Excitotoxic mediated cell death is currently thought to be an underlying mechanism responsible for the neuronal degeneration associated with a wide spectrum of neurological diseases and insults (e.g. epilepsy, Huntington's disease, anoxia, ischemia, hypoglycemia). There are at least three classes of excitatory amino acid receptors at which L-glutamate and L-aspartate can act (e.g. NMDA, KA, and QA receptors). Recent studies have identified the NMDA receptor as a key component in excitotoxicity and have demonstrated that NMDA receptor antagonists can offer some protection from the toxic action of NMDA agonists. The goal of this proposal is to elucidate the mechanism and contribution of non-NMDA receptors to this neurodegenerative process. The experimental approach to be used will examine the pharmacology, biochemistry, and toxicity of an exogenous neurotoxin thought to be a non-NMDA agonist, beta-N-oxalyl-L-alpha, beta-diaminopropionic acid (beta-L-ODAP). This toxin has been identified as the causitive agent of human neurolathyrism, a disease characterized by neuronal degeneration an spastic paralysis. Experiments will first focus on beta-L-ODAP itself, elucidating the specificity and kinetics of its binding, the anatomical distribution of its sites of action, and its transport properties. These experiments will not only provide a detailed understanding of the mechanism through which this toxin acts, but will also serve to evaluate its usefulness as a model compound of non-NMDA mediated excitotoxicity. Indeed, preliminary studies in this proposal support the hypothesis of beta-L-ODAP's non-NMDA selectivity and indicate that the agonist interacts most selectively with QA receptors. Thus, with beta-L-ODAP as a selective probe of non-NMDA toxicity, experiments will be conducted to evaluate the role, contribution, and possible interaction of non-NMDA receptors with NMDA receptors in the process of excitotoxicity. These studies will also provide a foundation for the longer range goals of elucidating the biochemical mechanisms of excitotoxicity that follow receptor activation. The experimental approach of this proposal will provide both a detailed characterization of the action of a specific neurotoxin and, on a more fundamental level, a better understanding of the role of non-NMDA receptors in excitotoxic mediated cell death.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS027056-02
Application #
3413225
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1989-04-01
Project End
1992-03-31
Budget Start
1990-04-01
Budget End
1991-03-31
Support Year
2
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of California Irvine
Department
Type
Schools of Medicine
DUNS #
161202122
City
Irvine
State
CA
Country
United States
Zip Code
92697
Miller, S; Nunn, P B; Bridges, R J (1993) Induction of astrocyte glutamine synthetase activity by the Lathyrus toxin beta-N-oxalyl-L-alpha,beta-diaminopropionic acid (beta-L-ODAP). Glia 7:329-36
Bridges, R J; Hatalski, C G; Shim, S N et al. (1992) Gliotoxic actions of excitatory amino acids. Neuropharmacology 31:899-907
Bridges, R J; Hatalski, C; Shim, S N et al. (1991) Gliotoxic properties of the Lathyrus excitotoxin beta-N-oxalyl-L-alpha,beta-diaminopropionic acid (beta-L-ODAP). Brain Res 561:262-8