Abstract

Induction of NAD(P)H:quinone oxidoreductase (QR) by tert-butylhydroquinone (tBHQ) prior to glutamate treatment significantly decreased glutamate-mediated cytotoxicity. Stable overexpression of QR, however, did not protect cells from glutamate-, dopamine or H2O2-induced apoptosis. Thus, the protection afforded by tBHQ is not due simply to an increase in QR, but the coordinate regulation of multiple genes by a common mechanism. Our laboratory has shown that tBHQ increases QR through activation of its antioxidant response element (ARE) in human neuroblastoma cells and primary glial cell cultures. We hypothesize that increased expression of ARE-driven genes block oxidative stress-induced cell death.
The specific aims of this proposal are to: 1) Determine the molecular mechanism(s) by which tBHQ activates the ARE and increases QR in human neuroblstoma cells; 2) Characterize the expression pattern and regulation of the ARE in vivo; 3) Determine the effect of overexpresion of amyloid precursor protein on QR and ARE in transgenic mouse models of alzheimer's disease; 4) Characterize the expression pattern of QR in human brains from control and AD patients. Increased oxidative stress is associated with neuronal cell death following acute insults such as epilepsy, ischemia, and hypoglycemia. Oxidative stress is also believed to be a principle factor in the development of many chronic neurodegenerative diseases such as Alzheimer's, Parkinson's Huntington's and Amyotrophic Lateral Sclerosis. Oxidative stress is an imbalance in which free radicals and their products exceed the capacity of antioxidant defense mechanisms. A gain in product formation and /or loss in protective mechanisms can disturb this equilibrium. Presently, we have little knowledge of how or by neurodegenerative diseases such as Alzheimer's disease (Specific Aims 3 and 4). Elucidating the molecular mechanisms (s) regulating ARE genes in brain, therefore, may be crucial for developing therapeutic approaches to mitigate, or prevent, neurotoxicity.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES010042-03
Application #
6635496
Study Section
Alcohol and Toxicology Subcommittee 4 (ALTX)
Program Officer
Lawler, Cindy P
Project Start
2001-05-01
Project End
2006-04-30
Budget Start
2003-05-01
Budget End
2004-04-30
Support Year
3
Fiscal Year
2003
Total Cost
$341,925
Indirect Cost

  Institution

Name
University of Wisconsin Madison
Department
Type
Schools of Pharmacy
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715

  Publications

Johnson, Delinda A; Johnson, Jeffrey A (2015) Nrf2--a therapeutic target for the treatment of neurodegenerative diseases. Free Radic Biol Med 88:253-267
Gan, Li; Johnson, Jeffrey A (2014) Oxidative damage and the Nrf2-ARE pathway in neurodegenerative diseases. Biochim Biophys Acta 1842:1208-18
Fischedick, Justin T; Standiford, Miranda; Johnson, Delinda A et al. (2013) Structure activity relationship of phenolic diterpenes from Salvia officinalis as activators of the nuclear factor E2-related factor 2 pathway. Bioorg Med Chem 21:2618-22
Williamson, Tracy P; Johnson, Delinda A; Johnson, Jeffrey A (2012) Activation of the Nrf2-ARE pathway by siRNA knockdown of Keap1 reduces oxidative stress and provides partial protection from MPTP-mediated neurotoxicity. Neurotoxicology 33:272-9
Fischedick, Justin T; Standiford, Miranda; Johnson, Delinda A et al. (2012) Activation of antioxidant response element in mouse primary cortical cultures with sesquiterpene lactones isolated from Tanacetum parthenium. Planta Med 78:1725-30
LaPash Daniels, Christine M; Austin, Elizabeth V; Rockney, Danica E et al. (2012) Beneficial effects of Nrf2 overexpression in a mouse model of Alexander disease. J Neurosci 32:10507-15
Joshi, Gururaj; Johnson, Jeffrey A (2012) The Nrf2-ARE pathway: a valuable therapeutic target for the treatment of neurodegenerative diseases. Recent Pat CNS Drug Discov 7:218-29
Williamson, Tracy P; Amirahmadi, Sara; Joshi, Gururaj et al. (2012) Discovery of potent, novel Nrf2 inducers via quantum modeling, virtual screening, and in vitro experimental validation. Chem Biol Drug Des 80:810-20
Gan, Li; Vargas, Marcelo R; Johnson, Delinda A et al. (2012) Astrocyte-specific overexpression of Nrf2 delays motor pathology and synuclein aggregation throughout the CNS in the alpha-synuclein mutant (A53T) mouse model. J Neurosci 32:17775-87
Escartin, Carole; Won, Seok Joon; Malgorn, Carole et al. (2011) Nuclear factor erythroid 2-related factor 2 facilitates neuronal glutathione synthesis by upregulating neuronal excitatory amino acid transporter 3 expression. J Neurosci 31:7392-401

Showing the most recent 10 out of 44 publications