Central hypoxic neuronal injury (HNI) contributes to the morbidity and mortality of many neurological diseases, including stroke, drowning, cardiac arrest, and head injury. However, the responsible cellular mechanisms are not currently defined, and no proven therapy is available. The proposed study is viewed broadly as initiating a investigation into these cellular mechanisms, in the hope of eventually developing an effective pharmacological therapy. A recent, rapidly growing body of evidence suggests that HNI may be in large part mediated by the neurotoxicity of endogenous excitatory amino acids (EAAs), accumulating in brain extracellular space under hypoxic conditions. The proposed study will focus specifically on postsynaptic antagonists of EAA neurotoxicity, utilizing an established murine cortical cell culture model system to achieve both rapid screening, and quantitative drug characterization at the neuronal level, free of the systemic effects which can complicate studies in vivo. The study should be synergistically facilitated by an ongoing parallel investigation of the neurotoxicity of exogenously applied EAAs. In addition to identifying and characterizing promising compounds (or combinations of compounds) with protective efficacy against cortical HNI, the study will seek to define several principles governing this pharmacological approach, including comparative efficacy among different classes of EAA antagonists, time constraints (efficacy of """"""""late"""""""" administration of antagonists), effect of zinc (likely co-released with EAAs at many central synapses), and differences in the intrinsic vulnerability (or response to various therapies) of specific neuronal subpopulations. Information gathered during this study will likely be helpful in guiding testing in vivo, and furthermore should produce insight into the basic nature of EAA involvement in HNI.
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