Abstract

This proposal deals with the examination of two compounds, quinolinic acid (QUIN) and kynurenic acid (KYNA), in brain tissue. Interest in QUIN, an excitotoxin present in mammalian brain, is based on its potential involvement in the precipitation of nerve cell death in neurodegenerative disorders such as Huntington's disease. KYNA, a brain constituent metabolically related to QUIN, is a neuroprotectant in animal paradigms and may participate in the prevention of neurodegenerative processes in man. The proposed studies are designed to examine these concepts from several perspectives, employing in vitro studies in brain slices and in an established model of the rat corticostriatal system, in vivo animal experimentation, and studies in post-mortem human brain tissue. The work will include biochemical, immunohistochemical, histological and ultrastructural evaluation. To accomplish these goals, the following projects will be included. 1) In rat brain slices, the biochemical machinery responsible for the neosynthesis of QUIN and KYNA from their respective bioprecursors will be investigated. Attempts will be made to characterize and purify enzymes involved in QUIN and KYNA production; 2) In organotypic tissue cultures of the rat corticostriatal system, the toxic effects of QUIN and its bioprecursor 3-hydroxyanthranilic acid will be studied, and three avenues of pharmacological intervention to achieve neuroprotection will be assessed. The effects of neuronal damage on QUIN's immediate biosynthetic enzyme, 3-hydroxyanthranilic acid oxygenase will be investigated by ultrastructural immunocytochemistry; 3) Using brain microdialysis and osmotic minipumps, selected issues related to kynurenine metabolism, excitotoxicity and neuroprotection will be investigated in the in vivo situation. Experimental protocols will be in part dictated by the outcome of studies 1 and 2; 4) In human control and Huntington's disease post-mortem brain tissue, the presence and characteristics of four enzymes involved in the biosynthesis of QUIN and KYNA, respectively, will be investigated. In these studies, expertise from pre-clinical work e=will be used for a direct assessment of brain kynurenines in a human neurodegenerative disorder.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS028236-02
Application #
3414750
Study Section
Neurology A Study Section (NEUA)
Project Start
1990-01-01
Project End
1994-12-31
Budget Start
1991-01-01
Budget End
1991-12-31
Support Year
2
Fiscal Year
1991
Total Cost
Indirect Cost

  Institution

Name
University of Maryland Baltimore
Department
Type
Schools of Medicine
DUNS #
003255213
City
Baltimore
State
MD
Country
United States
Zip Code
21201

  Publications

Schwarcz, Robert; Guidetti, Paolo; Sathyasaikumar, Korrapati V et al. (2010) Of mice, rats and men: Revisiting the quinolinic acid hypothesis of Huntington's disease. Prog Neurobiol 90:230-45
Guidetti, P; Charles, V; Chen, E Y et al. (2001) Early degenerative changes in transgenic mice expressing mutant huntingtin involve dendritic abnormalities but no impairment of mitochondrial energy production. Exp Neurol 169:340-50
Lehrmann, E; Molinari, A; Speciale, C et al. (2001) Immunohistochemical visualization of newly formed quinolinate in the normal and excitotoxically lesioned rat striatum. Exp Brain Res 141:389-97
Guidetti, P; Wu, H Q; Schwarcz, R (2000) In situ produced 7-chlorokynurenate provides protection against quinolinate- and malonate-induced neurotoxicity in the rat striatum. Exp Neurol 163:123-30
Guidetti, P; Reddy, P H; Tagle, D A et al. (2000) Early kynurenergic impairment in Huntington's disease and in a transgenic animal model. Neurosci Lett 283:233-5
Wu, H Q; Lee, S C; Schwarcz, R (2000) Systemic administration of 4-chlorokynurenine prevents quinolinate neurotoxicity in the rat hippocampus. Eur J Pharmacol 390:267-74
Battaglia, G; Rassoulpour, A; Wu, H Q et al. (2000) Some metabotropic glutamate receptor ligands reduce kynurenate synthesis in rats by intracellular inhibition of kynurenine aminotransferase II. J Neurochem 75:2051-60
Poeggeler, B; Pappolla, M A; Hardeland, R et al. (1999) Indole-3-propionate: a potent hydroxyl radical scavenger in rat brain. Brain Res 815:382-8
Guidetti, P; Schwarcz, R (1999) 3-Hydroxykynurenine potentiates quinolinate but not NMDA toxicity in the rat striatum. Eur J Neurosci 11:3857-63
Hodgkins, P S; Wu, H Q; Zielke, H R et al. (1999) 2-Oxoacids regulate kynurenic acid production in the rat brain: studies in vitro and in vivo. J Neurochem 72:643-51

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