Biochemical Mechanisms of Brain Injury

Virginia Commonwealth University, Richmond VA

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Abstract

DESCRIPTION (provided by applicant): Long range goal: Our long range goal is to further understand the dynamic cellular events which occur in the early period after traumatic brain injury (TBI) and to use this knowledge to more rationally predict and test therapeutic interventions to reduce secondary injury and increase cell recovery. To accomplish our goal we will continue to use a reductionist, cell culture model of traumatic injury wherein brain-derived cells are grown on flexible Silastic membranes and subjected to rapid, reversible strain (stretch) injury.Progress: We have made significant progress in four inter-related areas. Progress relevant to the current renewal application is our finding of striking changes in intracellular free calcium ( aboutCa2+] i) dynamics, signal transduction and capacitative calcium entry (CCE). After injury there is a 1000% increase in astrocyte IP3 which is mediated by activation of group I metabotropic glutamate receptors (mGluR1) and is associated with an uncoupling of IP3 and its target. the intracellular calcium store. Also, immediately post-injury there is a depletion of intracellular calcium stores, followed by a repletion, and concomitant enhanced neuronal CCE. Our preliminary studies suggest mGluR1 antagonism reduces depletion of Ca2+ stores.Hypothesis: Disruption of Ca2+ stores and CCE could affect multiple parameters including neuronal excitability, plasticity, protein synthesis, exocytosis and neuronal-glial interactions. We will test the hypothesis that following strain injury disruption of Ca2+ stores and CCE is a receptor-mediated consequence that is mediated in part by P-450 metabolites of arachidonic acid (AA). We will also test whether pre- or post-traumatic pharmacologic blockade of plasma membrane group I metabotropic receptors, or blockers of intracellular Ca2+ store release, will prevent or reduce depletion of intracellular Ca2+ stores and alterations in the capacitative calcium pathway. Aims and Methods: Our approach will use astrocytes and neuronal plus glial cultures, Fura-2 measurement.