Calcium antagonists in the treatment of experimental cerebral ischemia

M. D. Ginsberg, B. Lin, E. Morikawa, W. D. Dietrich, R. Busto, M. Y.T. Globus

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

Calcium ion functions widely as an intracellular messenger and regulator. Intracellular calcium dyshomeostasis occurs during hypoxic/ischemic cell injury, and pharmacological antagonism of calcium entry into neurons has been considered to be of potential therapeutic value. Calcium antagonists, in addition, tend to improve cerebral perfusion of both the normal and abnormal (post-ischemic) brain. Studies of these agents have shown variable degrees of cerebroprotection in focal and global ischemia models. (S)-Emopamil is a phenylalkylamine-type calcium channel blocker which also exhibits stereoselective antagonism of the serotonin S2 receptor and has excellent blood-brain barrier penetrability. Protection of hippocampal CA1 neurons has been demonstrated with pre-ischemic administration of (S)-emopamil in global ischemia models. Our laboratory has compared the efficacy of pre- vs. post-ischemic (S)-emopamil treatment on neuronal necrosis resulting from 10 min of transient normothermic global ischemia in the rat. (S)-Emopamil pre-treatment, 20 mg/kg i.p., 30 min prior to ischemia, with a second dose 2.5 h later, resulted in 1.8-2.4 fold increases in numbers of surviving CA1 pyramidal neurons. Post-ischemic administration was ineffective. Intracerebral microdialysis has revealed a partial attenuation of dopamine release with pre-ischemic (S)-emopamil administration. In focal cerebral ischemia (middle cerebral artery occlusion in the rat), our laboratory has demonstrated a marked reduction in cortical infarct volume with (S)-emopamil pre- or post-treatment. In additional studies in Sprague-Dawley rats with permanent MCA occlusion plus transient hypotension we have confirmed a 52% mean reduction in cortical infarct volume in 1-h post-treated rats; a trend toward reduced infarct volume when treatment was deferred to 2 h; but absence of an effect with initiation of treatment at 3 h. Thus, a temporal window for therapeutic efficacy may exist in focal infarction, lying between 1 and 2 h.

Original languageEnglish (US)
Pages (from-to)334-337
Number of pages4
JournalArzneimittel-Forschung/Drug Research
Volume41
Issue number3 A
StatePublished - Jan 1 1991

ASJC Scopus subject areas

  • Drug Discovery

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