Effect of dichloroacetate on regional energy metabolites and pyruvate dehydrogenase activity during ischemia and reperfusion in gerbil brain.
The objective of this study was to determine whether administration of dichloroacetate (DCA), an activator of pyruvate dehydrogenase (PDH), improves recovery of energy metabolites following transient cerebral ischemia. Gerbils were pretreated with DCA, and cerebral ischemia was produced using bilateral carotid artery occlusion for 20 min, followed by reperfusion up to 4 h. DCA had no effect on the accumulation of lactic acid and the decrease in ATP and phosphocreatine (PCr) during the 20-min insult, nor on the recovery of these metabolites measured at 20 and 60 min reperfusion. However, at 4 h reperfusion, levels of ATP and PCr were significantly higher in DCA-treated animals than in controls, as PCr exhibited a secondary decrease in caudate nucleus of control animals. PDH was markedly inhibited at 20 min reperfusion in both groups, but was reactivated to a greater extent in DCA-treated animals at 60 min and 4 h reperfusion. These results demonstrate that DCA had no effect on the initial recovery of metabolites following transient ischemia. However, later in reperfusion, DCA enhanced the postischemic reactivation of PDH and prevented the secondary failure of energy metabolism in caudate nucleus. Thus, inhibition of PDH may limit the recovery of energy metabolism following cerebral ischemia.
Katayama
Y
Y
Division of Neurosurgery, University of Pennsylvania School of Medicine, Philadelphia 19104-6070.
Welsh
F A
FA
D000085:Acetates / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000201:enzymology / Q000378:metabolism*; D002545:Brain Ischemia / Q000201:enzymology / Q000378:metabolism*; D003999:Dichloroacetic Acid / Q000494:pharmacology*; D004734:Energy Metabolism / Q000187:drug effects*; D005849:Gerbillinae; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism*; D015424:Reperfusion; D013997:Time Factors
D000085:Acetates; D011768:Pyruvate Dehydrogenase Complex; D003999:Dichloroacetic Acid