Inhibition of Rho kinase by hydroxyfasudil attenuates brain edema after subarachnoid hemorrhage in rats.
The blood-brain barrier (BBB) disruption and brain edema are important pathophysiologies of early brain injury after subarachnoid hemorrhage (SAH). This study is to evaluate whether Rho kinase (Rock) enhances BBB permeability via disruption of tight junction proteins during early brain injury. Adult male rats were assigned to five groups; Sham-operated, SAH treated with saline, a Rock inhibitor hydroxyfasudil (HF) (10 mg/kg) treatment at 0.5 h after SAH, HF treatment at 0.5 and 6 h (10 mg/kg, each) after SAH, and another Rock inhibitor Y27632 (10 mg/kg) treatment at 0.5 h after SAH. The perforation model of SAH was performed and neurological score and brain water content were evaluated 24 and 72 h after surgery. Evans blue extravasation, Rock activity assay, and western blotting analyses were evaluated 24 h after surgery. Treatment of HF significantly improved neurological scores 24 h after SAH. Single treatment with HF and Y27632, and two treatments with HF reduced brain water content in the ipsilateral hemisphere. HF reduced Evans blue extravasation in the ipsilateral hemisphere after SAH. Rock activity increased 24 h after SAH, and HF reversed the activity. SAH significantly decreased the levels of tight junction proteins, occludin and zonula occludens-1 (ZO-1), and HF preserved the levels of occluding and ZO-1 in ipsilateral hemisphere. In conclusion, HF attenuated BBB permeability after SAH, possibly by protection of tight junction proteins.
Department of Physiology and Pharmacology, Loma Linda University, 11234 Anderson Street, Loma Linda, CA 92354, USA.
Mutsumi
M
Fujii
Kamil
K
Duris
Orhan
O
Altay
Yoshiteru
Y
Soejima
Prativa
P
Sherchan
John H
JH
Zhang
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000577:Amides / Q000494:pharmacology; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects; D015153:Blotting, Western; D001834:Body Water / Q000378:metabolism; D001923:Brain Chemistry / Q000502:physiology; D001929:Brain Edema / Q000188:drug therapy* / Q000209:etiology* / Q000401:mortality; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007839:Functional Laterality / Q000502:physiology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D019635:Neurosurgical Procedures; D062793:Occludin; D010750:Phosphoproteins / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013345:Subarachnoid Hemorrhage / Q000150:complications* / Q000401:mortality; D019108:Tight Junctions / Q000187:drug effects; D016896:Treatment Outcome; D062826:Zonula Occludens-1 Protein; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000577:Amides; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D062793:Occludin; C568987:Ocln protein, rat; D010750:Phosphoproteins; D011725:Pyridines; C569044:Tjp1 protein, rat; D062826:Zonula Occludens-1 Protein; C431085:hydroxyfasudil; C108830:Y 27632; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D054460:rho-Associated Kinases