Temporal Thresholds for Hyperglycemia-Augmented Ischemic Brain Damage in Rats

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Abstract
Background and Purpose Although acute hyperglycemia is known to increase global ischemic brain damage, the duration of ischemia necessary to elicit such an effect is unknown. Accordingly, an experiment was performed to determine the duration of forebrain ischemia at which hyperglycemia becomes a factor in histological and behavioral outcome in rats. Methods Fasted rats were anesthetized and prepared for forebrain ischemia. Before ischemia, rats received either intravenous saline (plasma glucose, 112±18 mg/dL) or glucose (plasma glucose, 343±50 mg/dL). After 4, 8, 12, or 15 minutes of ischemia (n=12), recovery was allowed. Rats surviving 7 days underwent evaluation of motor function and then histological analysis of damage in the caudate putamen, hippocampal CA1, and substantia nigra pars reticulata. Results After 4 minutes of ischemia, damage was present in all structures. Only in the caudate putamen was hyperglycemia associated with worsened damage, but this did not result in seizures or death. After 8 minutes of ischemia, seizures occurred in 33% of hyperglycemic rats, and a hyperglycemic effect on damage in the CA1 and substantia nigra pars reticulata was observed. No seizures or mortality occurred in normoglycemic rats regardless of duration of ischemia. Longer durations of ischemia resulted in an increased incidence of seizures and mortality in hyperglycemic rats only. Among surviving rats, motor function was worsened in hyperglycemic rats after 12 minutes of ischemia. Conclusions Hyperglycemia-augmented brain damage is evident after global ischemic insults as brief as 4 minutes and becomes critical to survival after 8 minutes of ischemia.