Amelioration of endothelial damage/dysfunction is a possible mechanism for the neuroprotective effects of Rho-kinase inhibitors against ischemic brain damage.
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 (10mg/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 alpha-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.
Satoh
Shin-Ichi
S
Research Center, Asahi Kasei Pharma Corporation 632-1, Mifuku, Izunokuni-shi, Shizuoka 410-2321, Japan. sato.sn@om.asahi-kasei.co.jp
Hitomi
Asako
A
Ikegaki
Ichiro
I
Kawasaki
Koh
K
Nakazono
Osamu
O
Iwasaki
Masakazu
M
Mohri
Mitsunobu
M
Asano
Toshio
T
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology; D002199:Capillary Permeability / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004727:Endothelium / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020521:Stroke / Q000188:drug therapy / Q000473:pathology; D013925:Thromboplastin / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014471:Umbilical Veins / Q000187:drug effects / Q000378:metabolism; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors*
D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D014409:Tumor Necrosis Factor-alpha; C431085:hydroxyfasudil; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D013925:Thromboplastin; D054460:rho-Associated Kinases; C049347:fasudil