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Molecular and Cellular Biochemistry

, Volume 452, Issue 1–2, pp 95–104 | Cite as

Inhibition of glutathione S-transferase-pi triggers c-jun N-terminal kinase-dependent neuronal death in Zn-induced Parkinsonism

  • Amit Kumar Chauhan
  • Namrata Mittra
  • Brajesh Kumar Singh
  • Chetna SinghEmail author
Article
  • 85 Downloads

Abstract

Oxidative stress is recognized as one of the major wrongdoers in Parkinson’s disease (PD) while glutathione S-transferase (GST), an endogenous antioxidant, protects from oxidative stress-induced neurodegeneration. Despite GST-pi (GST-π) encounters the toxic manifestations in PD, its role in zinc (Zn)-induced nigrostriatal dopaminergic neurodegeneration remains elusive. The study aimed to explore the role of GST-π in Zn-induced Parkinsonism and its underlying molecular mechanism. Male Wistar rats were treated intraperitoneally with zinc (zinc sulfate), twice a week, for 2–12 weeks. GST-π inducer, benzyl isothiocyanate (BITC) was also administered in a few sets of experiments along with respective vehicle. Catalytic activity and expression of GST-π protein, total GST activity, neurobehavioral indexes, striatal dopamine and its metabolites, nigral tyrosine hydroxylase (TH)-positive neurons and expression of TH and B-cell lymphoma-2 (Bcl-2) proteins were reduced in Zn-treated rats. Conversely, oxidative stress indicators, c-jun N-terminal kinase (JNK) activation, c-jun phosphorylation, cytochrome c release, Bcl-2-associated X protein (Bax) translocation, and procaspase 3/9 to caspase 3/9 conversion were significantly increased in Zn-exposed rats. BITC ameliorated GST-π activity/expression and normalized Zn-induced changes in neurodegenerative indicators, oxidative stress, JNK activation, c-jun phosphorylation and apoptotic indexes. The results demonstrate that Zn inhibits GST-π expression leading to increased oxidative stress and JNK activation, which induce apoptosis thereby degeneration of the nigrostriatal dopaminergic neurons.

Keywords

Zinc Nigrostriatal dopaminergic neurodegeneration Oxidative stress Glutathione S-transferase-pi 

Notes

Acknowledgements

The research scholarship provided by the Council of Scientific and Industrial Research (CSIR), New Delhi, Department of Science and Technology (DST), New Delhi and University Grants Commission (UGC), New Delhi to Amit Kumar Chauhan, Namrata Mittra and Brajesh Kumar Singh respectively, are sincerely acknowledged. The financial aid rendered by the CSIR to Chetna Singh through CSIR-network programme ‘Integrated NextGen Approaches in Health, Disease and Environmental Toxicity’ [INDEPTH (BSC-0111)] is highly appreciated. The CSIR-IITR communication number of this article is 3546.

Compliance with ethical standards

Conflict of interest

The authors declare no conflicts of interests.

Ethical approval

The institutional animal ethics committee approved the present study. All the experiments were performed as per the guidelines of the committee for the purpose of control and supervision of experiments on animals (CPCSEA).

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Amit Kumar Chauhan
    • 1
    • 2
  • Namrata Mittra
    • 1
    • 2
  • Brajesh Kumar Singh
    • 1
  • Chetna Singh
    • 1
    • 2
    Email author
  1. 1.Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment GroupCSIR-Indian Institute of Toxicology Research (CSIR-IITR)LucknowIndia
  2. 2.Academy of Scientific and Innovative Research (AcSIR)CSIR-Indian Institute of Toxicology Research CampusLucknowIndia

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