the preferred route because of its efficient CNS delivery and the much lower dose compared with oral delivery. Our results showed that intranasal delivery of FSD-C10 effectively ameliorated the clinical severity of EAE and CNS inflammatory infiltration and promoted neuroprotection. FSD-C10 effectively induced CNS production of the immunoregulatory cytokine interleukin-10 and boosted expression of nerve growth factor and brain-derived neurotrophic factor proteins, while inhibiting activation of p-nuclear factor-κB/p65 on astrocytes and production of multiple pro-inflammatory cytokines. In addition, FSD-C10 treatment effectively induced CD4(+) CD25(+) , CD4(+) FOXP3(+) regulatory T cells. Together, our results demonstrate that intranasal delivery of the novel ROCK inhibitor FSD-C10 has therapeutic potential in EAE, through mechanisms that possibly involve both inhibiting CNS inflammation and promoting neuroprotection.

• Authors: Yan-Hua Li, Jie-Zhong Yu, Chun-Yun Liu, Hui Zhang, Hai-Fei Zhang, Wan-Fang Yang, Jun-Lian Li, Qian-Jin Feng, Ling Feng, Guang-Xian Zhang, Bao-Guo Xiao, Cun-Gen Ma
• Journal: Immunology (Immunology) Vol. 143 Issue 2 Pg. 219-29 (Oct 2014) ISSN: 1365-2567 [Electronic] England
• PMID: 24749492 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 John Wiley & Sons Ltd.

Chemical References

• Anti-Inflammatory Agents
• Brain-Derived Neurotrophic Factor
• DNA-Binding Proteins
• FSD-C10 compound
• Forkhead Transcription Factors
• Foxp3 protein, mouse
• IL10 protein, mouse
• Il2ra protein, mouse
• Inflammation Mediators
• Interleukin-2 Receptor alpha Subunit
• Nerve Tissue Proteins
• NeuN protein, mouse
• Neuroprotective Agents
• Nuclear Proteins
• Protein Kinase Inhibitors
• Rela protein, mouse
• Transcription Factor RelA
• Interleukin-10
• 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
• Nerve Growth Factor
• rho-Associated Kinases

Topics

• 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine (administration & dosage, analogs & derivatives)
• Administration, Intranasal
• Animals
• Anti-Inflammatory Agents (administration & dosage)
• Brain-Derived Neurotrophic Factor (metabolism)
• CD4-Positive T-Lymphocytes (drug effects, enzymology, immunology)
• Central Nervous System (drug effects, enzymology, immunology)
• DNA-Binding Proteins
• Encephalomyelitis, Autoimmune, Experimental (drug therapy, enzymology, immunology)
• Female
• Forkhead Transcription Factors (metabolism)
• Humans
• Inflammation Mediators (metabolism)
• Interleukin-10 (metabolism)
• Interleukin-2 Receptor alpha Subunit (metabolism)
• Mice
• Mice, Inbred C57BL
• Nerve Growth Factor (metabolism)
• Nerve Tissue Proteins (metabolism)
• Neuroprotective Agents (administration & dosage)
• Nuclear Proteins (metabolism)
• Protein Kinase Inhibitors (administration & dosage)
• Severity of Illness Index
• Spleen (drug effects, enzymology, immunology)
• Time Factors
• Transcription Factor RelA (metabolism)
• rho-Associated Kinases (antagonists & inhibitors, metabolism)