Our overall, broad research mission is to understand the neuropharmacologic and neuroimmunologic modulation of nitric oxide (NO) synthesis in neurodegenerative diseases. Pathological production of NO has blood-cerebrospinal fluid (B-CSF) barrier permeability changes during experimentally - induced meningitis and determine the extent to which NO contributes to this disruption. Preventing B-B and B-CSF barrier changes is important as adverse neurological outcomes are related to alterations in B-B and B-CSF barrier permeability. Moreover, this knowledge may help to develop adjunctive treatment therapies for meningitis. In vivo studies have demonstrated alterations in the B-B barrier were also observed following exposure to bacterial lipopolysaccharides (LPS). LPS is known to induce nitric oxide (NO) synthase in a variety of cell types, including brain endothelial cells and meningeal fibroblasts in vitro. We hypothesize that pathological production of NO may solely or partially contribute to the disruption of the B-B and B-CSF barriers during meningitis. A rat model of meningitis will be induced by the intracisternal administration of LPS. No production will be measured by an ex vivo biochemical technique developed in our laboratory. LPS- mediated alterations in the B-B and B-CSF barriers will be quantitated by in vivo pharmacokinetic methods or in vitro tissue culture methods, utilizing molecular size markers ({14C}-source, {14C}-inulin and {3H}- dextran) which ordinarily do not cross the B-B and B-CSF barrier permeability will be examined under in vivo and in vitro conditions.
The specific aims of the proposal are: 1. To further improve the ex vivo technique of measuring central nervous tissue production of NO. 2. To examine the in vivo B-B and B-CSF permeability kinetics of different molecular size radiotracer in relationship to LPS administration and subsequent meningeal production of NO 3. To examine the potential role of NO as a mediator of in vivo B-B and B-CSF barrier permeability kinetics following administration of NO synthase inhibitors or NO generating drugs. 4. TO understand the B-B transport mechanisms of various NOS inhibitors in control and LPS treated rats. These studies could possibly identify novel therapeutic strategies to prevent permeability changes in the B-B and B-CSF barriers in necroinflammatory disease states.
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