Postischemic inhibition of cerebral cortex pyruvate dehydrogenase.
Postischemic, mitochondrial respiratory impairment can contribute to prolonged intracellular lactic acidosis, secondary tissue deenergization, and neuronal cell death. Specifically, reperfusion-dependent inhibition 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) from homogenates of canine frontal cortex were measured following 10 min of cardiac arrest and systemic reperfusion from 30 min to 24 h. Although no change in PDH activity occurred following ischemia alone, a 72% reduction in activity was observed following only 30 min of reperfusion and a 65% inhibition persisted following 24 h of reperfusion. In contrast, no significant alteration in LDH activity was observed in any experimental group relative to nonarrested control animals. A trend toward reversal of PDH inhibition was observed in tissue from animals treated following ischemia with acetyl-L-carnitine, a drug previously reported to inhibit brain protein oxidation, and lower postischemic cortical lactate levels and improve neurological outcome. In vitro experiments indicate that PDH is more sensitive than LDH to enzyme inactivation by oxygen dependent free radical-mediated protein oxidation. This form of inhibition is potentiated by either elevated Ca2+ concentrations or substrate/cofactor depletion. These results suggest that site-specific protein oxidation may be involved in reperfusion-dependent inhibition of brain PDH activity.
Bogaert
Y E
YE
Dept. of Biochemistry and Molecular Biology, George Washington University Medical Center, Washington, DC 20037.
Rosenthal
R E
RE
Fiskum
G
G
D000704:Analysis of Variance; D000818:Animals; D002118:Calcium / Q000494:pharmacology; D002540:Cerebral Cortex / Q000201:enzymology*; D004285:Dogs; D005260:Female; D005296:Ferrous Compounds / Q000494:pharmacology; D006323:Heart Arrest / Q000201:enzymology*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D002546:Ischemic Attack, Transient / Q000201:enzymology*; D007700:Kinetics; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008928:Mitochondria / Q000201:enzymology; D011768:Pyruvate Dehydrogenase Complex / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015424:Reperfusion; D012151:Resuscitation; D013997:Time Factors
D005296:Ferrous Compounds; D011768:Pyruvate Dehydrogenase Complex; C020748:ferrous sulfate; D006861:Hydrogen Peroxide; D007770:L-Lactate Dehydrogenase; D002118:Calcium