Delayed treatment with SM-20220, a potent Na^+ /H^+ exchange inhibitor attenuates the brain damage following focal ischemia in rats

We have already reported Na^+ /H^+ exchanger (NHE) inhibitor SM-20220 reduced the water content in rat transient focal ischemia model (Jpn. J. Pharmacol. 76, Suppl. I, 251P). The purpose of the present study was to investigate the effect of SM-20220 on ischemic cerebral infarction in rats. (a)Transient ischemia： Male Wistar rats were anesthetized with halothane. The left middle cerebral artery (MCA) occlusion was induced for 2 hr with a silicone-tipped 4-0 nylon thread. Reperfusion was established by pulling the thread. After 22 hr of reperfusion, brain was stained with TTC for determination of infarcted area using a computerized image analysis system. SM-20220 (0.3, 1.0 mg/kg) or vehicle (8% polyethyleneglycol 400) was given intravenously 60 min after MCA occlusion. SM-20220 dose-dependently reduced the infarcted area. (b)Permanent ischemia： The animals were anesthetized with chloral hydrate, and MCA was electrocauterized. The animals were decapitated 24 hr after occlusion, and infarcted area was determined using the same method described above. SM-20220 (1.0 mg/kg) was given intravenously 5 or 30 or 60 min after occlusion. Although the efficacy progressively declined, with a delay of 60 min still exhibited cerebroprotection. This study demonstrates that SM-20220 was effective in both transient and permanent focal ischemia model in rats. These findings suggest that SM-20220 may serve as a cerebroprotective agent of ischemic stroke.