The glucose paradox of cerebral ischemia: evidence for corticosterone involvement

Abstract

Aggravation of neuronal damage by preischemic hyperglycemia, i.e. the glucose paradox of cerebral ischemia, is a well-established phenomenon that has prompted clinicians around the world to closely monitor and control blood glucose levels in surgical cases at high risk for ischemic episodes. The widely prevalent idea that lactic acidosis is responsible for hyperglycemia-enhanced ischemic neuronal damage is challenged with the hypothesis that glucose-elicited corticosterone release is a more compelling explanation of the glucose paradox. Corticosterone is the main rodent glucocorticoid, and has important effects on glucose metabolism. Rats were exposed to 7 min of cardiac arrest-induced transient global ischemia. Plasma glucose and corticosterone (CT) levels were manipulated and monitored to assess their effects on delayed neuronal damage as measured 7 days postischemia using electrophysiological and histological methods. Seizure activity was assessed 24 h postischemia. The results demonstrate that the extent of postischemic neuronal damage correlates with plasma CT level, not glucose, at the onset of ischemia. Moreover, an elevation in plasma glucose levels triggers a significant increase in CT plasma levels. Pretreatment of hyperglycemic rats with the CT synthesis inhibitor metyrapone or the CT receptor antagonist, RU38486, prevents hyperglycemic aggravation of ischemic neuronal damage. The increased incidence of seizure and delayed neuronal damage resulting from preischemic hyperglycemia corresponds with CT levels rather than with glucose levels and suggests that CT has a greater prognostic value than glucose in predicting cerebral ischemic damage.