This study shows that cilostazol displayed a potent inhibition of PARP with IC(50) of 883+/-41 nM in the enzyme assay, and also significantly reversed H(2)O(2)-evoked elevated PARP activity and reduced NAD(+) levels in the PC12 cells with improvement of cell viability. In in vivo study, inhibition of PARP activity by cilostazol prevented cerebral ischemic injury induced by 2-h middle cerebral artery occlusion (MCAO) and 24-h reperfusion. The ischemic infarct was significantly reduced in the rats that received cilostazol (30 mg/kg, twice orally) with improvement of neurological function. Moreover, cilostazol treatment significantly decreased the number of terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL)- and poly(ADP-ribose)-positive cells associated with apoptosis-inducing factor (AIF) translocation to the nucleus in the penumbral region. Further, cilostazol significantly reduced myeloperoxidase activity, a marker of neutrophil infiltration. In line with these findings, the OX-42- (a marker of microglia) and TNF-alpha-positive cells (a marker of proapoptotic protein) were markedly increased in the vehicle samples, both of which were significantly attenuated by treatment with cilostazol. Taken together, these results suggest that neuroprotective potentials of cilostazol against focal cerebral ischemic injury are, at least in part, ascribed to its anti-inflammatory effects and PARP inhibitory activity.