The goals of this proposal are based on the fundamental assumption that the same basic cellular and molecular mechanisms that produce enduring adaptive changes in neuronal information flow, e.g., memory, can also when stimulated in excess produce enduring dysfunction and death such as occurs with brain injury. Such a role has been proposed for the neuronal glutamate NMDA receptor. In previous studies we have demonstrated that: a even the mildly traumatized brain is more vulnerable to acute (within 1 hour) or delayed (within 24 hours) secondary cerebral ischemia, and b this post-traumatic increased ischemic sensitivity is in part mediated by aberrant agonist-receptor interactions involving cholinergic muscarinic and/or glutamate NMDA receptors. Our data also suggests the novel possibility that simultaneous antagonism of both cholinergic muscarinic and glutamate NMDA receptors may be more beneficial in reducing post-traumatic ischemic vulnerability than the blockage of either receptor population alone. We therefore, wish to determine if: 1) does a synergistic interaction between muscarinic and NMDA receptors exist in the phenomenon of increased post-traumatic ischemic vulnerability? 2. If this interaction exists, is it associated with increased neuronal excitability as determined by differences in generalized seizure thresholds? 3. Does the antagonism of muscarinic and NMDA receptors produce beneficial effects in this paradigm via direct improvements in cerebrovascular function and/or neural function via changes in neuronal excitability and receptor sensitivity as determined by post-injury CBF, seizure thresholds and muscarinic and NMDA receptor binding? Employing qualitative and quantitative light microscopic neuronal death quantitative autoradio-graphic CBF and muscarinic and glutamate NMDA and non-NMDA receptor binding, and post-injury seizure thresholds as endpoints; the effects of muscarinic and NMDA antagonism on post-traumatic vulnerability will be evaluated temporally in fasted rats subjected to mild trauma and acute or delayed secondary ischemia. These studies should provide considerable insight into not only the mechanisms responsible for increased ischemic vulnerability of the traumatized brain, but their temporal course and window for practical clinical intervention.
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