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N-Acetylcysteine Prevents the Increase in Spontaneous Oxidation of Dopamine During Monoamine Oxidase Inhibition in PC12 Cells

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Abstract

The catecholaldehyde hypothesis for the pathogenesis of Parkinson’s disease proposes that the deaminated dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL) is toxic to nigrostriatal dopaminergic neurons. Inhibiting monoamine oxidase (MAO) should therefore slow the disease progression; however, MAO inhibition increases spontaneous oxidation of dopamine, as indicated by increased 5-S-cysteinyl-dopamine (Cys-DA) levels, and the oxidation products may also be toxic. This study examined whether N-acetylcysteine (NAC), a precursor of the anti-oxidant glutathione, attenuates the increase in Cys-DA production during MAO inhibition. Rat pheochromocytoma PC12 cells were incubated with NAC, the MAO-B inhibitor selegiline, or both. Selegiline decreased DOPAL and increased Cys-DA levels (p < 0.0001 each). Co-incubation of NAC at pharmacologically relevant concentrations (1–10 µM) with selegiline (1 µM) attenuated or prevented the Cys-DA response to selegiline, without interfering with the selegiline-induced decrease in DOPAL production or inhibiting tyrosine hydroxylation. NAC therefore mitigates the increase in spontaneous oxidation of dopamine during MAO inhibition.

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Abbreviations

ALDH:

Aldehyde dehydrogenase

DA:

Dopamine

DHPG:

3,4-Dihydroxyphenylglycol

DOPAC:

3,4-Dihydroxyphenylacetic acid

DOPAL:

3,4-Dihydroxyphenylacetaldehyde

DOPET:

3,4-Dihydroxyphenylethanol

NE:

Norepinephrine

PD:

Parkinson disease

VMAT:

Vesicular monoamine transporter

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Acknowledgements

The research reported here was supported by the intramural research program of the National Institute of Neurological Disorders and Stroke.

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Authors and Affiliations

  1. Clinical Neurocardiology Section, CNP/DIR/NINDS/NIH, 9000 Rockville Pike, Bldg. 10 Rm. 5N220, Bethesda, MD, 20892-1620, USA

    David S. Goldstein, Yunden Jinsmaa, Patti Sullivan & Yehonatan Sharabi

  2. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

    Yehonatan Sharabi

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  1. David S. Goldstein
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  2. Yunden Jinsmaa
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  3. Patti Sullivan
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  4. Yehonatan Sharabi
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Contributions

DSG conception and design, data analysis, data interpretation, drafting the article, final approval. YJ data acquisition, data analysis, conception and design, drafting the article, revising the article. PS data acquisition, data analysis. YS conception and design, data analysis, drafting the article, revising the article critically for important intellectual content.

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Correspondence to David S. Goldstein.

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None of the authors has a conflict of interest to report. Dr. Goldstein is Chair of the Education Committee and sits on the Board of Directors of the American Autonomic Society, under approved Outside Activities. For these services he receives no payment in cash or kind.

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Goldstein, D.S., Jinsmaa, Y., Sullivan, P. et al. N-Acetylcysteine Prevents the Increase in Spontaneous Oxidation of Dopamine During Monoamine Oxidase Inhibition in PC12 Cells. Neurochem Res 42, 3289–3295 (2017). https://doi.org/10.1007/s11064-017-2371-0

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  • DOI: https://doi.org/10.1007/s11064-017-2371-0

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