The long-term goal of the his project is to delineate the molecular mechanisms whereby the uneven distribution of zinc, the synthesis of zinc metallothioneins and their receptors, and the zinc- mediated events associated with synaptic events in various areas of the brain are regulated. The immediate objective of this proposal is to assess the role of zinc metallothionein in preventing the generation of oxygen radicals and oxidative damage in experimental models generating free radicals. It has been hypothesized that Parkinson's disease results from the ongoing exposure to one or more of endogenously or exogenously generated toxins, perhaps similar to 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine, with consequent free radical generation regulating in a compromised scavenging mechanism, thus causing impairment of complex I of the respiratory chain and subsequent lipid peroxidation and cell death. Electron spin resonance studies have shown that 6-hydroxydopamine generates hydroxyl radicals (OH) which is prevented by forming by selegiline and once formed is scavenged by metallothionein isoforms I and II.
The specific aims of this proposal are to learn A) the effects of metallothionein in modulating the cytokine-glutathione-mediated induction of nitric oxide synthase and nitric oxide production; B) the influence of selegiline in enhancing the synthesis of metallothionein and/or superoxide dismutase and hence nullifying the neurotoxic properties of superoxide anion (OS) and/or peroxynitrite (ONOO) capable of killing striatal neurons c) the actions of metallothionein in potential the trophic effects of brain-derived neurotrophic factor in rescuing neurons against methylsalsolinol and other dopa-mediated tetrahydroisoquinoline derivatives. The information to be gained from completing these studies will contribute to understanding further the biochemical defects in dopaminergic transmission in Parkinson's disease and the neuroprotective action of metallothionein isoforms. In addition, it will explore the possibility that selegiline in addition to inhibiting monoamine oxides B, may avert neurodegeneration of striatal neurons by reducing the production of nitric oxide, superoxide anions, and peroxynitrite; and/or selegiline may foster neuroprotection by augmenting the actions of superoxide dismutase, metallothionein, or neurotrophins.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS034566-04
Application #
2691795
Study Section
Neurology A Study Section (NEUA)
Program Officer
Oliver, Eugene J
Project Start
1995-08-01
Project End
2002-07-31
Budget Start
1998-08-15
Budget End
1999-07-31
Support Year
4
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Nebraska Medical Center
Department
Pharmacology
Type
Schools of Medicine
DUNS #
City
Omaha
State
NE
Country
United States
Zip Code
68198
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Sharma, Sushil; Ebadi, Manuchair (2008) SPECT neuroimaging in translational research of CNS disorders. Neurochem Int 52:352-62
Wanpen, Sawitri; Kooncumchoo, Patcharee; Shavali, Shaik et al. (2007) Salsolinol, an endogenous neurotoxin, activates JNK and NF-kappaB signaling pathways in human neuroblastoma cells. Neurochem Res 32:443-50
Kooncumchoo, Patcharee; Sharma, Sushil; Porter, James et al. (2006) Coenzyme Q(10) provides neuroprotection in iron-induced apoptosis in dopaminergic neurons. J Mol Neurosci 28:125-41
Ebadi, Manuchair; Brown-Borg, Holly; Ren, Jun et al. (2006) Therapeutic efficacy of selegiline in neurodegenerative disorders and neurological diseases. Curr Drug Targets 7:1513-29
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Ajjimaporn, Amornpan; Swinscoe, John; Shavali, Shaik et al. (2005) Metallothionein provides zinc-mediated protective effects against methamphetamine toxicity in SK-N-SH cells. Brain Res Bull 67:466-75
Bollimuntha, Sunitha; Singh, Brij B; Shavali, Shaik et al. (2005) TRPC1-mediated inhibition of 1-methyl-4-phenylpyridinium ion neurotoxicity in human SH-SY5Y neuroblastoma cells. J Biol Chem 280:2132-40
Chagkutip, Jaturaporn; Govitrapong, Piyarat; Klongpanichpak, Sirirat et al. (2005) Mechanism of 1-methyl-4-phenylpyridinium-induced dopamine release from PC12 cells. Neurochem Res 30:633-9

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