Ischemic brain injury constitutes a major source of morbidity and mortality in the United States. In patients presenting with nontraumatic coma, 61 percent will die without awakening, 12 percent will remain in a vegetative state, and 11 percent will survive with severe neurologic disability. An estimated 67 percent of the patients who survive a cardiac arrest will suffer permanent and disabling neurologic injury. Recent work suggests that a significant portion of ischemic brain injury may be due to the excessive release of excitatory amino acids (EAAs) and an ensuring cascade of events that leads eventually to neuronal death. Elevated extracellular concentrations of EEA (e.g., glutamate and aspartate) are known to occur in such diverse forms of brain injury as ischemia, hypoxia, and hypoglycemia, as well as in various forms of neurodegenerative diseases. In vitro experiments have clearly demonstrated the toxic effects of EEAs on neuronal cell cultures and microinjection studies have shown that EEAs can act as in vivo neurotoxins. Evidence now exists that glutamate concentrations reach toxic levels during episodes of ischemia and neuronal injury can be attenuated by lesioning glutaminergic pathways. A significant proportion of the EEAs released during ischemia are of synaptosomal origin and this release is calcium-dependent. That ischemic brain injury may be an evolving process raises the hope that therapeutic interventions in the periischemic period may markedly improve outcome. The proposed studies will examine effects of agents that may attenuate EAA release, including N-type calcium channel antagonists, sodium channel blockers, and adenosine A1 agonists on MRI-derived indices of intracellular swelling, histologic outcome, and neurobehavioral outcome after episodes of transient global ischemia. The technique of microdialysis will be sued to achieve fine temporal resolution of regional brain tissue concentrations of EAAs postulated to mediate delayed neuronal death. These studies will provide a better understanding of the mechanisms involved in neurologic injury and will help to resolve questions regarding the possible therapeutic benefits of these potential neuroprotective agents.
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