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Cruciferous Nutraceutical 3H-1,2-dithiole-3-thione Protects Human Primary Astrocytes Against Neurocytotoxicity Elicited by MPTP, MPP+, 6-OHDA, HNE and Acrolein

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Abstract

Astrocytes possess important roles in maintaining normal brain function and providing trophic support to the neurons. They also suffer a range of toxic insults, being a chief target of prooxidants such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 1-methyl-4-phenylpyridinium (MPP+), 6-hydroxydopamine (6-OHDA), 4-hydroxy-2-nonenal (HNE), and acrolein. Recently, we have observed that the cellular antioxidants and phase 2 enzymes can be upregulated by 3H-1,2-dithiole-3-thione (D3T), a nutraceutical found in cruciferous vegetables, against many prooxidants in human neuroblastoma cell lines (SH-SY5Y). However, the regulation of the above cellular factors by D3T in astrocytes and their role in ameliorating the neurotoxic effects of the above neurotoxins have not been investigated. In this study, we show that incubation of human primary astrocytes with micromolar concentrations (5–100 μM) of D3T for 24 h resulted in significant increases in the levels of reduced glutathione (GSH), glutathione reductase (GR), and the phase 2 enzyme NAD(P)H:quinone oxidoreductase 1 (NQO1). D3T treatment also caused time-dependent increases in mRNA expression of the gamma-glutamylcysteine ligase catalytic subunit (GCLC), GR, and of NQO1 in these cells. Pretreatment of astrocytes with D3T was found to afford remarkable protection against the neurocytotoxicity elicited by MPTP, MPP+, 6-OHDA, HNE and acrolein. Taken together, this study demonstrates for the first time that in human astrocytes, the cruciferous nutraceutical D3T potently induces the cellular GSH system and the phase 2 enzyme NQO1, which is accompanied by dramatically increased resistance of these cells to the damage induced by various neurotoxicants. The results of this study may have important implications for the development of novel neuroprotective strategies.

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Abbreviations

6-OHDA:

6-Hydroxydopamine

BSA:

Bovine serum albumin

CDNB:

1-Chloro-2,4-dinitrobenzene

D3T:

3H-1,2-dithiole-3-thione

DCIP:

2,6-Dichloroindophenol

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

GCLC:

γ-Glutamylcysteine ligase catalytic subunit

GPx:

Glutathione peroxidase

GR:

Glutathione reductase

GSH:

Reduced glutathione

GSSG:

Oxidized form of glutathione

GST:

Glutathione S-transferase

HNE:

4-Hydroxy-2-nonenal

MAO:

Monoamine oxidase

MPP+ :

1-Methyl-4-phenylpyridinium

MPTP:

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine

MTT:

3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyltetrazolium

NQO1:

NAD(P)H:quinone oxidoreductase 1

ROS:

Reactive oxygen species

SOD:

Superoxide dismutase

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Acknowledgments

This work was supported in part by NIH grant R01HL071190 and a grant from Harvey Peters Research Center Foundation.

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Authors and Affiliations

  1. Division of Biomedical Sciences, Edward Via Virginia College of Osteopathic Medicine, Virginia Tech Corporate Research Center, 2265 Kraft Drive, Blacksburg, VA, 24060, USA

    Zhenquan Jia, Hong Zhu, Yunbo Li & Hara P. Misra

  2. Department of Biomedical Sciences and Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Tech, Blacksburg, VA, 24061, USA

    Yunbo Li & Hara P. Misra

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  1. Zhenquan Jia
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Correspondence to Yunbo Li or Hara P. Misra.

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Jia, Z., Zhu, H., Li, Y. et al. Cruciferous Nutraceutical 3H-1,2-dithiole-3-thione Protects Human Primary Astrocytes Against Neurocytotoxicity Elicited by MPTP, MPP+, 6-OHDA, HNE and Acrolein. Neurochem Res 34, 1924–1934 (2009). https://doi.org/10.1007/s11064-009-9978-8

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