In this application, the investigators explore the theme that traumatic brain injury results in excessive release of excitatory neurotransmitters (acetylcholine and glutamate) which elicit pathologic agonist-receptor interactions. While most investigators advocate that these excitatory transmitters derive from terminals within the brain parenchyma, the hypothesis to be tested in the present application is that some excitatory transmitters reach the brain front from the systemic circulation via an altered blood-brain-barrier (BBB).
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 nature of the altered barrier permeability within the brain parenchyma. Parallel permeability studies will be conducted in the related pial vasculature, whose functional status will be assessed through cranial windows. This will be done to detect any relationship between altered pial vascular permeability and abnormal pial vascular reactivity. Having determined the sites of BBB dysfunction within the brain, (14C) a-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 the blood-to-brain transfer following injury. The brain uptake 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 and CSF will be considered. Lastly, through the use of superoxide dismutase, the possible role of superoxide anion in the genesis of altered barrier permeability will be evaluated. The applicants suggest that the successful conduct of this study should provide new insights into the factors at work in traumatic brain injury as well as their potential therapeutic regulation. Also, this study should provide new and novel approaches for anatomically followed altered cerebrovascular permeability over time, while better appreciating the linkage between vascular permeability and functional change.
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