Protective Effect of Sulforaphane against Dopaminergic Cell Death

Abstract

Parkinson's disease (PD) is a progressive neurodegenerative disorder with a selective loss of dopaminergic neurons in the substantia nigra. Evidence suggests oxidation of dopamine (DA) to DA quinone and consequent oxidative stress as a major factor contributing to this vulnerability. We have previously observed that exposure to or induction of NAD(P)H:quinone reductase (QR1), the enzyme that catalyzes the reduction of quinone, effectively protects DA cells. Sulforaphane (SF) is a drug identified as a potent inducer of QR1 in various nonneuronal cells. In the present study, we show that SF protects against compounds known to induce DA quinone production (6-hydroxydopamine and tetrahydrobiopterin) in DAergic cell lines CATH.a and SK-N-BE(2)C as well as in mesencephalic DAergic neurons. SF leads to attenuation of the increase in protein-bound quinone in tetrahydrobiopterin-treated cells, but this does not occur in cells that have been depleted of DA, suggesting involvement of DA quinone. SF pretreatment prevents membrane damage, DNA fragmentation, and accumulation of reactive oxygen species. SF causes increases in mRNA levels and enzymatic activity of QR1 in a dose-dependent manner. Taken together, these results indicate that SF causes induction of QR1 gene expression, removal of intracellular DA quinone, and protection against toxicity in DAergic cells. Thus, this major isothiocyanate found in cruciferous vegetables may serve as a potential candidate for development of treatment and/or prevention of PD.Parkinson's disease (PD) is a progressive neurodegenerative disorder associated with a selective loss of the neurons containing dopamine (DA) in the substantia nigra pars compacta. Among the proposed underlying causes of DAergic neurodegeneration, oxidative stress is believed to play an important role. Lines of evidence suggest oxidation of DA and consequent quinone modification and oxidative stress as a major factor contributing to the vulnerability of DA cells (Hastings and Zigmond, 1997;Asanuma et al., 2003;Choi et al., 2003a). DA is easily oxidized spontaneously (Hastings and Zigmond, 1997) or enzymatically (Maker et al., 1981) to produce DA quinones. The DA quinone species are capable of covalently modifying cellular nucleophiles, including low molecular weight sulfhydryls and protein cysteinyl residues (Graham, 1978). In addition, when in excess, DA quinone cyclizes to become the highly reactive aminochrome, whose redox-cycling leads to generation of superoxide and depletion of cellular NADPH. The detrimental role of DA quinones suggests a requirement for effective mechanisms to remove the cellular quinones. NAD(P)H:quinone reductase (QR1) [DT-diaphorase; NAD(P):H-(quinone acceptor)oxidoreductase; EC 1.6.5.2] is an enzyme that catalyzes two-electron reduction of quinone to the redox-stable hydroquinone (Joseph et al., 2000;Cavelier and Amzel, 2001) and therefore might effectively protect DA cells from quinone-induced damages. A safe and effective inducer of QR1 would be a good candidate with which to p...

Inhibition of 6-hydroxydopamine-induced endoplasmic reticulum stress by sulforaphane through the activation of Nrf2 nuclear translocation

“…It has also been reported that SF may serve as a potential candidate for the treatment and/or prevention of PD. SF causes the induction of NAD(P)H:quinoine oxidoreductase 1 and glutathione, removal of intracellular dopamine quinone and protects against 6-OHDA-induced toxicity (18,22). To date, the beneficial bioactivities of SF have been attributed mainly to its anti-oxidant properties, such as radical scavenging and the induction of anti-oxidant genes (26,27).…”

“…Recent studies have indicated that SF can serve as Inhibition of 6-hydroxydopamine-induced endoplasmic reticulum stress by sulforaphane through the activation of Nrf2 nuclear translocation a potential candidate for the development of treatments for and/or the prevention of PD (21). SF has been shown to protect dopaminergic neurons against 6-OHDA-induced cytotoxicity (18,22,23). ER stress is a contributory factor to neuronal death and is involved in the pathogenesis of PD.…”

Viewpoint: Mechanisms of Action and Therapeutic Potential of Neurohormetic Phytochemicals

“…BDNF, brainderived neurotrophic factor; CBP, CREB-binding protein; DAG, diacylglycerol; IP3, inositol triphosphate; NGF, nerve growth factor; PLC, phospholipase C. This figure is modified from Mattson and Cheng, 2006. lial cells against photooxidative damage (Gao and Talalay, 2004). In a model of Parkinson's disease, sulforaphane protected dopaminergic neurons (Han et al, 2007).…”

Sulforaphane protects against 6-hydroxydopamine-induced cytotoxicity by increasing expression of heme oxygenase-1 in a PI3K/Akt-dependent manner

“…SF also has been reported to be a potential candidate for development of treatment and/or prevention of PD (22). SF protects dopaminergic neurons against 6-OHDA-induced cytotoxicity (23,24). However, the molecular mechanisms by which SF protects against 6-OHDA-induced cytotoxicity are poorly elucidated.…”