Poly(ADP-ribose) polymerase inhibition by cilostazol is implicated in the neuroprotective effect against focal cerebral ischemic infarct in rat.
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.
Lee
Jeong Hyun
JH
Department of Pharmacology, College of Medicine, Pusan National University, Busan 602-739, Korea.
Park
So Youn
SY
Shin
Hwa Kyung
HK
Kim
Chi Dae
CD
Lee
Won Suk
WS
Hong
Ki Whan
KW
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D018845:CD11 Antigens / Q000096:biosynthesis; D000077407:Cilostazol; D020287:In Situ Nick-End Labeling; D020244:Infarction, Middle Cerebral Artery / Q000209:etiology / Q000517:prevention & control*; D002546:Ischemic Attack, Transient / Q000150:complications*; D008297:Male; D009243:NAD / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016716:PC12 Cells; D009195:Peroxidase / Q000378:metabolism; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D021381:Protein Transport; D051381:Rats; D017207:Rats, Sprague-Dawley; D013777:Tetrazoles / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
C494831:Aifm1 protein, rat; D000894:Anti-Inflammatory Agents, Non-Steroidal; D051033:Apoptosis Inducing Factor; D018845:CD11 Antigens; D018696:Neuroprotective Agents; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D013777:Tetrazoles; D014409:Tumor Necrosis Factor-alpha; D009243:NAD; D009195:Peroxidase; D011065:Poly(ADP-ribose) Polymerases; D000077407:Cilostazol