Abstract
We simultaneously measured neurotransmitter amino acids by the microdialysis technique and cortical CBF by laser-Doppler flowmetry in the ischemic penumbral cortex of rats subjected to 2-h normothermic (36.5–37.5°C) transient middle cerebral artery (MCA) clipocclusion. Brains were perfusion-fixed 3 days later and infarct volume measured. CBF (% of preischemic values) fell to 32 ± 2% (mean ± SD) during ischemia and rose to 157 ± 68% during recirculation. Extracellular glutamate levels increased from a baseline value of 7 ± 3 μM to a peak value of 180 ± 247 μM 20–30 min following onset of ischemia but subsequently returned to near baseline levels after 70 min of ischemia despite ongoing MCA occlusion. The threshold CBF for moderate glutamate release was 48%. Massive glutamate release was seen during the first 60 min of MCA occlusion in the two animals showing the largest infarcts and occurred at CBF values ≤20% of control levels. Mean CBF during ischemia exhibited an inverse relationship with infarct volume, and the magnitude of glutamate release during ischemia was positively correlated with infarct volume. Extracellular γ-aminobutyrate and glycine changes were similar to those of glutamate but showed no significant correlation with infarct volume. These results suggest that (a) accumulation of extracellular glutamate is an important determinant of injury in the setting of reversible MCA occlusion and (b) reuptake systems for neurotransmitter amino acids may be functional in the penumbra during transient focal ischemia.
We have shown that during temporary MCA occlusion, penumbral levels of amino acid neurotransmitter initially rise but subsequently decline to baseline despite ongoing ischemia and that moderate extracellular glutamate release and massive release of GABA and glycine occur at a CBF threshold of 48%. It was suggested that massive glutamate release might require a lower ischemic threshold of 20%. The magnitude of glutamate release is correlated to the size of the resultant cortical infarct. These results are consistent with the impressions of previous investigations that have implicated glutamatergic mechanisms in focal ischemic injury. It is well known that MK-801 and other glutamate-related receptor antagonists are effective in reducing infarct size in focal ischemia models (Ozyurt et al., 1988; Park et al., 1988b; Simon and Shiraishi, 1990; Buchan et al., 1991; Smith and Meldrum, 1992). While glutamate is a contributory factor, it is nonetheless unlikely to be the sole cause of infarction during transient focal ischemia, and other neurotransmitter systems as well as nonneuronal events may also participate in infarct formation (Plum, 1983; Dietrich et al., 1991; Globus et al., 1991).
