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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29NS031939-05
Application #
2669024
Study Section
Pharmacology A Study Section (PHRA)
Program Officer
Kerza-Kwiatecki, a P
Project Start
1994-04-01
Project End
2000-02-29
Budget Start
1998-03-01
Budget End
2000-02-29
Support Year
5
Fiscal Year
1998
Total Cost
Indirect Cost
Name
State University of New York at Buffalo
Department
Other Health Professions
Type
Schools of Pharmacy
DUNS #
038633251
City
Buffalo
State
NY
Country
United States
Zip Code
14260
Boje, Kathleen M K; Jaworowicz Jr, David; Raybon, Joseph J (2003) Neuroinflammatory role of prostaglandins during experimental meningitis: evidence suggestive of an in vivo relationship between nitric oxide and prostaglandins. J Pharmacol Exp Ther 304:319-25
Raybon, J J; Boje, K M (2001) A critical evaluation of the brain efflux index method as applied to the nitric oxide synthase inhibitor, aminoguanidine. Biopharm Drug Dispos 22:391-401
Mahar Doan, K M; Boje, K M (2000) Theoretical pharmacokinetic and pharmacodynamic simulations of drug delivery mediated by blood--brain barrier transporters. Biopharm Drug Dispos 21:261-78
Mahar Doan, K M; Ng, S; Boje, K M (2000) Cellular transport processes of aminoguanidine, a nitric oxide synthase inhibitor, in the opossum kidney cell culture line. Int J Pharm 194:209-20
Boje, K M; Lakhman, S S (2000) Nitric oxide redox species exert differential permeability effects on the blood-brain barrier. J Pharmacol Exp Ther 293:545-50
Mahar Doan, K M; Lakhman, S S; Boje, K M (2000) Blood-brain barrier transport studies of organic guanidino cations using an in situ brain perfusion technique. Brain Res 876:141-7
Jaworowicz Jr, D J; Filipowski, M T; Boje, K M (1999) Improved high-performance liquid chromatographic assay for nimesulide. J Chromatogr B Biomed Sci Appl 723:293-9
Jaworowicz Jr, D J; Korytko, P J; Singh Lakhman, S et al. (1998) Nitric oxide and prostaglandin E2 formation parallels blood-brain barrier disruption in an experimental rat model of bacterial meningitis. Brain Res Bull 46:541-6
Boje, K M (1996) Inhibition of nitric oxide synthase attenuates blood-brain barrier disruption during experimental meningitis. Brain Res 720:75-83
Korytko, P J; Boje, K M (1996) Pharmacological characterization of nitric oxide production in a rat model of meningitis. Neuropharmacology 35:231-7

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