Beneficial synergistic effects of concurrent treatment with cilostazol and probucol against focal cerebral ischemic injury in rats.
In the present study, we assessed the beneficial synergistic effects of concurrent treatment with low doses of cilostazol and probucol against focal cerebral ischemic infarct in rats. The ischemic infarct induced by 2-h occlusion of middle cerebral artery (MCA) and 22-h reperfusion was significantly reduced in rat brain that received cilostazol (20 mg/kg) and probucol (30 mg/kg) twice together with prominent improvement of neurological function compared to the effect of cilostazol or probucol monotherapy. Increased myeloperoxidase activity, a marker of neutrophil infiltration, observed in the penumbral zone of vehicle-treated brain was more significantly reduced by cilostazol plus probucol in combination. Increased superoxide-, nitrotyrosine (a marker of peroxynitrite)-, poly(ADP-ribose) [a marker for poly(ADP-ribose) polymerase activity]-, and cleaved caspase-3-positive cells (a proapoptotic marker) in the vehicle sample were significantly attenuated by the combination therapy, while individual treatment with low dose of cilostazol or probucol showed a marginal effect. Taken together, it is suggested that the neuroprotective potentials of combination therapy with low doses of cilostazol plus probucol may provide beneficial therapeutic intervention in reducing the focal cerebral ischemic infarct in rats.
Park
So Youn
SY
Department of Pharmacology, College of Medicine, Pusan National University, Busan 602-739, Republic of Korea.
Lee
Jeong Hyun
JH
Kim
Chi Dae
CD
Rhim
Byung Yong
BY
Hong
Ki Whan
KW
Lee
Won Suk
WS
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D015415:Biomarkers / Q000032:analysis / Q000378:metabolism; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D053148:Caspase 3 / Q000032:analysis / Q000378:metabolism; D002544:Cerebral Infarction / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000502:physiology; D000077407:Cilostazol; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004357:Drug Synergism; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D009195:Peroxidase / Q000032:analysis / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000032:analysis / Q000378:metabolism; D011341:Probucol / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D013481:Superoxides / Q000037:antagonists & inhibitors / Q000378:metabolism; D013687:Telencephalon / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D013777:Tetrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D016896:Treatment Outcome; D014443:Tyrosine / Q000031:analogs & derivatives / Q000032:analysis / Q000378:metabolism
D000975:Antioxidants; D015415:Biomarkers; D004338:Drug Combinations; D018696:Neuroprotective Agents; D013777:Tetrazoles; D013481:Superoxides; C002744:3-nitrotyrosine; D014443:Tyrosine; D009195:Peroxidase; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3; D000077407:Cilostazol; D011341:Probucol