A central challenge to modern neuroscience is to understand mechanisms of interneuronal communications, and the regulation and synthesis of endogenous sigal molecules in the brain, in both normal and pathological conditions. Unlike classical neurotransmitters and neuropeptides, gaseous nitric oxide (NO) is synthesized and released without the intermediary of special storage, subsequently freely crossing membrane barriers and affecting targets relatively large distances away, by direct covalent bonding. Although NO is crucial for most of the major neuronal functions (including learning, memory, differentiation and apoptosis), the resulting NO action depends on its local concentrations and the local microenvironment. NO can act either as a versatile signal molecule, and neuroprotective agent, or as a prominent neurotoxic intermediate. The development of postschemic brain injury, stroke, and neurodegenerative diseases are directly associated with a prominent overproduction of NO. NO synthase (NOS) is accepted as the only source of NO synthesis in the nervous system, and, although NOS inhibitors show promise as pharmacological instruments to prevent overproduction of NO, their effectiveness is controversial. However, since all these pathologies are generally associated with tissue acidification, we propose an alternative NOS-independent mechanism of NO formation in the nervous system, the non-enzymatic NO synthesis from nitrites in acidified and reducing micro-environments. This synthetic pathway may account for the excess O in these pathologies. Nitrites themselves are the main product of NO oxidation and can be accumulated in specific cells and tissues. Furthermore, due to the relatively high endogenous nitrite concentrations and the substantial pH transients associated with neuronal activity, this pathway is likely an additional mechanism for tonic NO production under normal conditions. The long-term objectives of this proposal are to analyze the distribution and functional significance of this complimentary NOS-independent pathway of NO formation in the nervous tissues, and, specifically, to characterize nitregic (NO producing) neuron and their postsynaptic targets. To separate enzymatic and non-enzymatic No synthesis we will use selective NOS inhibitors and microchemical analysis of major metabolites involved in these two pathways. Microelectrode electrical recording and pH1 measurements will provide further functional chracterization of individual nitregic neurons. Thus, significant gains can be made in our understanding of the synthesis of this gaseous messenger in the brain. This work will also contribute to our understanding of the neural functions in normal and pathological conditions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS039103-01
Application #
2899203
Study Section
Special Emphasis Panel (ZRG1-MDCN-5 (01))
Program Officer
Nichols, Paul L
Project Start
1999-08-24
Project End
2003-04-30
Budget Start
1999-08-24
Budget End
2000-04-30
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Florida
Department
Type
Organized Research Units
DUNS #
073130411
City
Gainesville
State
FL
Country
United States
Zip Code
32611
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