title: Improvement of cognitive deficit and neuronal damage in rats with chronic cerebral ischemia via relative long-term inhibition of rho-kinase.
abstract: (1) The role of activation of Rho-kinase in the pathogenesis of cognitive deficit and neuronal damage caused by chronic global ischemia is not clear. In this study, hydroxyfasudil, a Rho-kinase inhibitor, was found to improve the learning and memory performance significantly in rats with ischemia induced by chronic cerebral hypoperfusion after permanent bilateral carotid artery ligation (BCAL). This was observed by the administration of hydroxyfasudil (1 mg/kg or 10 mg/kg, once per day for 30 days) to ischemic rats and the measurements of escape latency and time spent in the target quadrant among the ischemic, sham, and ischemic plus hydroxyfasudil rats by the method of Morris water maze. (2) In electrophysiological study, hydroxyfasudil abolished the inhibition of long-term potentiation (LTP) in rats with ischemia. Morphologically, it also markedly reduced pathological changes such as neuronal cells loss and nuclei shrinkage in cortex and hippocampus of ischemic rats. Biochemical analysis showed that the inhibition of Rho-kinase by hydroxyfasudil reduced the amount of MDA and increased the activities of SOD and GPx in ischemic rats that had increased MDA and decreased SOD and GPx activities. (3) To explore mechanism (s) of the beneficial effects of hydroxyfasudil in ischemia, we performed immunohistochemistry and RT-PCR analyses of NMDA NR2B subunit and for the first time found that hydroxyfasudil increased the expression of NR2B in cortex and hippocampus at both protein and mRNA levels. (4) Taken together, our data further support the notion that the inhibition of Rho-kinase provides neuroprotective effects in cerebral ischemia.
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China. linhuang621@hotmail.com
authors.forename: Lin
authors.initials: L
authors.lastname: Huang
authors.forename: Zhi
authors.initials: Z
authors.lastname: He
authors.forename: Lianjun
authors.initials: L
authors.lastname: Guo
authors.forename: Hongxing
authors.initials: H
authors.lastname: Wang
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D020520:Brain Infarction / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D002540:Cerebral Cortex / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology; D002908:Chronic Disease; D003072:Cognition Disorders / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D013482:Superoxide Dismutase / Q000187:drug effects / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D016896:Treatment Outcome; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; C121001:NR2B NMDA receptor; D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; C431085:hydroxyfasudil; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; C000606292:Sod1 protein, rat; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D054460:rho-Associated Kinases