Insulin treatment of corticosteroid-associated hyperglycemia and its effect on outcome after forebrain ischemia in rats

Abstract

Background: Recent studies have reported that dexamethasone worsens neuronal injury after brain ischemia. This effect is assumed to be secondary to drug-induced hyperglycemia. The current study used a rat model to test the hypotheses that insulin treatment of dexamethasone-induced hyperglycemia would result in a postischemic neurologic outcome that is: (1) better than that of hyperglycemic, dexamethasone-treated subjects; and (2) better than, or equal to, that of saline-treated control subjects. Methods: Twenty-four halothane-anesthetized (1.0% inspired) rats were randomly assigned to one of three treatment groups (N = 8 in each group): (1) normoglycemic, placebo- treated rats (group P) received an intravenous saline infusion; (2) hyperglycemic, dexamethasone-treated rats (group D) received 2 mg/kg intraperitoneal dexamethasone at 2 days, 1 day, and 3 h before ischemia plus an intravenous saline infusion; and (3) normoglycemic, dexamethasone- and insulin-treated rats (group DI) received the same treatment as group D, plus an intravenous insulin infusion shortly before ischemia. Blood gases and acid-base status were maintained within normal physiologic ranges. Pericranial and rectal temperatures were maintained at normothermia. Forebrain ischemia of 10 min duration was produced using an established model. Neurologic function was assessed by a blinded observer at 24 and 48 h postischemia. Brain histopathology was assessed at the time of ischemia- related death or after the examination at 48 h. All 24 rats were included in the analysis of neurologic function; however, only 21 rats that survived for ≥24 h postischemia were included in the histologic analysis. Results: Rats were well matched for systemic physiologic variables, with the exception of glucose concentrations. Plasma glucose concentration immediately before ischemia was as follows: group P = 129 ± 8 mg/dl (mean ± SD), group D = 344 ± 29 mg/dl, and group DI = 123 ± 17 mg/dl. At 48 h postischemia, groups P and DI were minimally injured and had similar functional scores. In contrast, all group D rats died of cerebral ischemia. Histologic injury was significantly worse in group D than in either group P or DI, but did not differ significantly between groups P and DI. When all groups were combined, there was a significant correlation between neurologic function and total histopathology score ranks. Conclusions: In the current study, dexamethasone administration before brain ischemia resulted in a worsening of postischemic outcome that was related to drug-induced hyperglycemia. Restoration of normoglycemia, using insulin, resulted in a functional outcome similar to that in group P, and an attenuation of dexamethasone-associated histologic injury.