The goal of this project is to define the role of excitotoxicity by the neurotransmitter glutamate in brain injury due to hypothermic circulatory arrest (HCA). Excessive stimulation of glutamate receptors by high concentrations of glutamate itself has recently been linked to neuronal death in conditions of metabolic stress, such as hypoxia and ischemia. The characteristic neurologic sequelae and patterns of selective neuronal necrosis associated with HCA suggest a role for glutamate excitotoxicity. It is now possible to precisely define this role for the first time in a clinically relevant model of HCA because of the recently developed selective glutamate receptor antagonists. A canine survival model of HCA closely simulating clinical practice has been established. A consistent neurologic injury was obtained following 2 hrs of circulatory arrest at a brain temperature of 18degreeC. The neurologic deficit and the histopathologic pattern of selective neuronal necrosis parallel the brain injury seen after HCA in the clinical setting. Experimental evidence has demonstrated a close correlation between inhibition of glutamate release and mild hypothermia. Preliminary studies in which brain temperature varied from 33degreeC to 37degreeC following HCA demonstrated significantly improved cerebral protection in animals maintained at the lower temperature, providing indirect evidence for glutamate-induced excitotoxicity in HCA-induced brain injury. In further preliminary work subtypes of glutamate receptors (NMDA and non-NMDA) have been defined in all areas of the dog brain by receptor autoradiography. Using the selective NMDA glutamate receptor antagonist MK801, selective protection of the CA3 region of the Hippocampus and Cerebellar Purkinje cells has been demonstrated, yielding the first direct evidence implicating glutamate excitotoxicity in HCA- associated injury. To comprehensively examine this mechanism, selective glutamate receptor antagonists will be used as single agents and in combination in the canine model of HCA. The resulting patterns of selective neuronal protection will be studied by histopathology and correlated with the altered distribution patterns of autoradiographically labelled glutamate receptor subtypes. An extension of these studies will involve the use of monosialogangliosides, compounds known to inhibit glutamate excitotoxicity while leaving the physiologic actions of glutamate unaffected. The proposed research will not only define the role of excitotoxicity in HCA but may provide a novel therapeutic approach to ameliorating the associated neurologic injury. The ability to provide and extend a safe period of circulatory arrest could potentially result in better patient care and broaden the scope of many cardiothoracic and other non-cardiac procedures using HCA.
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