NF-E2-related factor 2 activation in PC12 cells: its protective role in manganese-induced damage

Abstract

Manganese neurotoxicity presents with Parkinson-like symptoms that are associated with the generation of reactive oxygen species. Thus, its occurrence and severity can be reduced by cellular antioxidants. The components of the transcription factor NF-E2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway are the central regulators of cellular antioxidant responses. In this study, we investigated the role of activation of Nrf2 in response to oxidative damage induced by manganese chloride (MnCl(2)) in rat adrenal pheochromocytoma (PC12) cells. Exposure of PC12 cells to MnCl(2) for 24 h promoted an increased cytosolic and nuclear accumulation of Nrf2 and enhanced the binding of Nrf2 to the HO-1 gene ARE, thereby inducing the expression of an Nrf2-regulated gene, HO-1. Pre-treatment with tert-butylhydroquinone (tBHQ), a known agent that activates the Nrf2/ARE-HO-1 pathway, for 16 h prior to the 24 h MnCl(2) exposure attenuated both the cytotoxicity and the apoptosis induced by MnCl(2). These protective effects of tBHQ indicated a protective role for Nrf2 against MnCl(2)-induced cell damage. Taken together, these findings suggest that Nrf2 may play an important role in the protection of PC12 cells against MnCl(2) neurotoxicity.

Paraquat and MPTP induce neurodegeneration and alteration in the expression profile of microRNAs: the role of transcription factor Nrf2

“… 20 , 21 Many studies have shown that Nrf2 plays an important role in protecting dopaminergic neurons from damage 22 , 23 induced by pesticides such as PQ, 8 , 24 deltamethrin 25 – 27 and manganese. 28 , 29 Since loss or failed activation of Nrf2 can increase cellular sensitivity to stressors, Nrf2 may well play a protective role in PQ-induced neurodegeneration.…”

Manganese potentiates LPS-induced heme-oxygenase 1 in microglia but not dopaminergic cells: Role in controlling microglial hydrogen peroxide and inflammatory cytokine output

“…However, in vitro, the toxic metabolite of MPTP, 1-methyl-4-phenyl-pyridium (MPP+), induced a time dependent increase of HO-1 in dopamine producing pheochromocytoma (PC12) cells that was cytoprotective (Bae et al, 2010), while dieldrin, an environmental neurotoxicant linked to PD, increased HO-1 expression in SN4741 dopaminergic neuronal cells (Kim et al, 2005). Furthermore, a recent report demonstrated that high, cytotoxic concentrations of Mn (300 μM) induce HO-1 in PC12 cells via the Nrf2-ARE pathway (Li et al, 2010). …”

Tertiary-Butylhydroquinone Upregulates Expression of ATP-Binding Cassette Transporter A1 via Nuclear Factor E2-Related Factor 2/Heme Oxygenase-1 Signaling in THP-1 Macrophage-Derived Foam Cells

“…Nrf2 is a transcription factor that forms a cytoplasmic complex with Keap1. 39 Upon exposure to phenolic chemicals such as tBHQ, Nrf2 dissociates from Keap1, translocates into the nucleus, and activates the transcription of antioxidant genes through ARE-dependent transcription, thereby protecting cells against the adverse effects of chemical/radiation exposure. 12 tBHQ exhibits a wide range of pharmacological activities, including antioxidant and anti-inflammatory actions.…”