Amelioration of endothelial damage/dysfunction is a possible mechanism for the neuroprotective effects of Rho-kinase inhibitors against ischemic brain damage

Abstract We investigated the neuroprotective effects of fasudil's active metabolite, hydroxyfasudil, a Rho-kinase inhibitor, in a rat stroke model in which endothelial damage and subsequent thrombotic occlusion were selectively induced in perforating arteries. By examining the effects on the en...

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Bibliographic Details
Published in:Brain research bulletin 2010-01, Vol.81 (1), p.191-195
Main Authors: Satoh, Shin-ichi, Hitomi, Asako, Ikegaki, Ichiro, Kawasaki, Koh, Nakazono, Osamu, Iwasaki, Masakazu, Mohri, Mitsunobu, Asano, Toshio
Format: Article
Language:English
Subjects:
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - administration & dosage
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - analogs & derivatives
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - pharmacokinetics
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - pharmacology
Animals
Brain - blood supply
Brain - drug effects
Brain - pathology
Brain Ischemia - drug therapy
Brain Ischemia - pathology
Capillary Permeability - drug effects
Cells, Cultured
Cerebral ischemia
Disease Models, Animal
Endothelial damage/dysfunction
Endothelium - drug effects
Endothelium - metabolism
Endothelium - pathology
Enzyme Inhibitors - administration & dosage
Enzyme Inhibitors - pharmacokinetics
Enzyme Inhibitors - pharmacology
Fasudil
Humans
Hydroxyfasudil
In Vitro Techniques
Male
Neurology
Neuroprotective Agents - administration & dosage
Neuroprotective Agents - pharmacokinetics
Neuroprotective Agents - pharmacology
Rats
Rats, Sprague-Dawley
rho-Associated Kinases - antagonists & inhibitors
Rho-kinase
Stroke - drug therapy
Stroke - pathology
Thromboplastin - metabolism
Tumor Necrosis Factor-alpha - metabolism
Umbilical Veins - drug effects
Umbilical Veins - metabolism
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Summary:Abstract We investigated the neuroprotective effects of fasudil's active metabolite, hydroxyfasudil, a Rho-kinase inhibitor, in a rat stroke model in which endothelial damage and subsequent thrombotic occlusion were selectively induced in perforating arteries. By examining the effects on the endothelial damage/dysfunction, we thought to explore the mechanism of Rho-kinase inhibitors. Hydroxyfasudil (10 mg/kg, i.p., once daily for 3 days) significantly improved neurological functions and reduced the size of the infarct area produced by internal carotid artery injection of sodium laurate in a rat cerebral microthrombosis model. Treatment with fasudil or hydroxyfasudil concentration-dependently inhibited tumor necrosis factor α-induced tissue factor expression on the surface of cultured human umbilical vein endothelial cells. They also inhibited thrombin-induced endothelial hyperpermeability. The present findings suggest that hydroxyfasudil is efficacious in preventing brain damage associated with cerebral ischemia, and is partially responsible for fasudil's cytoprotective potential. The results also suggest that the therapeutic benefits against ischemic injury of Rho-kinase inhibitors are attributed, at least in part, to activity upon endothelial damage/dysfunction.
ISSN:0361-9230
1873-2747
DOI:10.1016/j.brainresbull.2009.08.021