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Disubstituted Dithiolethione ACDT Exerts Neuroprotective Effects Against 6-Hydroxydopamine-Induced Oxidative Stress in SH-SY5Y Cells

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Abstract

Parkinson’s disease (PD) is a prevalent, progressive, neurodegenerative disorder with no known cure. Oxidative stress has been found to play a significant role in its etiology, and the search for novel neuroprotective compounds that actively prevent disease progression is currently ongoing. Dithiolethiones are a group of sulfur-containing heterocyclic compounds found in cruciferous vegetables. Using the 6-hydroxydopamine (6-OHDA) model of PD, we tested a previously identified disubstituted dithiolethione 5-amino-3-thioxo-3H-(1,2) dithiole-4-carboxylic acid ethyl ester (ACDT) for its neuroprotective potential. Pretreatment of SH-SY5Y cells with ACDT led to a time- and concentration-dependent induction of the antioxidant glutathione (GSH). ACDT also diminished 6-OHDA-induced cell death, lactate dehydrogenase release, elevation of caspase 3/7 activity, and increase in levels of reactive oxygen species. Inhibition of the GSH-synthesizing enzyme glutamate-cysteine ligase catalytic subunit (GCLC) led a corresponding dissipation of ACDT’s neuroprotective effects, hence underlining the importance of GSH in ACDT’s neuroprotective response. ACDT caused the stabilization and nuclear translocation of nuclear factor erythroid-2 related factor (Nrf2), resulting in increased protein expression of the phase II enzyme NADPH:quinone oxidoreductase 1 (NQO1), and the excitatory amino acid cysteine membrane transporter (EAAT3). Interestingly, no changes in the levels of other Nrf2-dependent molecules including GCLC were observed, indicating the possible involvement of additional alternate mechanisms behind ACDT’s GSH-inducing property. Collectively, the data demonstrated ACDT to be a promising new dithiolethione for the treatment of PD, with two modifiable functional groups offering additional avenues for enhanced pharmacological application.

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Acknowledgements

This work was supported by Manchester University College of Pharmacy, Natural & Health Science, Fort Wayne, IN, and MCPHS University School of Pharmacy, Boston, MA. The authors wish to thank Evan Beakas, Rosary Ajaelu, and Iman Aoude for their participation in the project.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, School of Pharmacy, MCPHS University, 179 Longwood Avenue, Boston, MA, 02115, USA

    Swati Betharia & Alejandro N. Rondόn-Ortiz

  2. Department of Pharmaceutical Sciences, College of Pharmacy, Natural & Health Sciences, Manchester University, Fort Wayne, IN, USA

    Dennis A. Brown

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  1. Swati Betharia
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Correspondence to Swati Betharia.

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Betharia, S., Rondόn-Ortiz, A.N. & Brown, D.A. Disubstituted Dithiolethione ACDT Exerts Neuroprotective Effects Against 6-Hydroxydopamine-Induced Oxidative Stress in SH-SY5Y Cells. Neurochem Res 44, 1878–1892 (2019). https://doi.org/10.1007/s11064-019-02823-3

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