The long-term objectives of this work are to identify mechanisms of hippocampal selective neuronal vulnerability to ischemia and to determine the efficacy and appropriate timing of select strategies to """"""""rescue"""""""" hippocampal neurons which have suffered an ischemic insult. It has been shown that roughly 80% of individuals with closed head injury suffer hippocampal damage as a result of secondary post-traumatic compression ischemia. This pattern of damage has also been shown, clinically, to produce memory deficits and may account for continued neurologic impairment observed following head injury. An increasing awareness of the importance of hippocampus to neurologic outcome, and compelling evidence that this brain structure is perhaps the most sensitive to delayed ischemic insult, makes post-traumatic ischemia a significant health concern which may be very amenable to therapeutic intervention. The present work examined parenchymal mechanisms of selective vulnerability of hippocampal CA1 pyramidal cells to artificial ischemia in organotypic hippocampal slice cultures. This preparation will also allow the examination of strategies to rescue neurons in the absence of vascular and systemic effects. This study of parenchymal mechanisms of ischemia will complement the work of component 6 examining secondary post-traumatic effects in isolated microvessels. Specifically, the present work will: 1) examine the role played by hyperexcitability in individual neuronal populations in conferring selective vulnerability; 2) investigate the role of NMDA- and quisqualate- type ionotropic glutamate receptors and of the metabotropic glutamate receptor in conferring selective vulnerability to ischemia; 3) therapeutic interventions will be examined which are directed at specific events which occur post-ischemia in an attempt to rescue neurons at different time periods relative to ischemia. These will include antagonists of both ionotropic and metabotropic glutamate receptors, blocking intracellular calcium release, free radical scavengers and/or antagonists of lipid peroxidation, and antagonists of proteolysis. In addition, the efficacy of nerve growth factor in protecting neurons from ischemia will be examined. This work will complement the studies of component 1 examining the efficacy of trophic factors on primary neuronal damage. Successful rescue strategies will be analyzed further to determine if protected neurons exhibit physiologic abnormalities, as determined by single-cell and population responses recorded in vitro. Finally, the effects of intoxicating levels of alcohol on selective vulnerability to ischemia will also be examined and the compounding effects that alcohol may have on successful rescue attempts will be determined.
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