Real-time glutamate release into, and removal from, the extracellular space in low flow states, and a novel eleven-vessel occlusion model, of rat forebrain ischemia: Correlation with EEG spectral analysis

There remains controversy over the damaging effects of residual blood flow to the ischemic brain. In order to study the effects of a low flow state of cerebral ischemia, a novel eleven-vessel occlusion (11VO) rat model was devised, to more closely simulate complete forebrain ischemia, and compared to the four-vessel occlusion model (4VO), without exsanguination, and carotid transection (CT). Real time glutamate levels, in the extracellular space, were measured by microdialysis electrode, during control, ischemia and the early reperfusion phase in all animals. Finally, the EEG obtained during control, and ischemic periods, was compared by EEG spectral analysis. Ten-min periods of ischemia were tested.; Results show that the elapsed time, from the onset of ischemia to the ischemic plateau, is faster during 11VO (12–16 sec) than 4VO (72–155 sec). Cerebral blood flow falls to a lower mean level during 11VO (4–5%) than during 4VO (13–15%). Concomitantly, the peak interstitial glutamate concentration rises less during 11VO (138 μM, as opposed to 4VO (257 μM). Peak glutamate levels after CT (137 μM) are also significantly lower than during 4VO. There are no significant differences in glutamate release during 11VO and 10-min after CT. During the first 90-sec of reperfusion, glutamate levels rise to a second higher peak (315 μM) in 7 of 12 animals. Elapsed time to the normalization of glutamate following the onset of reperfusion is faster following 11VO (157 sec) than 4VO (547 sec). Finally, EEG spectral analysis reveals that the relative powers of δ₁, [δ ₁ + δ₁], and [δ₁ + δ₂ + &thetas;] are significantly lower during ischemia in 11VO, than in 4VO animals (δ₁ = 40% vs 74%; [δ₁ + δ₂] = 47% vs 82%; [δ₁ + δ₂ + &thetas;] = 51% vs 84%.; In conclusion, 11VO attains a level of profound, reversible ischemia, faster, than during 4VO. The 4VO model, without exsanguination, creates a low flow state (13–15% of control) of cerebral ischemia. The dialysis electrode provides real time evidence that glutamate levels in the interstitial space are enhanced during a low flow state of cerebral ischemia. Glutamate transients are seen to occur during the first 90 sec of reperfusion, and, the glutamate levels recorded, during ischemia, are the highest in the literature. A low flow state also requires a longer period of reperfusion, for glutamate normalization, than following 11VO. Finally, 4VO yields a greater power of slow waves, as determined by fast Fourier transform, than 11VO. Therefore, a low flow state of rat cerebral ischemia (13–15%) may be more damaging to the rat's brain than no flow at all.