Sulforaphane protects cortical neurons against 5-S-cysteinyl-dopamine-induced toxicity through the activation of ERK1/2, Nrf-2 and the upregulation of detoxification enzymes

Mol Nutr Food Res. 2010 Apr;54(4):532-42. doi: 10.1002/mnfr.200900197.

Abstract

The degeneration of dopaminergic neurons in the substantia nigra has been linked to the formation of the endogenous neurotoxin 5-S-cysteinyl-dopamine. Sulforaphane (SFN), an isothiocyanate derived from the corresponding precursor glucosinolate found in cruciferous vegetables has been observed to exert a range of biological activities in various cell populations. In this study, we show that SFN protects primary cortical neurons against 5-S-cysteinyl-dopamine induced neuronal injury. Pre-treatment of cortical neurons with SFN (0.01-1 microM) resulted in protection against 5-S-cysteinyl-dopamine-induced neurotoxicity, which peaked at 100 nM. This protection was observed to be mediated by the ability of SFN to modulate the extracellular signal-regulated kinase 1 and 2 and the activation of Kelch-like ECH-associated protein 1/NF-E2-related factor-2 leading to the increased expression and activity of glutathione-S-transferase (M1, M3 and M5), glutathione reductase, thioredoxin reductase and NAD(P)H oxidoreductase 1. These data suggest that SFN stimulates the NF-E2-related factor-2 pathway of antioxidant gene expression in neurons and may protect against neuronal injury relevant to the aetiology of Parkinson's disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Death / drug effects
  • Cells, Cultured
  • Cerebral Cortex / cytology*
  • Dopamine / analogs & derivatives*
  • Dopamine / toxicity
  • Enzyme Activation / drug effects
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Glutathione / analysis
  • Glutathione Reductase / metabolism
  • Glutathione Transferase / metabolism
  • Isothiocyanates
  • Mice
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • NAD(P)H Dehydrogenase (Quinone) / metabolism
  • NF-E2-Related Factor 2 / drug effects
  • NF-E2-Related Factor 2 / physiology*
  • Neurons / drug effects*
  • Neuroprotective Agents / pharmacology
  • Phosphorylation / drug effects
  • Thiocyanates / pharmacology*
  • Thioredoxin-Disulfide Reductase / metabolism

Substances

  • Isothiocyanates
  • NF-E2-Related Factor 2
  • Neuroprotective Agents
  • Thiocyanates
  • 5-S-cysteaminyldopamine
  • NAD(P)H Dehydrogenase (Quinone)
  • Nqo1 protein, mouse
  • Glutathione Reductase
  • Thioredoxin-Disulfide Reductase
  • Glutathione Transferase
  • Extracellular Signal-Regulated MAP Kinases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • sulforafan
  • Glutathione
  • Dopamine