This proposal examines the relationship between hypoxic neuronal damage and glutamate (GLU) neurotoxicity. An hypoxic-ischemic episode, as might occur focally during stroke or cerebral hemorrhage or globally during cardiac arrest, results in the accumulation of external GLU and neurodegeneration. It is unknown if hypoxia-induced neuronal lysis liberates excessive GLU or if metabolically compromised, intact neurons release GLU which then exerts further toxic effects. A detailed hypothesis is presented to explain the elevations of intracellular free calcium ion (Cal) and accumulation of endogenous GLU following metabolic compromise. In this model, eventual toxicity results from the enhanced deleterious effects GLU rather than the initial hypoxia. Combinations of hypoxic insult and exogenously applied GLU are expected to produce additive, or supraadditive, effects in this scheme. Experiments are proposed to measure survival of dissociated, hippocampal neurons maintained in a tissue culture environment after individual and combined exposure to excitatory amino acids (EAA), oxygen deprivation, and sodium cyanide (NaCN) as a model of """"""""chemical hypoxia"""""""". Additional measurements will be made of resting and altered levels of Cal and intracellular pH (pH1) to determine involvement of these ions in the response to toxic insult and in the signal pathway leading to neuronal death. Methods are proposed for documenting the release of endogenous glutamate after hypoxic insult. Surviving neurons will be examined for their physiological responses to EAA and for the presence or absence of specific cytoplasmic calcium-binding proteins to identify cellular processes possibly conferring resistance to toxic insults.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG010034-03
Application #
3122007
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1991-08-01
Project End
1994-05-31
Budget Start
1993-08-01
Budget End
1994-05-31
Support Year
3
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of Texas Health Science Center San Antonio
Department
Type
Schools of Medicine
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229
Brustovetsky, Nickolay; Dubinsky, Janet M; Antonsson, Bruno et al. (2003) Two pathways for tBID-induced cytochrome c release from rat brain mitochondria: BAK- versus BAX-dependence. J Neurochem 84:196-207
Brustovetsky, Nickolay; Brustovetsky, Tatiana; Jemmerson, Ronald et al. (2002) Calcium-induced cytochrome c release from CNS mitochondria is associated with the permeability transition and rupture of the outer membrane. J Neurochem 80:207-18
Brustovetsky, N; Brustovetsky, T; Dubinsky, J M (2001) On the mechanisms of neuroprotection by creatine and phosphocreatine. J Neurochem 76:425-34
Araki, E; Forster, C; Dubinsky, J M et al. (2001) Cyclooxygenase-2 inhibitor ns-398 protects neuronal cultures from lipopolysaccharide-induced neurotoxicity. Stroke 32:2370-5
Lakkaraju, A; Dubinsky, J M; Low, W C et al. (2001) Neurons are protected from excitotoxic death by p53 antisense oligonucleotides delivered in anionic liposomes. J Biol Chem 276:32000-7
Brustovetsky, N; Dubinsky, J M (2000) Dual responses of CNS mitochondria to elevated calcium. J Neurosci 20:103-13
Brustovetsky, N; Dubinsky, J M (2000) Limitations of cyclosporin A inhibition of the permeability transition in CNS mitochondria. J Neurosci 20:8229-37
Dubinsky, J M; Brustovetsky, N; Pinelis, V et al. (1999) The mitochondrial permeability transition: the brain's point of view. Biochem Soc Symp 66:75-84
Brustovetsky, N; Dubinsky, J M (1999) EDTA-induced monovalent fluxes through the Ca2+ uniporter in brain mitochondria. Ann N Y Acad Sci 893:258-60
Dubinsky, J M; Levi, Y (1998) Calcium-induced activation of the mitochondrial permeability transition in hippocampal neurons. J Neurosci Res 53:728-41

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