Cilostazol, a phosphodiesterase inhibitor, attenuates photothrombotic focal ischemic brain injury in hypertensive rats.
The aim of this study was to evaluate and compare the effects of anti-platelet agents with different modes of action (cilostazol, aspirin, and clopidogrel) on brain infarction produced by photothrombotic middle-cerebral-artery (MCA) occlusion in male, spontaneously hypertensive rats. Cerebral blood flow (CBF) was measured with laser-Doppler flowmetry in the penumbral cortex. Infarct size was evaluated 24 h after MCA occlusion. The effects of these drugs on infarct size were examined by pretreatment of rats undergoing MCA occlusion. Pretreatment with cilostazol (100 mg/kg) significantly reduced infarct size. In contrast, aspirin (10 mg/kg) and clopidogrel (3 mg/kg) failed to mitigate infarct size, regardless of their apparent inhibitory effects on platelet aggregation. Post-treatment with cilostazol also significantly attenuated the infarct size, associated with improved CBF in the penumbral region. In support of this effect, cilostazol increased nitric oxide (NO) production and prostaglandin-I(2) (PGI(2)) release in cultured human brain microvascular endothelial cells. Cilostazol-induced NO production and PGI(2) release were completely abolished by an NO synthase inhibitor and aspirin, respectively. These findings show that cilostazol reduced brain infarct size due to an improvement in penumbral CBF possibly in association with increased endothelial NO and PGI(2) production.
Ito
Hideki
H
First Institute of New Drug Discovery, Otsuka Pharmaceutical Co Ltd, Tokushima, Japan. h_ito@research.otsuka.co.jp
Hashimoto
Ayako
A
Matsumoto
Yutaka
Y
Yao
Hiroshi
H
Miyakoda
Goro
G
D000818:Animals; D001241:Aspirin / Q000494:pharmacology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D002478:Cells, Cultured; D002560:Cerebrovascular Circulation / Q000187:drug effects; D000077407:Cilostazol; D000077144:Clopidogrel; D042783:Endothelial Cells / Q000187:drug effects; D011464:Epoprostenol / Q000096:biosynthesis; D006801:Humans; D006973:Hypertension / Q000150:complications / Q000188:drug therapy*; D017078:Laser-Doppler Flowmetry; D008297:Male; D009569:Nitric Oxide / Q000096:biosynthesis; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D013777:Tetrazoles / Q000494:pharmacology*; D013988:Ticlopidine / Q000031:analogs & derivatives / Q000494:pharmacology
D010726:Phosphodiesterase Inhibitors; D010975:Platelet Aggregation Inhibitors; D013777:Tetrazoles; D009569:Nitric Oxide; D000077144:Clopidogrel; D011464:Epoprostenol; D000077407:Cilostazol; D013988:Ticlopidine; D001241:Aspirin