Bench-to-bedside review: a possible resolution of the glucose paradox of cerebral ischemia

Abstract

The glucose paradox of cerebral ischemia (namely, the aggravation of delayed ischemic neuronal damage by preischemic hyperglycemia) has been promoted as proof that lactic acidosis is a detrimental factor in this brain disorder. Recent studies, both in vitro and in vivo, have demonstrated lactate as an excellent aerobic energy substrate in the brain, and possibly a crucial one immediately postischemia. Moreover, evidence has been presented that refutes the lactic acidosis hypothesis of cerebral ischemia and thus has questioned the traditional explanation given for the glucose paradox. An alternative explanation for the aggravating effect of preischemic hyperglycemia on the postischemic outcome has consequently been offered, according to which glucose loading induces a short-lived elevation in the release of glucocorticoids. When an episode of cerebral ischemia in the rat coincided with glucose-induced elevated levels of corticosterone (CT), the main rodent glucocorticoid, an aggravation of the ischemic outcome was observed. Both the blockade of CT elevation by chemical adrenalectomy with metyrapone or the blockade of CT receptors in the brain with mifepristone (RU486) negated the aggravating effect of preischemic hyperglycemia on the postischemic outcome.

Figure 1

The effects of glucose administration (2 g/kg, intraperitoneally [i.p.]) on three different parameters. Blood glucose and corticosterone levels in samples taken from one group of rats at the time points indicated after glucose injection, and the degree of ischemic hippocampal damage (as measured 7 days postischemia) in another group of rats administered glucose at the same time points prior to induction of ischemia. Also shown are the effects of either metyrapone (100 g/kg, i.p.) or mifepristone (RU486; 40 mg/kg, i.p.) on the degree of ischemic damage in rats that were administered glucose 15 min preischemia. ^*Significantly different from control, normoglycemic rats (P < 0.05); ^**significantly different from hyperglycemic rats injected with glucose 15 min preischemia (P < 0.05) using an unpaired t test.