Effect of dichloroacetate on recovery of brain lactate, phosphorus energy metabolites, and glutamate during reperfusion after complete cerebral ischemia in rats.
The effects of dichloroacetate (DCA) on brain lactate, intracellular pH (pHi), phosphocreatine (PCr), and ATP during 60 min of complete cerebral ischemia and 2 h of reperfusion were investigated in rats by in vivo 1H and 31P magnetic resonance spectroscopy; brain lactate, water content, cations, and amino acids were measured in vitro after reperfusion. DCA, 100 mg/kg, or saline was infused before or immediately after the ischemic period. Preischemic treatment with DCA did not affect brain lactate or pHi during ischemia, but reduced lactate and increased pHi after 30 min of reperfusion (p < 0.05 vs. controls) and facilitated the recovery of PCr and ATP during reperfusion. Postischemic DCA treatment also reduced brain lactate and increased pHi during reperfusion compared with controls (p < 0.05), but had little effect on PCr, ATP, or Pi during reperfusion. After 30 min of reperfusion, serum lactate was 67% lower in the postischemic DCA group than in controls (p < 0.05). The brain lactate level in vitro was 46% lower in the postischemic DCA group than in controls (p < 0.05). DCA did not affect water content or cation concentrations in either group, but it increased brain glutamate by 40% in the preischemic treatment group (p < 0.05). The potential therapeutic effects of DCA on brain injury after complete ischemia may be mediated by reduced excitotoxin release related to decreased lactic acidosis during reperfusion.
Department of Pharmaceutical Chemistry, School of Pharmacy, University of California, San Francisco.
L H
LH
Chang
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H
Shimizu
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H
Abiko
R A
RA
Swanson
A I
AI
Faden
T L
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James
P R
PR
Weinstein
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy*; D002412:Cations / Q000378:metabolism; D003999:Dichloroacetic Acid / Q000494:pharmacology*; D004195:Disease Models, Animal; D005971:Glutamates / Q000378:metabolism*; D018698:Glutamic Acid; D006863:Hydrogen-Ion Concentration; D007773:Lactates / Q000378:metabolism*; D019344:Lactic Acid; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D010725:Phosphocreatine / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy; D014867:Water / Q000378:metabolism
D002412:Cations; D005971:Glutamates; D007773:Lactates; D010725:Phosphocreatine; D014867:Water; D019344:Lactic Acid; D018698:Glutamic Acid; D000255:Adenosine Triphosphate; D003999:Dichloroacetic Acid