Neuronal degeneration has been proposed to cause neurological and/or neuropsychiatric disorders (e.g., schizophrenia, Alzheimer's dementia, hepatic encephalopathy, and Parkinson's disease). Our research goal is to investigate the pathophysiological role of reactive oxygen species in degenerative brain disorders. Animal models are developed and used for studying neuro-degenerative processes and neuroprotective strategies on brain dopaminergic neurons in vivo. In vitro methods for the detection of free radical generation and the brain lipid peroxidation are also used to investigate underlying neurotoxic and/or neuroprotective mechanisms. We have demonstrated that brain neurons are vulnerable to oxidative stress caused by iron but not copper and zinc. In fact, intranigral infusion of ferrous citrate creates a parkinsonian animal model because it acutely increases dopamine overflow and chronically depletes dopamine levels. We discovered that iron-induced oxidative brain injury was protected by treatment with typical and atypical antioxidants (e.g., U-78517F, a-lipoic acid, manganese and S-nitrosoglutathione). Further in vitro results indicate that these antioxidants indeed inhibit the generation of free radicals and the peroxidation of brain lipids. The present in vivo neuroprotective results of manganese are somewhat at odds with current concepts on the pathogenesis of Parkinson's disease. In fact, manganese exposure induces pallidum injury and psychosis rather than the previously proposed nigral injury and parkinsonism. Our new finding that S-nitrosoglutathione is approximately 100-fold more potent than the classical antioxidant glutathione could have important implications for understanding the antioxidative role of nitric oxide and cellular defense systems in the brain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Intramural Research (Z01)
Project #
1Z01MH002648-06
Application #
6111173
Study Section
Special Emphasis Panel (LCS)
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
1998
Total Cost
Indirect Cost
Name
U.S. National Institute of Mental Health
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Chiueh, Chuang C; Andoh, Tsugunobu; Chock, P Boon (2005) Roles of thioredoxin in nitric oxide-dependent preconditioning-induced tolerance against MPTP neurotoxin. Toxicol Appl Pharmacol 207:96-102
Wang, Xuting; Tomso, Daniel J; Liu, Xuemei et al. (2005) Single nucleotide polymorphism in transcriptional regulatory regions and expression of environmentally responsive genes. Toxicol Appl Pharmacol 207:84-90
Chiueh, Chuang C; Andoh, Tsugunobu; Chock, P Boon (2005) Induction of thioredoxin and mitochondrial survival proteins mediates preconditioning-induced cardioprotection and neuroprotection. Ann N Y Acad Sci 1042:403-18
Andoh, Tsugunobu; Chock, P Boon; Murphy, Dennis L et al. (2005) Role of the redox protein thioredoxin in cytoprotective mechanism evoked by (-)-deprenyl. Mol Pharmacol 68:1408-14
Chiueh, Chuang; Lee, Sang; Andoh, Tsugunobu et al. (2003) Induction of antioxidative and antiapoptotic thioredoxin supports neuroprotective hypothesis of estrogen. Endocrine 21:27-31
Andoh, Tsugunobu; Chiueh, Chuang Chin; Chock, P Boon (2003) Cyclic GMP-dependent protein kinase regulates the expression of thioredoxin and thioredoxin peroxidase-1 during hormesis in response to oxidative stress-induced apoptosis. J Biol Chem 278:885-90
Vaananen, Antiii J; Moed, Mikaela; Tuominen, Raimo K et al. (2003) Angeli's salt induces neurotoxicity in dopaminergic neurons in vivo and in vitro. Free Radic Res 37:381-9
Andoh, Tsugunobu; Chock, P Boon; Chiueh, Chuang C (2002) Preconditioning-mediated neuroprotection: role of nitric oxide, cGMP, and new protein expression. Ann N Y Acad Sci 962:1-7
Chiueh, C C (2001) Iron overload, oxidative stress, and axonal dystrophy in brain disorders. Pediatr Neurol 25:138-47
Andoh, T; Lee, S Y; Chiueh, C C (2000) Preconditioning regulation of bcl-2 and p66shc by human NOS1 enhances tolerance to oxidative stress. FASEB J 14:2144-6

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