Neurological protection by dichloroacetate depending on the severity of injury in the paraplegic rat.
Hyperglycemia has been shown to exacerbate neurological deficit associated with central nervous system ischemia. Iodoacetate or dichloroacetate was administered intraperitoneally to rats in a study to examine the role of glycolysis in hyperglycemic exacerbation of neurological deficit. Sprague-Dawley rats were injected with saline, iodoacetate, or dichloroacetate and then made paraplegic by temporary occlusion for 10, 12, 13, or 15 minutes of the right and left subclavian arteries and the aorta distal to the left subclavian artery. Glycolytic blockage by iodoacetate was lethal in doses of 15 mg/kg or more, whereas rats receiving 10 mg/kg survived but showed no significant neurological improvement compared to the saline-treated control group. Dichloroacetate, 500 mg/kg, protected neurological function, which suggests a possible detrimental role for lactate accumulation and the benefit of maintaining tricarboxylic acid cycle activity by stimulating pyruvate dehydrogenase. The protection seen with dichloroacetate depended on the severity of ischemic injury. Dichloroacetate administration had a minimal effect on neurological outcome with occlusion periods of 13 and 15 minutes, mild improvement with 12 minutes of occlusion, and a significant protective effect with a 10-minute occlusion period. The dose-response nature of ischemic injury and neurological outcome in this rat model of paraplegia therefore appears to play an important role in determining the effect observed with a specific intervention.
LeMay
D R
DR
Department of Physiology, University of Michigan Medical School, Ann Arbor.
Zelenock
G B
GB
D'Alecy
L G
LG
D000085:Acetates / Q000494:pharmacology*; D000818:Animals; D002545:Brain Ischemia / Q000150:complications / Q000378:metabolism*; D002952:Citric Acid Cycle / Q000187:drug effects; D003999:Dichloroacetic Acid / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006019:Glycolysis / Q000187:drug effects*; D006943:Hyperglycemia / Q000150:complications; D007461:Iodoacetates / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D010264:Paraplegia / Q000209:etiology / Q000378:metabolism; D011768:Pyruvate Dehydrogenase Complex / Q000502:physiology; D051381:Rats; D011919:Rats, Inbred Strains; D013119:Spinal Cord Injuries / Q000150:complications / Q000378:metabolism
D000085:Acetates; D007461:Iodoacetates; D011768:Pyruvate Dehydrogenase Complex; D003999:Dichloroacetic Acid