(S')-Emopamil Protects Against Global Ischemic Brain Injury in Rats

(S)-Emopamil is a novel calcium channel blocker of the phenylalkylamine class, with potent serotonin S2 antagonist activity. We investigated the effect of (S)-emopamil on the histopatho-logic consequences of global brain ischemia in anesthetized rats. Pretreated rats ( « = 15) received 20 mg/kg i.p. (S)-emopamil 30 minutes before and 2 hours following 10 minutes of bilateral common carotid artery occlusion plus arterial hypotension (50 mm Hg). Quantitative cell counts following 3 days ' survival revealed a marked loss of pyramidal neurons in all subsectors of the hippocampal CA1 area of untreated ischemic rats (n=15). In contrast, in (S)-emopamil pretreated rats numbers of normal neurons were significantly higher, by 2.4-, 1.9-, and 1.8-fold, respectively, in the medial, middle, and lateral subsectors of the CA1 area. For example, normal neuron counts in the medial CA1 subsector were 34±9 (mean±SEM) in untreated ischemic rats compared with 82 ±13 in (S)-emopamil pretreated rats (control nonischemic value [«=5] 157±2). By semiquantitative grading, (S)-emopamil also decreased ischemic changes in the cerebral cortex. No significant effect of (S)-emopamil on ischemic injury was detected in rats treated beginning 30 minutes after the ischemic insult (n=10). Thus, pretreatment with (S)-emopamil is beneficial in decreasing the severity of neuronal injury in global brain ischemia. (Stroke 1990:21:1734-1739) Aischemic cerebrovascular disease is a majorsource of death and disability throughout thecivilized world, the development of thera-peutic means of protecting the brain from ischemic damage represents a clinical challenge of great im-portance.1 Calcium channel blockers have attracted wide attention as possible therapeutic agents in brain ischemia, but conflicting studies continue to ap-pear.2-3 (S)-Emopamil is a novel compound of the phenylalkylamine class of calcium channel blockers having exceptionally high blood-brain barrier pene-trability; it is also a potent antagonist of serotonin S2 receptors. In a previous investigation, we reported that (S)-emopamil was capable of reducing infarct size following middle cerebral artery (MCA) occlu-sion in rats, even when administered 1 hour after occlusion.4 We designed the present study to asses