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NEUROPHARMACOLOGY

Cilostazol Prevents Focal Cerebral Ischemic Injury by Enhancing Casein Kinase 2 Phosphorylation and Suppression of Phosphatase and Tensin Homolog Deleted from Chromosome 10 Phosphorylation in Rats

Department of Pharmacology (J.H.L., K.Y.K., S.Y.P., C.D.K., W.S.L., B.Y.R., K.W.H.), College of Medicine, Pusan National University, Busan, Korea; and Department of Molecular Biochemistry and Toxicology (Y.-K.L.), Dongseo University, Busan, Korea

This study shows the in vivo neuroprotective effect of cilostazol against cerebral ischemic injury evoked by subjecting rats to 2-h occlusion of middle cerebral artery (MCAO) followed by 24-h reperfusion. We observed the signaling pathway by which cilostazol suppressed MCAO-induced increased phosphorylation of phosphatase and tensin homolog deleted from chromosome 10 (PTEN) and apoptosis via increased phosphorylation of casein kinase 2 (CK2). When rats received 30 mg/kg cilostazol orally two times at 5 min and 4 h after the completion of ischemia, the infarct area was significantly reduced in the cortex and striatum with improvement of neurological deterioration. Increased DNA fragmentation in the penumbral zone was significantly reduced by cilostazol. Cilostazol significantly elevated phosphorylation levels of CK2, Akt, and cyclic AMP response element-binding protein (CREB) in association with increased Bcl-2 in the ischemic area, whereas the elevated PTEN phosphorylation was significantly reduced, all of which were antagonized by iberiotoxin, a maxi-K channel blocker, administered intracisternally 30 min before ischemia. In conclusion, cilostazol ameliorates the neuronal damage by suppression of apoptotic cell death via the maxi-K channel opening-coupled up-regulation of CK2 phosphorylation and down-regulation of PTEN phosphorylation with resultant increase in the Akt and CREB phosphorylation and increased Bcl-2 protein.

Address correspondence to: Dr. Ki Whan Hong, Department of Pharmacology, College of Medicine, Pusan National University, 10 Ami-Dong, 1-Ga, Seo-Gu, Busan 602-739, Korea. E-mail: kwhong{at}pusan.ac.kr

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