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

• Published in: Brain research bulletin Vol. 81; no. 1; pp. 191 - 195
• Main Authors: Satoh, Shin-ichi, Hitomi, Asako, Ikegaki, Ichiro, Kawasaki, Koh, Nakazono, Osamu, Iwasaki, Masakazu, Mohri, Mitsunobu, Asano, Toshio
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.01.2010
• 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; Rho-kinase; Cerebral ischemia; Hydroxyfasudil; Endothelial damage/dysfunction; Fasudil
• ISSN: 0361-9230; 1873-2747
• DOI: 10.1016/j.brainresbull.2009.08.021

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.