The purpose of this proposal is to evaluate the effect of a secondary ischemic insult on the previously traumatized brain in order to determine if head trauma renders the central nervous system more vulnerable to ischemic brain damage. Secondly, we will determine if post-traumatic serum hyperglycemia plays a major role in the vulnerability of the traumatized brain to ischemia. Lastly, we will determine if the manipulation of serum glucose levels following head injury employing insulin administration decreases the risk of the traumatized brain to secondary ischemic insults. Through such studies we will test our hypotheses: 1) that the traumatized brain is more vulnerable to ischemic injury than the normal brain; 2) that the increased vulnerability of the brain to ischemia following head injury is primarily the result of serum hyperglycemia; 3) that by decreasing serum glucose levels with insulin administration following head trauma, the vulnerability of the brain to secondary ischemia will be significantly reduced. By combining a model of fluid percussion head injury and a model of global incomplete cerebral ischemia induced by hemorrhagic hypotension, we propose to produce a consistent and mild to moderate level of head trauma followed by a consistent level of incomplete ischemia for a 7-minute period. Traumatic and ischemic brain injury will be assessed both separately and in combination by employing measurements of total and regional CBF with 15 Mum microspheres, multimodality evoked potentials, regional quantitative morphometric neuropathology, and regional assessments of brain energy metabolites. CBF and evoked potentials will be measured in all animals in combination with either morphopathology or neurochemistry. By assessing these different measurements of brain function and structure in the same animal (with the exception of the neuropathology and neurochemistry which are incompatible), a more accurate and efficient evaluation of our hypotheses will be obtained. If our hypotheses prove correct, a new and rational therapeutic approach in the management of head injury patients may evolve.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS019550-03
Application #
3399639
Study Section
Neurology A Study Section (NEUA)
Project Start
1985-09-01
Project End
1988-08-31
Budget Start
1987-09-01
Budget End
1988-08-31
Support Year
3
Fiscal Year
1987
Total Cost
Indirect Cost
Name
Virginia Commonwealth University
Department
Type
Schools of Medicine
DUNS #
City
Richmond
State
VA
Country
United States
Zip Code
23298
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
Lyeth, B G; Jiang, J Y; Robinson, S E et al. (1993) Hypothermia blunts acetylcholine increase in CSF of traumatically brain injured rats. Mol Chem Neuropathol 18:247-56
Phillips, L L; Belardo, E T (1992) Expression of c-fos in the hippocampus following mild and moderate fluid percussion brain injury. J Neurotrauma 9:323-33
Jiang, J Y; Lyeth, B G; Kapasi, M Z et al. (1992) Moderate hypothermia reduces blood-brain barrier disruption following traumatic brain injury in the rat. Acta Neuropathol 84:495-500
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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