Increased nuclear factor‐erythroid 2 p45‐related factor 2 activity protects SH‐SY5Y cells against oxidative damage

Abstract

The ability of cells to control the balance between the generation and quenching of reactive oxygen species is important in combating potentially damaging effects of oxidative stress. One mechanism that cells use to maintain redox homeostasis is the antioxidant response pathway. Antioxidant response elements (AREs) are cis-acting elements located in regulatory regions of antioxidant and phase II detoxification genes. Nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) is a member of the Cap 'n' Collar family of transcription factors that binds to the ARE and regulates the transcription of specific ARE-containing genes such as NAD(P)H:quinone oxidoreductase 1, glutamylcysteine synthetase and heme oxygenase. Activation of Nrf2 results in release from its negative repressor, Kelch-like ECH-associated protein 1 (Keap1), and allows Nrf2 to translocate into the nucleus to induce gene expression. In this study, we demonstrate that increasing Nrf2 activity by various methods, including chemical induction, Nrf2 overexpression or Keap1 siRNA knockdown, protects cells against specific types of oxidative damage. Cells were protected against 6-hydroxydopamine-and 3-morpholinosydnoniminemediated toxicity but not against 1-methyl-1-4-phenylpyridinium toxicity. As oxidative stress is a hallmark of several neurodegenerative disorders, including Parkinson's disease, pharmacological agents that selectively target the Keap1-Nrf2 pathway may provide a novel neuroprotective strategy for the treatment of these diseases. Oxidative stress plays a critical role in a number of neurodegenerative diseases, including Parkinson's disease (PD), Alzheimer's disease, stroke and amyotrophic lateral sclerosis (Klein and Ackerman 2003;Andersen 2004;Barnham et al. 2004;Emerit et al. 2004). In the case of PD, post-mortem analyses of PD brain samples revealed an increase in markers of oxidative stress (protein nitration and carbonylation, lipid peroxidation and DNA oxidation) compared with control brain samples (Dexter et al. 1989(Dexter et al. , 1994Alam et al. 1997;Good et al. 1998;Giasson et al. 2002). Furthermore, pharmacological agents used to model PD in vitro and in vivo [6-hydroxydopamine (6-OHDA) and 1-methyl-1-4-phenylpyridinium (MPP Abbreviations used: ARE, antioxidant response element; CMV, cytomegalovirus; ECH, erythroid cellderived protein with CNC homology; ECL, Electrochemiluminescence; GCS, glutamylcysteine synthetase; HO-1, heme oxygenase 1; Keap1, Kelch-like erythroid cellderived protein with CNC homology ECH-associated protein 1; MPP + , 1-methyl-1-4-phenylpyridinium; MUT, mutant; NQO1, NAD(P)H:quinone oxidoreductase; Nrf2, nuclear factor-erythroid 2 p45-related factor 2; 6-OHDA, 6-hydroxydopamine; PD, Parkinson's disease; ROS, reactive oxygen species; SIN-1, 3-morpholinosydnonimine; siRNA, short interfering RNA; tBHQ, tert-butylhydroquinone; WT, wild-type.

Genome-Wide Microarray Analysis of the Differential Neuroprotective Effects of Antioxidants in Neuroblastoma Cells Overexpressing the Familial Parkinson’s Disease α-Synuclein A53T Mutation

“…These findings are consistent with our previous report documenting that Nrf2 signaling protects SH-SY5Y cells from 6-OHDA but not MPP ? toxicity [46].…”

The pesticide deltamethrin increases free radical production and promotes nuclear translocation of the stress response transcription factor Nrf2 in rat brain

“…Previous studies have demonstrated that Nrf2-dependent transcription can prevent ROSinduced apoptosis in neurons and astrocytes in vitro (Cao et al, 2005;Kraft et al, 2004;Lee et al, 2003a, b;Shih et al, 2003). Several lines of evidence suggest that chemical induction of antioxidants and detoxification genes through Nrf2-ARE signaling protects against a number of different oxidative insults, including H 2 O 2 , 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (Lee et al, 2003a, b;Cao et al, 2005;Kraft et al, 2004;Shih et al, 2003).…”

“…Several lines of evidence suggest that chemical induction of antioxidants and detoxification genes through Nrf2-ARE signaling protects against a number of different oxidative insults, including H 2 O 2 , 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (Lee et al, 2003a, b;Cao et al, 2005;Kraft et al, 2004;Shih et al, 2003). Recently, we demonstrated that Nrf2-dependent transcription activated by tert-Butylhydroquinone (t BHQ), a known inducer of Nrf2-mediated transcription, can prevent DM-induced oxidative stress in PC12 cells through translocation of Nrf2 and increased HO-1 gene expression (Li et al, 2007a).…”

DJ-1, a cancer- and Parkinson's disease-associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2

“…Nrf2 drives the expression of detoxification enzymes, such as NQO1 [NAD(P)H quinone oxidoreductase 1] and Hmox-1, and enzymes that generate antioxidant molecules, such as glutathione (20,21). Nrf2 function and the expression of its regulated genes, including NQO1, have been implicated in the risk and͞or prevention of both cancer and PD (22)(23)(24)(25)(26)(27).…”