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NEUROPHARMACOLOGY

Combination Treatment with Normobaric Hyperoxia and Cilostazol Protects Mice against Focal Cerebral Ischemia-Induced Neuronal Damage Better Than Each Treatment Alone

Department of Biofunctional Evaluation, Molecular Pharmacology, Gifu Pharmaceutical University, Gifu, Japan (Y.N., A.K., K.H., M.S., H.H.); and Departments of Neurosurgery (Y.N., S.Y., T.I.) and Neurology and Geriatrics (A.K.), Gifu University Graduate School of Medicine, Gifu, Japan

Normobaric hyperoxia (NBO) and cilostazol (6-[4-(1-cyclohexy-1H-tetrazol-5-yl)butoxyl]-3,4-dihydro-2-(1H)-quinolinone) (a selective inhibitor of phosphodiesterase 3) have each been reported to exert neuroprotective effects against acute brain injury after cerebral ischemia in rodents. Here, we evaluated the potential neuroprotective effects of combination treatment with NBO and cilostazol against acute and subacute brain injuries after simulated stroke. Mice subjected to 2-h filamental middle cerebral artery (MCA) occlusion were treated with NBO (95% O₂, during the ischemia) alone, with cilostazol (3 mg/kg i.p. after the ischemia) alone, with both of these treatments (combination), or with vehicle. The histological and neurobehavioral outcomes were assessed at acute (1 day) or subacute (7 days) stages after reperfusion. We measured regional cerebral blood flow (rCBF) during and after ischemia by laser-Doppler flowmetry and recovery (versus vehicle) in the combination therapy group just after reperfusion. Mean acute and subacute lesion volumes were significantly reduced in the combination group but not in the two monotherapy groups. The combination therapy increased endothelial nitric-oxide synthase (eNOS) activity in the lesion area after ischemia versus vehicle. Combination therapy with NBO plus cilostazol protected mice subjected to focal cerebral ischemia by improvement of rCBF after reperfusion, in part in association with eNOS activity.

Address correspondence to: Dr. Hideaki Hara, Department of Biofunctional Evaluation, Molecular Pharmacology, Gifu Pharmaceutical University, 5-6-1 Mitabora-higashi, Gifu 502-8585, Japan. E-mail: hidehara{at}gifu-pu.ac.jp