Oxidative stress is an imbalance in which free radicals and their products exceed the capacity of antioxidant defense mechanisms. The harmful reactive compounds generated by oxidative stress are associated with neuronal cell death following acute insults and are also believed to be a principle factor in the development of many chronic neurodegenerative diseases such as Alzheimer's, Parkinson's (PD), Huntington's and Amyotrophic Lateral Sclerosis. The expression of many neuroprotective phase II detoxification enzymes and/or antioxidant genes is governed by the antioxidant responsive element (ARE). ARE-dependent gene expression is induced by the transcriptional factor, Nrf2, and is considered to be a novel and important pathway that confers protection to a variety of oxidative stress-related neurodegenerative insults. The long- range objective of the laboratory is to evaluate the regulation and cell-specific expression of ARE-driven genes and the potential role of these genes in prevention of neurodegeneration. In order to develop potential therapeutic strategies targeting Parkinson's disease through activation of the ARE, small molecules that penetrate the blood-brain barrier and robustly activate ARE will be required. We will use primary cortical cultures from Nrf2 knockout and wild-type mice as an in vitro system to examine potential chemical activators of the ARE. We will test whether compounds identified as potent ARE activators can attenuate nigrostriatal lesions in both 6-hydroxydopamine (6-OHDA) and MPTP induced Parkinson's models in Nrf2-/- and wild-type mice. Finally, we will examine Nrf2-mediated neuroprotection by infecting astrocyte cultures with adenovirus Nrf2 constructs and transplanting those cells into the striata of Nrf2-/- and wildtype mice after 6-OHDA or MPTP lesions.
The specific aims of this proposal are:
Specific Aim 1. Characterize Nrf2-dependent ARE activation by chemical activators and evaluate their neuroprotective potential in vitro.
Specific Aim 2. Determine that chemical activators of the Nrf2-ARE pathway confer protection from the 6-OHDA and MPTP-induced nigrostriatal lesions and loss of dopaminergic (DA) neurons.
Specific Aim 3. Determine that transplantation of Nrf2 overexpressing neural stem cells and/or astrocytes confers protection from 6-OHDA or MPTP-induced nigrostriatal lesions and loss of DA neurons.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IFCN-A (05))
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Lawler, Cindy P
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University of Wisconsin Madison
Schools of Pharmacy
United States
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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
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
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
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

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