Transient brain ischemia in rabbits: the effect of ω-conopeptide MVIIC on hippocampal excitatory amino acids

Neurologic injury that occurs after ischemia results from a cascade of events involving the release of various endogenous neurotoxins. A portion of the release of excitatory neurotransmitters is calcium dependent and may be attenuated by administration of calcium channel blockers. Using an in vivo model of ischemia, we studied the effects of ω-conopeptide MVIIC, a voltage-sensitive calcium channel blocker, and hypothermia (32°C) on hippocampal glutamate and aspartate release in the peri-ischemic period. Thirty-four New Zealand white rabbits of either sex were anesthetized with halothane, intubated, and mechanically ventilated. Monitored variables included blood gases, mean arterial blood pressure, and the electroencephalogram. Microdialysis catheters were transversely inserted through the anterior portion of the dorsal hippocampus and perfused with artificial cerebrospinal fluid at a rate of 2 μl/min. After stabilization period, animals were randomly assigned to one of the following groups: Control group (n = 8), 10 μM ω-conopeptide MVIIC group (n = 7), 100 μM ω-conopeptide MVIIC group (n = 7), Hypothermia group (n = 6; cranial temperature = 32°C), and ω-conopeptide MVIIC + hypothermia group (n = 6; 100 μM ω-conopeptide MVIIC and cranial temperature 32°C). All the rabbits were subjected to 10 minutes of global cerebral ischemia produced by neck tourniquet inflation combined with hypotension during halothane anesthesia. Conopeptide MVIIC was administered in the artificial cerebrospinal fluid used to perfuse the microdialysis catheter. In control animals, ischemia caused a significant increase in glutamate (9.7 fold) and aspartate (11.3 fold) concentrations. This increase was markedly attenuated (P < 0.05) in all treatment groups (MVIIC 10 μM, 100 μM, hypothemia, and MVIIC + hypothermia). These results demonstrate that ω-conopeptide MVIIC (10 μM and 100 μM) can attenuate ischemia-induced increases of glutamate and aspartate concentrations in the peri-ischemic period. This effect is probably caused by a blockade of presynaptic calcium channels and decreased synaptosomal release of excitatory neurotransmitters.