Dichloroacetate treatment of ischemic cerebral lactic acidosis in the fed rat.
Despite advances in cardiac resuscitation, ischemic brain injury remains generally untreatable. Animal studies of brain ischemia associate brain lactate levels of more than 18 mumol/g with irreversible neuronal injury. Lowering brain lactate therefore may prevent or minimize ischemic brain necrosis. Earlier studies in our laboratory using fasted rats demonstrated that sodium dichloroacetate (DCA) decreases ischemic brain lactate when given either before or immediately after partial global ischemia (PGI). Other investigators have shown that fed animals have more glucose and generate higher lactate levels by anaerobic metabolism during PGI. We evaluated the ability of DCA to lower brain lactate in fed male Wistar rats subjected to PGI. Four groups (n = 6 each) were studied--PGI and control rats with either placebo or DCA treatment. PGI was induced for 30 minutes by combining bilateral carotid artery occlusion with hemorrhagic hypotension. This was followed by release of carotid occlusion, reinfusion of shed blood, and immediate treatment with either DCA (25 mg/kg, IV) or placebo. Thirty minutes later brains were frozen in situ with liquid nitrogen for extraction and measurement of tissue glucose, glycogen, and lactate. Blood glucose and serum lactate were monitored throughout the experiment. No significant differences were found between the two PGI groups in brain glucose, brain glycogen, or ischemia-induced elevations in blood glucose and serum lactate. However, brain lactate was significantly lower in DCA-treated (12.5 mumol/g) than in untreated (22.8 mumol/g) PGI rats (P less than .001). In addition, all untreated PGI rats had levels of more than 18 mumol/g, and therefore were at high risk for neuronal necrosis.(ABSTRACT TRUNCATED AT 250 WORDS)
D000085:Acetates / Q000627:therapeutic use*; D000140:Acidosis, Lactic / Q000188:drug therapy*; D000818:Animals; D001786:Blood Glucose; D001794:Blood Pressure; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism; D003999:Dichloroacetic Acid / Q000627:therapeutic use*; D005502:Food; D006400:Hematocrit; D007773:Lactates / Q000097:blood; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains
D000085:Acetates; D001786:Blood Glucose; D007773:Lactates; D003999:Dichloroacetic Acid