Aberrations of function or metabolism of the putative amino acid (AA) neurotransmitters of glutamate (GLU) and GABA, have been implicated in the etiology or sequelae of several neurological disorders, e.g., Huntington's chorea, Parkinson's disease, epilepsy and certain forms of olivopontocerebellar atrophy. In addition, GLU-analogs, e.g., the excitotoxin kainic acid (KA), when injected directly into rat brain areas, cause neuronal death, raising the intriguing possibility that endogenous excitotoxic activity may be involved in such disorders. Studies have shown that an alteration in energy metabolism and the normal neuronal-glial metabolism of GLU may play a role in this neurotoxicity. Two possible antagonists of KA toxicity, acetazolamide (AZ), (a carbonic anhydrase inhibitor) and Alpha-aminopimelate (AP), a glutamate analogue, will be intensively studied as to the exact mechanism by which they attenuate excitotoxic effects in vitro (e.g., receptor antagonists, metabolic interactions) and whether they interact with other depolarizing agents such as veratridine or K+. Metabolism of GLU, aspartate, glutamine and GABA will be studied in vivo in various brain areas and in vitro in cerebellar and hippocampal slices after treatment with these drugs. Data will be evaluated in terms of neuronal and glial contributions to that metabolism and scrutinized for clues as to how they act. Carbonic anhydrase may be associated with CO2 fixation in glial cells. Therefore, 14C-bicarbonate metabolism into amino acids in the presence of AZ will also be investigated. AZ is especially interesting in that it is a clinically useful anticonvulsant whose mode of action is not well understood. In addition, AZ and AP will be administered to rats in vivo to see if they inhibit or attenuate the excitotoxic action of KA and related compounds injected directly into various brain areas. Studies will also be continued on key enzymes of GLU metabolism in CNS. Using inhibitors, drugs and various tissue preparations, glutamate dehydrogenase (GDH), will be studied as to whether it is involved with neurotransmitter AA pools. In addition, the direction of reaction (i.e., oxidative deamination of glutamate or reductive amination of 2-oxoglutarate) and its rate in situ will be ascertained. It is hoped that the experiments described in this proposal will lead to novel ways of studying normal and diseased states in the CNS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS017360-06
Application #
3397508
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1981-07-01
Project End
1987-06-30
Budget Start
1986-07-01
Budget End
1987-06-30
Support Year
6
Fiscal Year
1986
Total Cost
Indirect Cost
Name
University of Medicine & Dentistry of NJ
Department
Type
Schools of Medicine
DUNS #
622146454
City
Piscataway
State
NJ
Country
United States
Zip Code
08854
Zeevalk, G D; Bernard, L P; Nicklas, W J (2000) Oxidative stress during energy impairment in mesencephalic cultures is not a downstream consequence of a secondary excitotoxicity. Neuroscience 96:309-16
Zeevalk, G D; Bernard, L P; Sinha, C et al. (1998) Excitotoxicity and oxidative stress during inhibition of energy metabolism. Dev Neurosci 20:444-53
Zeevalk, G D; Bernard, L P; Nicklas, W J (1998) Role of oxidative stress and the glutathione system in loss of dopamine neurons due to impairment of energy metabolism. J Neurochem 70:1421-30
Zeevalk, G D; Davis, N; Hyndman, A G et al. (1998) Origins of the extracellular glutamate released during total metabolic blockade in the immature retina. J Neurochem 71:2373-81
Zeevalk, G D; Bernard, L P; Albers, D S et al. (1997) Energy stress-induced dopamine loss in glutathione peroxidase-overexpressing transgenic mice and in glutathione-depleted mesencephalic cultures. J Neurochem 68:426-9
Zeevalk, G D; Nicklas, W J (1996) Hypothermia and metabolic stress: narrowing the cellular site of early neuroprotection. J Pharmacol Exp Ther 279:332-9
Zeevalk, G D; Derr-Yellin, E; Nicklas, W J (1995) Relative vulnerability of dopamine and GABA neurons in mesencephalic culture to inhibition of succinate dehydrogenase by malonate and 3-nitropropionic acid and protection by NMDA receptor blockade. J Pharmacol Exp Ther 275:1124-30
Zeevalk, G D; Schoepp, D; Nicklas, W J (1995) Excitotoxicity at both NMDA and non-NMDA glutamate receptors is antagonized by aurintricarboxylic acid: evidence for differing mechanisms of action. J Neurochem 64:1749-58
Zeevalk, G D; Derr-Yellin, E; Nicklas, W J (1995) NMDA receptor involvement in toxicity to dopamine neurons in vitro caused by the succinate dehydrogenase inhibitor 3-nitropropionic acid. J Neurochem 64:455-8
Zeevalk, G D; Nicklas, W J (1994) Nitric oxide in retina: relation to excitatory amino acids and excitotoxicity. Exp Eye Res 58:343-50

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