Brain damage associated with anoxia/stroke or trauma is to a small degree due to the acute invasive focal lesion and to a large degree due to the non-acute massive neuronal degeneration in the perifocal area. The neuronal death in the perifocal area is characterized by a large increase of excitatory amino acids (EAA) release in the extracellular space (2,3) can be prevented, in part by the administration of N-methyl-D-aspartate (NMDA) receptor antagonists. However, the neuronal death following exaggerated and paroxysmal release of EAA is not always due to the stimulation of the so called NMDA-sensitive glutamate receptor subtype but can be a feature common to the stimulation of the NMDA-insensitive glutamate receptor subtypes insensitive to NMDA receptor antagonists. The first question we will try to answer in the proposed project is whether the NMDA-sensitive or NMDA-insensitive glutamate receptors are located on the same neuron. The second question we will address is whether the protracted stimulation of the two receptor subtypes triggers delayed neuronal death by identical or dissimilar underlying mechanisms. As a model to study slowly evolving neuronal damage observed in the perifocal tissue of hypoxic/ischemic brain regions. We will use primary cultured neurons in vitro. Our goal in the proposed project is to define in vitro the cascade of pathophysiological events (related to calcium channels, cyclic GMP, phosphatidyl inositol turnover, protein kinase C, protease activity) leading to the delayed neuronal damage induced by prolonged and exaggerated stimulation of EAA receptors. These studies will provide valuable information on the cascade of biochemical events associated with NMDA- sensitive and NMDA-insensitive glutamate receptor-induced neuronal death and should serve as a basis for future investigations of the """"""""exitotoxic hypothesis"""""""" of brain damage. In addition, the results may provide the basis for a rationale approach to the investigation of a new family of drugs which can protect neurons from EAA-induced neurotoxicity.
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