title: Neuroprotective potential of fasudil mesylate in brain ischemia-reperfusion injury of rats.
abstract: We previously reported that inhibition of Rho-kinase (ROCK) by hydroxyl fasudil improves cognitive deficit and neuronal damage in rats with chronic cerebral ischemia (Huang et al., Cell Mol Neurobiol 28:757-768, 2008). In this study, fasudil mesylate (FM) was investigated for its neuroprotective potential in rats with ischemia following middle cerebral artery occlusion (MCAO) and reperfusion. The effect of fasudil mesylate was also studied in rat brain cortical and hippocampal slices treated with oxygen-glucose deprivation (OGD) injury. Gross anatomy showed that cerebral infarct size, measured with 2,3,5-triphenyltetrazolium chloride (TTC) staining, was significantly smaller in the FM-treated than in the non-FM-treated ischemic rats. In the brain regions vulnerable to ischemia of ischemic rats, fasudil mesylate was also found to significantly restore the enzyme protein expression level of endothelial nitric oxide synthase (eNOS), which was decreased in ischemia. However, it remarkably reduced the protein synthesis of inducible nitric oxide synthase (iNOS) that was induced by ischemia and reperfusion. In rat brain slices treated with OGD injury, fasudil mesylate increased the neuronal cell viability by 40% for cortex and by 61% for hippocampus, respectively. Finally, in the presence of OGD and fasudil mesylate, superoxide dismutase (SOD) activity was increased by 50% for cortex and by 58% for hippocampus, compared to OGD only group. In conclusion, our in vivo study showed that fasudil mesylate not only decreased neurological deficit but also reduced cerebral infarct size, possibly and at least partially by augmenting eNOS protein expression and inhibiting iNOS protein expression after ischemia-reperfusion.
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China. liqin0626@yahoo.com.cn
authors.forename: Qin
authors.initials: Q
authors.lastname: Li
authors.forename: Xian-Ju
authors.initials: XJ
authors.lastname: Huang
authors.forename: Wei
authors.initials: W
authors.lastname: He
authors.forename: Jie
authors.initials: J
authors.lastname: Ding
authors.forename: Jun-Ting
authors.initials: JT
authors.lastname: Jia
authors.forename: Gang
authors.initials: G
authors.lastname: Fu
authors.forename: Hong-Xing
authors.initials: HX
authors.lastname: Wang
authors.forename: Lian-Jun
authors.initials: LJ
authors.lastname: Guo
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D052247:Nitric Oxide Synthase Type II / Q000187:drug effects / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000187:drug effects / Q000378:metabolism; D009924:Organ Culture Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D013482:Superoxide Dismutase / Q000187:drug effects / Q000378:metabolism; D013778:Tetrazolium Salts; D016896:Treatment Outcome
chemical_list: D002121:Calcium Channel Blockers; D018696:Neuroprotective Agents; D013778:Tetrazolium Salts; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D013482:Superoxide Dismutase; C049347:fasudil
references.citation: J Neurosci Methods. 1990 Jan;31(1):43-6
references.pmid: 2308380
references.citation: Nature. 2000 Sep 28;407(6803):538-41
references.pmid: 11029009
references.citation: J Cereb Blood Flow Metab. 1990 Mar;10(2):290-3
references.pmid: 1689322
references.citation: Neurochem Res. 1984 Jun;9(6):785-801
references.pmid: 6493439
references.citation: Nat Med. 2002 May;8(5):473-9
references.pmid: 11984591
references.citation: Life Sci. 2008 Jan 2;82(1-2):85-90
references.pmid: 18036617
references.citation: Cell Mol Neurobiol. 2008 Jun;28(4):559-68
references.pmid: 17712624
references.citation: Am J Physiol Regul Integr Comp Physiol. 2004 Apr;286(4):R642-8
references.pmid: 14656765
references.citation: Neuroscience. 2007 May 11;146(2):617-29
references.pmid: 17363173
references.citation: Neuropharmacology. 1994 Nov;33(11):1425-30
references.pmid: 7532825
references.citation: Stroke. 1999 Sep;30(9):1969-73
references.pmid: 10471452
references.citation: Stroke. 1989 Jan;20(1):84-91
references.pmid: 2643202
references.citation: Brain Res. 2007 Jun 18;1154:215-24
references.pmid: 17482584
references.citation: Stroke. 2005 Oct;36(10):2251-7
references.pmid: 16141422
references.citation: Stroke. 1999 Dec;30(12):2631-6
references.pmid: 10582989
references.citation: J Neurosci Methods. 1995 Jun;59(1):93-8
references.pmid: 7475256
references.citation: Mol Cell Biochem. 2004 Jul;262(1-2):51-9
references.pmid: 15532709
references.citation: Acta Pharmacol Sin. 2004 Dec;25(12):1590-6
references.pmid: 15569402
references.citation: J Cereb Blood Flow Metab. 2004 Sep;24(9):1046-56
references.pmid: 15356425
references.citation: Neuron. 1994 Aug;13(2):487-94
references.pmid: 7520256
references.citation: Behav Brain Res. 2007 Mar 28;178(2):221-8
references.pmid: 17250903
references.citation: Cell Mol Neurobiol. 2008 Aug;28(5):757-68
references.pmid: 17554619
references.citation: Stroke. 1997 Jun;28(6):1283-8
references.pmid: 9183363
references.citation: Gen Pharmacol. 1999 May;32(5):577-81
references.pmid: 10382860