Preischemic hyperglycemia-aggravated damage: Evidence that lactate utilization is beneficial and glucose-induced corticosterone release is detrimental

Aerobic lactate utilization is crucial for recovery of neuronal function po sthypoxia in vitro. In vivo models of cerebral ischemia pose a conceptual c hallenge when compared to in vitro models. First, the glucose paradox of ce rebral ischemia, namely, the aggravation of delayed neuronal damage by prei schemic hyperglycemia, cannot be reproduced in vitro. Second, in vitro elev ated glucose levels protect against ischemic (hypoxic) damage, an outcome t hat has seldom been reproduced in vivo. Employing a rat model of cardiac-ar rest-induced transient global cerebral ischemia (TGI), we found that hyperg lycemic conditions, when induced 120-240 min pre-TGI, significantly reduced post-TGI neuronal damage as compared to normoglycemic conditions. In contr ast, hyperglycemia, when induced 15-60 min pre-TGI, significantly aggravate d post-TGI neuronal damage. Brain lactate levels in rats loaded with glucos e either 15 min or 120 min pre-TGI were significantly and equally higher th an those of control, saline-injected rats. The beneficial effect of 120 min pre-TGI glucose loading was abolished by lactate transport inhibition. A s ignificant increase in blood corticosterone (CT) levels was observed upon g lucose loading that peaked at 15-30 min and returned to baseline levels by 60-120 min. When rats loaded with glucose 15 min pre-TGI were treated with metyrapone, a CT synthesis inhibitor, a significantly lower degree of delay ed neuronal damage in comparison to both untreated, 15 min glucose-loaded r ats and normoglycemic, control rats was observed. Thus, although elevated l evels of brain lactate cannot explain the glucose paradox of cerebral ische mia, hyperglycemia-induced, short-lived elevation in CT blood levels could. More importantly, lactate appears to play a crucial role in improving post ischemic outcome. (C) 2001 Wiley-Liss, Inc.