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.(ABSTRACT TRUNCATED AT 250 WORDS)