Neurotoxicity Research

, Volume 28, Issue 4, pp 302–318 | Cite as

Assessment of Protective Role of Multifunctional Dopamine Agonist D-512 Against Oxidative Stress Produced by Depletion of Glutathione in PC12 Cells: Implication in Neuroprotective Therapy for Parkinson’s Disease

  • Chandrashekhar Voshavar
  • Mrudang Shah
  • Liping Xu
  • Aloke K. Dutta
Original Article
First Online:
Received:
Revised:
Accepted:

Abstract

Oxidative stress has been strongly implicated in the progression of Parkinson’s disease (PD). Depletion of cytoplasmic glutathione levels is one of the indications of oxidative stress, which occur in the substantia nigra of PD patients at an early stage of the disease process. It has been shown that glutathione depletion causes the inhibition of mitochondrial complex I, thus affecting mitochondrial function leading to oxidative stress via production of reactive oxygen species. Studies were carried out to investigate the role of D-512, a potent multifunctional neuroprotective D2/D3 receptor agonist, in protecting dopaminergic PC12 cells treated with buthionine sulfoximine (BSO), an inhibitor of key enzyme in glutathione synthesis and 6-hydroxydopamine (6-OHDA), a widely used neurotoxin. D-512 was able to restore level of glutathione against BSO/6-OHDA-mediated glutathione depletion. D-512 also showed significant neuroprotection in PC12 cells against toxicity induced by combined treatment of BSO and 6-OHDA. Furthermore, D-512 was able to restore both phospho-extracellular signal-regulated kinase and phospho-Jun N-terminal kinase levels upon treatment with 6-OHDA providing an evidence on the possible mechanism of action for neuroprotection by modulating mitogen-activated protein kinases. We have further demonstrated the neuroprotective effects of D-512 against oxidative insult produced by BSO and 6-OHDA in PC12 cells.

Keywords

Parkinson’s disease D2/D3 agonist Oxidative stress Glutathione PC12 cells BSO 6-OHDA 
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Notes

Acknowledgments

This work is supported by National Institute of Neurological Disorders and Stroke/National Institute of Health (NS047198, AKD).

Authors’ contributions

Aloke K. Dutta was involved with all aspects of the studies including design of the study and biological (in vitro) experiments reported in the manuscript, analyzed the data, and wrote the manuscript. Chandrashekhar Voshavar, Mrudang Shah, and Liping Xu performed the experiments, involved with in vitro cell culture, Western blot, related biological studies, and data analysis. All authors discussed the results and provided comments on the manuscript. All authors read and approved the final manuscript.

Compliance with Ethical Standards

Conflict of interest

The authors declare no competing financial interests.

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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Chandrashekhar Voshavar
    • 1
  • Mrudang Shah
    • 1
  • Liping Xu
    • 1
  • Aloke K. Dutta
    • 1
    • 2
  1. 1.Department of Pharmaceutical SciencesWayne State UniversityDetroitUSA
  2. 2.Department of Pharmaceutical SciencesEugene Applebaum College of Pharmacy & Health SciencesDetroitUSA

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