ACUTE/SUBACUTE METABOLIC & HEMODYNAMIC TRAUMATIC BRAIN INJURY DETERMINANTS

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We propose to investigate in detail the interrelationships between local brain glucose metabolism (ICMRgl) and blood flow (ICBF) in the acute and subacute periods following cortical fluid-percussion injury (FPI) in the rat. Exciting pilot data obtained using novel 3D autoradiographic image- averaging strategies developed by us have disclosed marked metabolism > flow uncoupling in the acute period after FPI, which we believe imposes a severe metabolic stress upon the tissue. In contrast, hyperemia was observed at five days. Using matched animal groups and the disparity analysis algorithm, we shall comprehensively characterize ICBF, ICMRgl and the ICMRgl/ICBF ratio over the first five days following FPI. We hypothesize that uncoupling persists during the first few hours but remits after 1-2 days. Next, we shall ascertain how these perturbations are influenced by post-traumatic therapeutic hypothermia, administered either early (first 3 h). or initiated somewhat later (3-5 h) following trauma. We hypothesize that therapeutic hypothermia reverse uncoupling and thereby protects the tissue. We shall establish the role of the nitric oxide/nitric oxide synthase (NOS) system in post-traumatic ICBF changes, either via diminished vascular NO production acutely or by expression of iNOS at later time. This will be studied via in situ hybridization, immunohistochemistry, and enzymatic activity assays, coupled with assessment of cyclic GMP production in the traumatic brain. As endothelin and/or serotonin are potential modulators of ICBF following trauma, these will also be assessed via intracerebral microdialysis and the use of specific pharmacologic anatagonists. Finally, we intend to characterize more fully the relationship between the localized evidence of metabolic stress (metabolism > uncoupling) and the temporal and spatial features of gene expression: we shall concentrate on hsp7O, immediate early genes, glial fibrillary acidic protein, and the neurotrophin, brain- derived neurotrophic factor. Our pilot data, in each instance, have revealed trauma-related changes in gene expression. The relationship of these patterns of gene expression to apoptosis will be assessed. Finally, we shall investigate the effect of specific therapeutic interventions, including NMDA and non-NMDA antagonism, and the scavenging of oxygen radicals, on CMRgl/CBF interrelationships and gene expression. These studies will provide a comprehensive overview of hemodynamics and metabolism in the acute and subacute periods.