Anaerobic metabolism is a characteristic feature of CNS hypoxia/ischemia. Energy is obtained from anaerobic glycolysis, although the amount is not sufficient to maintain the metabolic activity of the CNS, and accumulation of the end-products of this metabolic pathway, lactate and H+, may result in additional injury to neurons recovering from ischemia. We have used a model of spinal cord ischemia to study CNS ischemia processes for 2 major reasons: 1) The effect of ischemia on specific synaptic and neuronal processes can be very well characterized in the spinal cord by electrophysiological means and 2) The effects of ischemia in terms of motor and sensory function can be predicted by the recovery of evoked potentials. Preliminary data have shown two periods of lactate accumulation associated with spinal cord ischemia. Immediately after occlusion of the aorta, lactic acid concentration in the spinal cord increases, as pyruvate becomes depleted. After release of the aortic occlusion, there is a second transient period of lactate accumulation in the spinal cord, associated with an increase in spinal cord pyruvate concentration. Preischemia reduction in spinal cord metabolic rate and in blood glucose concentration reduce both the ischemic and postischemic lactate accumulation. All of these therapeutic interventions improve electrophysiological recovery after ischemia. The metabolic inhibiting agents, thiopental and hypothermia, have been demonstrated to improve long-term neurological recovery from ischemia. This proposal outlines an investigation of two additional treatments of ischemic lactic acidosis. The first proposed treatment is to increase the availability of energy substrates such as ketone bodies and short chain fatty acids that cannot be anaerobically metabolized. The second proposed treatment is to inhibit lactic dehydrogenase, the enzyme that catalyzes the conversion of pyruvate to lactate. The effects of these two treatments on spinal cord lactate accumulation and on electrophysiological function will be studied.
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