This application explores issues germane to many of the proposals in this program project in that its goals relate to the theme that traumatic brain injury results in the excessive release of excitatory neurotransmitters (acetylcholine and glutamate) which elicit pathologic agonist-receptor interactions. While most advocate that these excitatory transmitters derive from terminals within the brain parenchyma, it is our hypothesis that some excitatory transmitters reach the brain front from the systemic circulation via an altered blood-brain barrier.
The specific aims of the application seek to address this possibility and, as such, consider the potential for traumatically induced barrier disruption, its anatomical localization, and its duration. Additionally, the subcellular changes associated with barrier disruption will be assessed and the functional implications will be evaluated. Lastly, the role of oxygen radical formation in the genesis of blood-brain barrier alteration will be explored. To address these specific aims, rats will be subjected to fluid- percussion injuries of differing severity. Endogenous and exogenous tracers will be followed via various immunocytochemical strategies at the light and electron microscopic level to determine the location duration and of the altered barrier permeability. Having determined this, (14C) alpha-Aminoisobutyric acid, a small molecular weight radiolabeled amino acid, of a size and nature similar to acetylcholine and glutamate, will be used to quantitatively determine its blood-to-brain transfer following injury. The brain uptake index of glutamate and acetylcholine will also be assessed to provide a direct measure of their uptake following traumatic brain injury. The levels of these transmitters in the systemic circulation will be considered. Lastly, through the use of superoxide dismutase, the possible role of the superoxide anion in the genesis of altered barrier permeability will be evaluated. The successful conduct of this study should provide new insights into those factors at work in traumatic brain injury as well as their potential therapeutic regulation.
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