SPINAL NEURAL ACTIVITY--ROLE IN POST ISCHEMIC INJURY

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Transient spinal cord ischemia secondary to aortic occlusion can induce spinal dysfunction. Because of collateral flow, spinal perfusion falls after occlusion to a very low level and this level gradually worsens with time, leading to an apparent irreversible loss of function. The failure of function may be ascribed to three principle variables: i) progressive loss of flow, ii) mismatch between supply of metabolic substrates and cellular requirements and iii) release of neurotransmitters, such as glutamate that serve to increase neuronal activity and to increase intracellular calcium. The elevated calcium activates a number of intracellular enzymes including phospholipase which yields arachidonic acid and a consequent increase in prostanoids. Prostanoids have powerful effects upon neuronal release and also signal the formation of free radicals formed as a consequence of the action of cyclooxygenase. Of interest to us is the fact that both transmitter release, enzymatic process and energy-requiring events within the cell show a high degree of temperature dependency. Such dependency may account for the efficacy of cooling on preserving post reflow function. Quantitative assessment of the effect of a broad range of temperatures on spinal transmitter release, spinal metabolic rate, spinal cord blood flow and outcome, as assessed by behavior and systematic histopathology would establish the potential relationship of these several variables to the evolution of the post reflow picture. Current data has already indicated that it is possible to dissociate the temperature sensitivity of spinal glutamate, taurine and TXB2 release. These studies will be accomplished with a simple, well characterized rat model where reversible aortic occlusion is achieved with a 2F Fogarty catheter passed from the femoral artery, with spinal drugs delivered by an intrathecal catheter, spinal transmitter release studied with a microdialysis catheter; spinal blood flow measured using laser Doppler; and, spinal glucose utilization assessed using 2-deoxyglucose.The results of these experiments will specifically address several issues: i) correlation between time of exposure to normothermic ischemia and degree of neurological and histopathological changes, ii) covariance of transmitter release (glutamate, taurine and TXB2), spinal glucose utilization, and spinal cord blood flow with neurological deficit and spinal histopathology as a consequence of aortic occlusion carried out while the cord is maintained during or after transient ischemia at temperatures of 29 to 40 degrees C; iii) whether exogenously increased neuronal activity (as with intrathecal NMDA or K+) increases neuronal vulnerability after short lasting ischemia and, iv) whether blockade of spinal NMDA and non-NMDA receptor sites produce a sparing effects and whether this effect is augmented in the presence of periischemic spinal cord hypothermia. From a practical standpoint, these studies will systematically address several points which we think have clinical impact: l) whether deeper hypothermia confers progressively greater protection, a trade off reflecting the problems associated with deep hypothermia, 2) importance of hypothermia during the ischemic interval versus following ischemia (when decreased metabolic activity may delay recovery of homeostasis) and 3) the benefit of intra- ischemic intervals of reflow on outcome.