Polymorphonuclear leukocytes (PMN, neutrophils) are inflammatory cells that possess halide-dependent myeloperoxidase (MPO). Activated PMN secrete MPO and release it upon death. MPO produces HOCl/OCl-, which reacts with taurine to form taurine monochloramine (Tau-Cl), a more stable and selective oxidant than HOCl/OCl. Elevated levels of extracellular taurine increase Tau-Cl concentrations at the site of inflammation via PMN associated MPO activity. It is our hypothesis that prophylactic administration of taurine may attenuate tissue damage resulting from aberrant inflammatory responses through formation of Tau-Cl and subsequent inhibition of the production of proinflammatory mediators. Astrocytes and microglia are a major source of tissue damaging proinflammatory mediators in the CNS and contribute to the neural damage that occurs during ischemic stroke. The primary goals of this proposal are to establish the inhibitory effects of Tau-Cl on the production of inflammatory mediators by activated glial cells and to determine the molecular mechanisms(s) through which Tau-Cl exerts this effect. This will be accomplished using primary cultures of rat astrocytes and microglia, and clonal cell lines derived from glial cells. The ability of Tau-Cl to inhibit production of proinflammatory mediators will be evaluated in a model of CNS hypoxic ischemia using culture systems of rat glial cells for in vitro studies. In addition, a rat model of transient middle cerebral artery occlusion will be used for in vivo studies of the efficacy of taurine to protect against the CNS damage that results from transient focal cerebral ischemia. Completion of these studies is not only important to determining the mechanism of Tau-Cl action in cells of neural origin, as occurs in ischemic and traumatic brain injury, but may also be relevant to modulating inflammatory responses in general.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS040721-02
Application #
6613786
Study Section
Special Emphasis Panel (ZRG1-BDCN-4 (01))
Program Officer
Jacobs, Tom P
Project Start
2002-08-01
Project End
2005-05-31
Budget Start
2003-06-01
Budget End
2004-05-31
Support Year
2
Fiscal Year
2003
Total Cost
$268,110
Indirect Cost
Name
New York State Cncl for Mtl Hygiene Plng
Department
Type
DUNS #
City
Albany
State
NY
Country
United States
Zip Code
12229