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Effects of Immediate, Post-Ischemic Selective Brain Cooling on Extracellular Ascorbate Release and Glutamate Re-Uptake during Reperfusion after Forebrain Ischemia in the Rat Hippocampus
Toshiko Yusa, M.D.
Anesthesiology, University of the Ryukyus, Okinawa, Japan
INTRODUCTION: Ascorbate, a major antioxidant in the brain, is highly concentrated in neuropils. In previous experiments 1), its extracellular release is closely related to that of glutamate during reperfusion after forebrain ischemia in rats. Although the protective effects of intra-ischemic hypothermia are known, the efficacy of post-ischemic hypothermia remains controversial. Thus, the effects of post-ischemic selective brain cooling on extracellular release of ascorbate and glutamate during forebrain ischemia-reperfusion in rat hippocampus was continuously measured in vivo using a microdialysis biosensor system.

METHODS: Male Wistar rats (n=20) were anesthetized with halothane under mechanical ventilation. Mean arterial pressure (MAP), cortical CBF measured by laser-Doppler flowmeter, and rectal and cortical temperature were continuously recorded. Two probes of a microdialysis biosensor electrode were inserted stereotaxically in the bilateral hippocampus. One probe was perfused with Ringer's solution and the oxidation signal of dialyzed ascorbate was recorded 2). A second probe was electropolymerised and perfused with Ringer's solution containing glutamate oxidase for glutamate measurement. Forebrain ischemia-reperfusion was performed by bilateral carotid artery occlusion with hemorrhagic hypotension (MAP=30mmHg) for 10 min followed by reperfusion for 60 min. Immediately after reperfusion, brain cortical temperature was controlled 36°C (Group N) or 32°C (Group H) while rectal temperature was held at normothermia (37-38°C). Repeated-measures of ANOVA followed by Scheffe's test and unpaired t-test were used for statistical analyses.

RESULTS: During ischemia, extracellular release of glutamate increased markedly from 40 to 160μM immediately after reperfusion, and then decreased rapidly. In Group N, however, it remained significantly higher for 15 - 25 min after reperfusion compared to that in Group H. Release of ascorbate (60 μM at control) increased slightly during ischemia, but increased significantly to maximums of 166μM in Group N and 212 μM in Group H after reperfusion. In Group H, it was significantly higher for 5 - 40 min after reperfusion compared to that in Group N.

CONCLUSION: The marked increase of extracellular ascorbate during reperfusion after ischemia was associated with the rapid decrease of extracellular glutamate in both groups. Post-ischemic brain cooling caused a significant increase in ascorbate release and glutamate re-uptake during reperfusion along with significantly higher MAP and cortical CBF. These results suggest that a marked extracellular release of ascorbate by post-ischemic hypothermia consistents with the reported ascorbate-mediated protection from glutamate cytotoxicity.

REFERENCE: 1) Brain Res (2001) in press, 2) Neurosci Lett (2000) 293:123

Anesthesiology 2001; 95:A781
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