Idazoxan reduces blood-brain barrier damage during experimental autoimmune encephalomyelitis in mouse.

Abstract

We have previously shown that Idazoxan (IDA), an imidazoline 2 receptor ligand, is neuroprotective against spinal cord injury caused by experimental autoimmune encephalomyelitis (EAE) in mouse, an animal modal of multiple sclerosis (MS). However, the protective mechanism remains unclear. Here, we provided evidence to show that IDA confers neuroprotection through reduction in blood-brain barrier (BBB) damage. EAE was induced by immunizing C57 BL/6 mice with myelin oligodendrocyte glycoprotein35-55 amino acid peptide (MOG35-55). IDA was administrated for 14 days after MOG immunization at 2 mg/kg (i.p., bid). Significant reduction in BBB damage occurred in the IDA-treated group of mice compared with the saline-treated group, as evidenced by the reduction in Evan׳s blue content in the brain tissue and the reduced BBB tight junction damage viewed under a transmission electron microscope. Moreover, EAE-induced reductions in tight junction proteins (JAM-1, Occludin, Claudin-5 and ZO-1) were also significantly ameliorated in IDA-treated mice, all of which supported the notion that IDA reduced BBB damage. Interestingly, the expression levels of extracellular matrix metalloproteinase-9 (MMP-9) and the ratio of MMP-9 against tissue inhibitor of metalloproteinase-1 (TIMP-1), which is known to be associated with MS-induced BBB damage, were significantly reduced in IDA-treated group, lending further support to the hypothesis that IDA confers brain protection through reducing BBB damage. This study raised a possibility that IDA is a promising pro-drug for development against MS.

• Authors: Xin-Shi Wang, Hui-Lin Fang, Yu Chen, Shan-Shan Liang, Zhen-Guo Zhu, Qing-Yi Zeng, Jia Li, Hui-Qin Xu, Bei Shao, Jin-Cai He, Sheng-Tao Hou, Rong-Yuan Zheng
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 736 Pg. 70-6 (Aug 05 2014) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 24797785 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier B.V. All rights reserved.

Chemical References

• Anti-Inflammatory Agents
• Neuroprotective Agents
• Timp1 protein, mouse
• Tissue Inhibitor of Metalloproteinase-1
• Matrix Metalloproteinase 9
• Mmp9 protein, mouse
• Idazoxan

Topics

• Animals
• Anti-Inflammatory Agents (pharmacology, therapeutic use)
• Behavior, Animal (drug effects)
• Blood-Brain Barrier (drug effects, metabolism, pathology, ultrastructure)
• Encephalomyelitis, Autoimmune, Experimental (drug therapy, metabolism, pathology)
• Female
• Idazoxan (pharmacology, therapeutic use)
• Matrix Metalloproteinase 9 (metabolism)
• Mice, Inbred C57BL
• Multiple Sclerosis (drug therapy)
• Neuroprotective Agents (pharmacology, therapeutic use)
• Permeability (drug effects)
• Tight Junctions (drug effects, pathology)
• Tissue Inhibitor of Metalloproteinase-1 (metabolism)