Hyperglycemia and neuronal damage in cerebral ischemia and beyond

Abstract The aggravation of cerebral ischemic neuronal damage by preischemic hyperglycemia has been lauded as the proof that lactic acidosis is a major detrimental factor in such damage. This phenomenon has steered clinicians to attenuate blood glucose levels as a means of brain protection against the risk of ischemia during cardiopulmonary bypass surgery and neurosurgical procedures. Researchers who use in vivo models of ischemia have repeatedly confirmed this paradoxical phenomenon where the only energy substrate capable of supporting ATP formation in the absence of oxygen must be avoided. Consequently, lactate, too, acquired a bad reputation among clinicians and researchers alike. The only investigators to defend glucose as a possible neuroprotectant have been those who use in vitro modelevated intraischemic lactic acidosis that exacerbates postischemic brain damage. Several highly cited studies [12- 14] demonstrated that normal preischemic brain levels of glucose fell drastically and those of lactate rose sharply by the end of cerebral ischemia/hypoxia. However, shortly after the onset of reperfusion/reoxygenation, brain glucose levels were significantly higher than the preischemic levels [12,13]. Despite the huge increase in lactate concentration after 10 min of hypoxia, the rate of its efflux from the brain to the venous blood remained unchanged from the very low control levels before hypoxia [12]. The postischemic increase in brain glucose level was accompanied by a rapid decrease in lactate level, termed by the investigators themselves as “lactate utilization” [14]. An oxidative utilization of lactate upon reperfusion would explain such postischemic decline in the monocarboxylate concentration and a concomitant rise in glucose to above its preischemic level [15] as the latter remains mostly unused, at least for a while. Other studies reported similar outcome [16], notwithstanding their claim of providing evidence for a damaging role of lactic acidosis following hyperglycemic ischemia [17]. A closer examination of these studies shows that aerobic lactate utilization had occurred postischemia. Nonetheless, almost a quarter of a century later [18] it was argued that hyperglyce- Brain Attack Research Laboratory, Department of Anesthesiology, University of Louisville School of Medicine, Louisville, KY 40292, USA (Drs Avital Schurr and Ralphiel S. Payne) Address requests for reprints to: Avital Schurr, Ph.D., Brain Attack Research Laboratory, Department of Anesthesiology, University of Louisville School of Medicine, Louisville, KY 40292, USA Tel: 502-852-6544, Fax: 502-852-6056 E-mail: a0schu01@louisville.edu els of ischemia/hypoxia, where the higher the glucose concentration preischemia, the lower the degree of neuronal damage postischemia. Nevertheless, after almost three decades since the inception of the lactic acidosis hypothesis of cerebral ischemia, no direct proof has been presented in its support. Recent studies in our laboratory provide evidence that refutes the lactic acidosis hypothesis of cerebral ischemia and offer a different explanation for the glucose paradox of cerebral ischemia in which hyperglycemia-induced increase in the release of the stress hormone corticosterone, not lactic acidosis, is responsible for the aggravation of the ischemic damage. These studies led us to explore the role of stress hormones in diabetic hyperglycemia and neuropathy.