Considerable evidence now supports a connection between toxic effects of glutamate,a nd the acute neuronal damage associated with hypoxia-ischemia. Additional evidence supports a possible role in certain chronic conditions including Alzheimer's disease (AD). Glutamate can produce injury through actions at least two types of ionophore-linked post-synaptic receptors. While the NMDA receptor likely contributes predominantly to injury in the setting of acute insults, the AMPA/kainate (non-NMDA) receptors likely contribute to more chronic neurodegenerative conditions. The major goal of this project is the investigation of cellular mechanisms of non-NMDA receptor-mediated neurodegeneration, a type of injury that has been little studied, yet may be relevant to neuronal damage in chronic degenerative diseases. Cortical neuronal cultures will be used to examine the basis of the selective vulnerability of small subgroups of neurons to non-NMDA injury. Particular scrutiny will be given to one such group, those contain high concentrations of the enzyme NADPH diaphorase (NADPH- d(+) neurons). The vulnerability of NADPH-d(+) neurons to non-NMDA injury will be studied in three ways: Ca2+ channel blockers will be tested for ability to block damage, effects of manipulations of intracellular Ca2+ concentrations (by Ca2+ ionophores and by increasing the K+ concentration) will be evaluated, and Ca2+ measures (fura-2 imaging and 45Ca2+ influx) will be correlated with injury. Interestingly, these same neurons may also be indirectly involved in NMDA receptor-mediated injury to other neurons. The possible critical role of nitric oxide (NO), produced in NADPH-d(+) neurons, in NMDA receptor- mediated injury will also be evaluated; NO synthesis blockers will be tested, the effect of selective destruction of NADPH-d(+) neurons on NMDA toxicity will be examined, and interactions between NO and Ca2+ in producing the injury will be assessed.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS030884-03
Application #
2268856
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1992-08-01
Project End
1995-07-31
Budget Start
1994-08-01
Budget End
1995-07-31
Support Year
3
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of California Irvine
Department
Neurology
Type
Schools of Medicine
DUNS #
161202122
City
Irvine
State
CA
Country
United States
Zip Code
92697
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