The chemical or biochemical processes which cause degeneration of rather selective areas of the brain in Alzheimer's Disease (AD) are unknown. It is known, however, that there is a serious serotonergic dysfunction in AD. Furthermore, the indolic neurotransmitter 5-hydroxytryptamine (5-HT) and related central indoles are easily oxidized compounds. Some oxidation products when centrally administered to mice evoke profound behavioral responses, and cause transmitter depletions and/or metabolite disruptions in the catecholaminergic, serotonergic and cholinergic neuronal systems, i.e., systems most profoundly affected in AD. Unidentified but oxidized forms of 5-HT and other central indoles are present in cerebrospinal fluid of AD patients but not in that of age-matched controls. And, conditions appear to exist in Alzheimer brain tissue which should facilitate oxidation reactions. Taken together this evidence leads to a hypothesis that a defect in the serotonergic system in Alzheimer brain results in aberrant oxidations of central indoles forming toxins. The hypothesis further proposes that these toxins attack not only the parent serotonergic neurons, principally the raphe nuclei, but are released and attack the physically proximate noradrenergic locus coeruleus and the cholinergic nucleus basalis complex. These three structures originate in the isodendritic core and project to cortical regions of the brain and are rather selectively degenerated in AD.
The specific aims of this proposal are to elucidate the oxidation chemistry and biochemistry of the central indoles under experimental conditions which might be relevant to those which exist in alzheimer brain tissue. Resulting products will be screened for toxicity and behavioral response following central administration to mice and rats. The effects of active drugs on the catecholaminergic serotonergic, and cholinergic neuronal systems will be investigated by neurotransmitter/metabolite analyses. In order to more fully understand the mode of action of active drugs, studies of transmitter uptake/release processes, effects on key biosynthetic and biodegradative enzymes, and on CNS receptors are planned. Histochemical and microscopic studies will be employed to assess specific regions of neuronal damage or destruction. Chemical mechanisms underlying the toxic effects of certain active drugs will be investigated. Evidence will also be sought to demonstrate that central indoles undergo oxidation reactions even under conditions of non-pathological aging, reactions which may be greatly accelerated in AD. Ultimately, it is expected that these studies might provide important insights into some aspects of the neuronal degeneration and biochemical defects underlying AD.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM032367-09
Application #
3281125
Study Section
Metallobiochemistry Study Section (BMT)
Project Start
1983-09-15
Project End
1995-08-31
Budget Start
1991-09-01
Budget End
1992-08-31
Support Year
9
Fiscal Year
1991
Total Cost
Indirect Cost
Name
University of Oklahoma Norman
Department
Type
Schools of Arts and Sciences
DUNS #
848348348
City
Norman
State
OK
Country
United States
Zip Code
73019
Foster, S B; Tang, H; Miller, K E et al. (2005) Increased extracellular glutamate evoked by 1-methyl-4-phenylpyridinium [MPP(+)] in the rat striatum is not essential for dopaminergic neurotoxicity and is not derived from released glutathione. Neurotox Res 7:251-63
Jiang, Xiang-Rong; Wrona, Monika Z; Alguindigue, Susan S et al. (2004) Reactions of the putative neurotoxin tryptamine-4,5-dione with L-cysteine and other thiols. Chem Res Toxicol 17:357-69
Foster, Steven B; Wrona, Monika Z; Han, Jilin et al. (2003) The parkinsonian neurotoxin 1-methyl-4-phenylpyridinium (MPP(+)) mediates release of l-3,4-dihydroxyphenylalanine (l-DOPA) and inhibition of l-DOPA decarboxylase in the rat striatum: a microdialysis study. Chem Res Toxicol 16:1372-84
Wrona, Monika Z; Jiang, Xiang-Rong; Kotake, Yashige et al. (2003) Stability of the putative neurotoxin tryptamine-4,5-dione. Chem Res Toxicol 16:493-501
Jiang, Xiang-Rong; Dryhurst, Glenn (2002) Inhibition of the alpha-ketoglutarate dehydrogenase and pyruvate dehydrogenase complexes by a putative aberrant metabolite of serotonin, tryptamine-4,5-dione. Chem Res Toxicol 15:1242-7
Horstman, Joseph A; Wrona, Monika Z; Dryhurst, Glenn (2002) Further insights into the reaction of melatonin with hydroxyl radical. Bioorg Chem 30:371-82
Wrona, M Z; Dryhurst, G (2001) A putative metabolite of serotonin, tryptamine-4,5-dione, is an irreversible inhibitor of tryptophan hydroxylase: possible relevance to the serotonergic neurotoxicity of methamphetamine. Chem Res Toxicol 14:1184-92
Li, H; Dryhurst, G (2001) Oxidative metabolites of 5-S-cysteinyldopamine inhibit the pyruvate dehydrogenase complex. J Neural Transm 108:1363-74
Dryhurst, G (2001) Are dopamine, norepinephrine, and serotonin precursors of biologically reactive intermediates involved in the pathogenesis of neurodegenerative brain disorders? Adv Exp Med Biol 500:373-96
Shen, X M; Li, H; Dryhurst, G (2000) Oxidative metabolites of 5-S-cysteinyldopamine inhibit the alpha-ketoglutarate dehydrogenase complex: possible relevance to the pathogenesis of Parkinson's disease. J Neural Transm 107:959-78

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