Hyperglycemic exacerbation of neurologic deficit in the paraplegic rat: The role of glucose availability, uptake and metabolism

Clinical and experimental studies show that central nervous system ischemia in the presence of hyperglycemia results in a worse neurologic outcome than when normo- or mild hypoglycemia exists, but the mechanisms of injury is not known. The general goal of this study was to examine the effects of glucose availability, uptake and subsequent metabolism on neurologic outcome in an attempt to determine which if any of these processes may have a significant contribution in the hyperglycemic exacerbation of neurologic deficit. The hypothesis tested was that increasing glucose availability will increase ischemia induced neurologic deficit and decreasing glucose availability, uptake or metabolism will decrease neurologic deficit in the paraplegic rat. A newly developed rat model of spinal cord ischemia (SCI) was used where the right and left subclavian arteries and the aorta distal to the left subclavian artery were temporarily occluded for between 10 and 15 minutes. Plasma glucose was measured from a 0.5 cc tail snip blood sample. An observer performed neurologic evaluation was done at 1, 4, 18 and 24 hours following occlusion. Results demonstrated that exogenous glucose induced hyperglycemia exacerbated SCI injury while insulin induced mild hypoglycemia decreased SCI injury. 2-Deoxyglucose inhibition of initial glucose metabolism (hexokinase) decreased SCI injury and 3-O-methylglucose inhibition of cellular glucose uptake increased SCI injury. Finally, dichloroacetate, which accelerates the metabolism of lactate through pyruvate dehydrogenase into the tricarboxylic acid cycle, decreased SCI injury in the rat. Based on these results we conclude: (1) Hyperglycemia, while necessary, is not sufficient for the hyperglycemic exacerbation of neurologic deficit; (2) Glucose uptake through the glucose transporter alone is not necessary for the damaging effects of hyperglycemia possibly because simple diffusion of glucose may bypass the transporter through a compromised blood brain barrier; (3) Metabolism of glucose by hexokinase is necessary, but it may not be sufficient for the damaging effects of hyperglycemia; (4) Protection of neurologic function by both 2-deoxyglucose and dichloroacetate suggests that metabolic events initiated between hexokinase and pyruvate dehydrogenase are responsible for a significant part of the hyperglycemic exacerbation of neurologic deficit in the paraplegic rat.