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 may occur with brain injury. In previous studies we have demonstrated: 1. even the mildly traumatized brain (TBI) is more vulnerable to acute (within 1 hour) or delayed (within 24 hours) secondary cerebral ischemia in selective brain regions, 2. post-traumatic increased ischemic sensitivity is in part mediated by aberrant agonist-receptor interactions involving cholinergic M1 and/or glutamate NMDA receptors. 3. The hippocampal CA1 sector is especially sensitive to TBI receptor mediated pathophysiology 4. These receptors down regulate by 10 to 15% following TBI in selectively vulnerable brain regions such as the hippocampus 5. TBI produces a 25% increased phosphoinositide specific phospholipase C (PLC) activity which can be prevented by muscarinic and NMDA antagonism. 6. TBI produces increased CA1 protein kinase C (PKC) activation and translation. Our data also suggests the novel possibility that simultaneous antagonism of both cholinergic muscarinic and/or 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: a. Does an interaction involving RKC activation exist between M1 and NMDA receptors in combined trauma nad ischemic insults? b. Is this phenomenon associated with an increased neuronal excitability as determined by differences in CA1 non-tetanic input/output curves and post-injury CA1 spike activity c. Does the antagonism of M1 and NMDA receptors reduce increased post-TBI ischemic sensitivity by beneficial effects in CA1 neuronal excitability, receptor function, PDC activity in the absence of cerebrovasculature improvement as determined by CBF measures, CA1 electrophysiology, M1 and NMDA receptor binding and PKC-phorbol ester binding? The effects of M1 and NMDA antagonism on post-traumatic ischemic vulnerability will be evaluated temporally in fasted rats subjected to mild trauma and delayed secondary ischemia. These studies should provide considerable insight into not only the mechanisms responsible for increased post-traumatic ischemic vulnerability, but their temporal course and therapeutic window for practical intervention.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Neurology A Study Section (NEUA)
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Virginia Commonwealth University
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DeWitt, D S; Jenkins, L W; Prough, D S (1995) Enhanced vulnerability to secondary ischemic insults after experimental traumatic brain injury. New Horiz 3:376-83
Povlishock, J T; Jenkins, L W (1995) Are the pathobiological changes evoked by traumatic brain injury immediate and irreversible? Brain Pathol 5:415-26
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Hayes, R L; Jenkins, L W; Lyeth, B G (1992) Neurotransmitter-mediated mechanisms of traumatic brain injury: acetylcholine and excitatory amino acids. J Neurotrauma 9 Suppl 1:S173-87
Delahunty, T M (1992) Mild traumatic brain injury enhances muscarinic receptor-linked inositol phosphate production in rat hippocampus. Brain Res 594:307-10
Miller, L P; Lyeth, B G; Jenkins, L W et al. (1990) Excitatory amino acid receptor subtype binding following traumatic brain injury. Brain Res 526:103-7
Jenkins, L W; Moszynski, K; Lyeth, B G et al. (1989) Increased vulnerability of the mildly traumatized rat brain to cerebral ischemia: the use of controlled secondary ischemia as a research tool to identify common or different mechanisms contributing to mechanical and ischemic brain injury. Brain Res 477:211-24
Jenkins, L W; Lyeth, B G; Lewelt, W et al. (1988) Combined pretrauma scopolamine and phencyclidine attenuate posttraumatic increased sensitivity to delayed secondary ischemia. J Neurotrauma 5:275-87

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