POSTISCHEMIC INHIBITION OF CEREBRAL-CORTEX PYRUVATE-DEHYDROGENASE

Postischemic, mitochondrial respiratory impairment can contribute to p rolonged intracellular lactic acidosis, secondary tissue deenergizatio n, and neuronal cell death. Specifically, reperfusion-dependent inhibi tion of pyruvate dehydrogenase (PDH) may determine the degree to which glucose is metabolized aerobically vs. anaerobically. In this study, the maximal activities of pyruvate and lactate dehydrogenase (LDH) fro m homogenates of canine frontal cortex were measured following 10 min of cardiac arrest and systemic reperfusion from 30 min to 24 h. Althou gh no change in PDH activity occurred following ischemia alone, a 72% reduction in activity was observed following only 30 min of reperfusio n and a 65% inhibition persisted following 24 h of reperfusion. In con trast, no significant alteration in LDH activity was observed in any e xperimental group relative to nonarrested control animals. A trend tow ard reversal of PDH inhibition was observed in tissue from animals tre ated following ischemia with acetyl-L-carnitine, a drug previously rep orted to inhibit brain protein oxidation, and lower postischemic corti cal lactate levels and improve neurological outcome. In vitro experime nts indicate that PDH is more sensitive than LDH to enzyme inactivatio n by oxygen dependent free radical-mediated protein oxidation. This fo rm of inhibition is potentiated by either elevated Ca2+ concentrations or substrate/cofactor depletion. These results suggest that site-spec ific protein oxidation may be involved in reperfusion-dependent inhibi tion of brain PDH activity.