Protective Effect of Sulforaphane against Dopaminergic Cell Death

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 non-neuronal 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.

[1]  O. Hwang,et al.  Tetrahydrobiopterin is released from and causes preferential death of catecholaminergic cells by oxidative stress. , 2000, Molecular pharmacology.

[2]  D. Ross,et al.  Rapid polyubiquitination and proteasomal degradation of a mutant form of NAD(P)H:quinone oxidoreductase 1. , 2001, Molecular pharmacology.

[3]  G. Cohen,et al.  Coupling of Dopamine Oxidation (Monoamine Oxidase Activity) to Glutathione Oxidation Via the Generation of Hydrogen Peroxide in Rat Brain Homogenates , 1981, Journal of neurochemistry.

[4]  J. L. Stringer,et al.  Presence and induction of the enzyme NAD(P)H: Quinone oxidoreductase 1 in the central nervous system , 2004, The Journal of comparative neurology.

[5]  J. Choi,et al.  Immobilization stress causes increases in tetrahydrobiopterin, dopamine, and neuromelanin and oxidative damage in the nigrostriatal system , 2005, Journal of neurochemistry.

[6]  J. Flier,et al.  The Neuroprotective Antioxidant α-lipoic Acid Induces Detoxication Enzymes in Cultured Astroglial Cells , 2002, Free radical research.

[7]  Ikuko Miyazaki,et al.  Dopamine- or L-DOPA-induced neurotoxicity: The role of dopamine quinone formation and tyrosinase in a model of Parkinson’s disease , 2009, Neurotoxicity Research.

[8]  G. Peters,et al.  L-Dopa stimulates expression of the antioxidant enzyme NAD(P)H:quinone oxidoreductase (NQO) in cultured astroglial cells. , 2000, Free radical biology & medicine.

[9]  Jeffrey A. Johnson,et al.  An important role of Nrf2-ARE pathway in the cellular defense mechanism. , 2004, Journal of biochemistry and molecular biology.

[10]  S. Lee,et al.  JNK activation by tetrahydrobiopterin: Implication for Parkinson's disease , 2004, Journal of neuroscience research.

[11]  DelindaA . Johnson,et al.  Nuclear Factor E2-Related Factor 2-Dependent Antioxidant Response Element Activation by tert-Butylhydroquinone and Sulforaphane Occurring Preferentially in Astrocytes Conditions Neurons against Oxidative Insult , 2004, The Journal of Neuroscience.

[12]  G. Bowden,et al.  Phase II enzyme inducer, sulforaphane, inhibits UVB‐induced AP‐1 activation in human keratinocytes by a novel mechanism , 2004, Molecular carcinogenesis.

[13]  D. Choi,et al.  Particular vulnerability of rat mesencephalic dopaminergic neurons to tetrahydrobiopterin: Relevance to Parkinson’s disease , 2007, Neurobiology of Disease.

[14]  L. Landi,et al.  The two-electron quinone reductase DT-diaphorase generates and maintains the antioxidant (reduced) form of coenzyme Q in membranes. , 1997, Molecular aspects of medicine.

[15]  S. Lee,et al.  Involvement of apoptosis and calcium mobilization in tetrahydrobiopterin-induced dopaminergic cell death , 2003, Experimental Neurology.

[16]  O. Hwang,et al.  Degeneration of the nigrostriatal pathway and induction of motor deficit by tetrahydrobiopterin: an in vivo model relevant to Parkinson’s disease , 2003, Neurobiology of Disease.

[17]  A. Jaiswal,et al.  Role of NAD(P)H:quinone oxidoreductase 1 (DT diaphorase) in protection against quinone toxicity. , 2000, Biochemical pharmacology.

[18]  P. Talalay,et al.  Induction of phase 2 genes by sulforaphane protects retinal pigment epithelial cells against photooxidative damage. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[19]  S. Shimohama,et al.  p‐quinone mediates 6‐hydroxydopamine‐induced dopaminergic neuronal death and ferrous iron accelerates the conversion of p‐quinone into melanin extracellularly , 2005, Journal of neuroscience research.

[20]  Paul J Thornalley,et al.  Transcription factor Nrf2 is essential for induction of NAD(P)H:quinone oxidoreductase 1, glutathione S-transferases, and glutamate cysteine ligase by broccoli seeds and isothiocyanates. , 2004, The Journal of nutrition.

[21]  C. Cho,et al.  A major inducer of anticarcinogenic protective enzymes from broccoli: isolation and elucidation of structure. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[22]  L. Amzel,et al.  Mechanism of NAD(P)H:Quinone reductase: Ab initio studies of reduced flavin , 2001, Proteins.

[23]  Peter T. Lansbury,et al.  Kinetic Stabilization of the α-Synuclein Protofibril by a Dopamine-α-Synuclein Adduct , 2001, Science.

[24]  G. Beckett,et al.  Sulforaphane, erucin, and iberin up-regulate thioredoxin reductase 1 expression in human MCF-7 cells. , 2005, Journal of agricultural and food chemistry.

[25]  J. Bol,et al.  Expression of NAD(P)H:quinone oxidoreductase in the normal and Parkinsonian substantia nigra , 2004, Neurobiology of Aging.

[26]  D. Graham.  Oxidative pathways for catecholamines in the genesis of neuromelanin and cytotoxic quinones. , 1978, Molecular pharmacology.

[27]  S. Lee,et al.  Dopamine‐dependent cytotoxicity of tetrahydrobiopterin: a possible mechanism for selective neurodegeneration in Parkinson's disease , 2003, Journal of neurochemistry.

[28]  E. Jeffery,et al.  Induction of quinone reductase by sulforaphane and sulforaphane N-acetylcysteine conjugate in murine hepatoma cells. , 2005, Journal of medicinal food.

[29]  S. Harada,et al.  An association between idiopathic Parkinson's disease and polymorphisms of phase II detoxification enzymes: glutathione S-transferase M1 and quinone oxidoreductase 1 and 2. , 2001, Biochemical and biophysical research communications.

[30]  M. Zigmond,et al.  Loss of dopaminergic neurons in parkinsonism: possible role of reactive dopamine metabolites. , 1997, Journal of neural transmission. Supplementum.

[31]  M. Tanito,et al.  Sulforaphane induces thioredoxin through the antioxidant-responsive element and attenuates retinal light damage in mice. , 2005, Investigative ophthalmology & visual science.

[32]  O. Hwang,et al.  Loss of striatal dopaminergic fibers after intraventricular injection of tetrahydrobiopterin in rat brain , 2004, Neuroscience Letters.

[33]  D. Liebler,et al.  The Reduction of α-Tocopherolquinone by Human NAD(P)H:Quinone Oxidoreductase: The Role of α-Tocopherolhydroquinone as a Cellular Antioxidant , 1997 .

[34]  J. Lubinski,et al.  Sulforaphane-mediated induction of a phase 2 detoxifying enzyme NAD(P)H:quinone reductase and apoptosis in human lymphoblastoid cells. , 2004, Acta biochimica Polonica.

[35]  Guncheol Kim,et al.  Synthetic phytoceramides induce apoptosis with higher potency than ceramides. , 2001, Molecular pharmacology.