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Molecular Pharmacology

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Research ArticleArticle

Perturbation of Dopamine Metabolism by 3-Amino-2-(4′-halophenyl)propenes Leads to Increased Oxidative Stress and Apoptotic SH-SY5Y Cell Death

Warren C. Samms, Rohan P. Perera, D. S. Wimalasena and K. Wimalasena
Molecular Pharmacology September 2007, 72 (3) 744-752; DOI: https://doi.org/10.1124/mol.107.035873
Warren C. Samms
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Rohan P. Perera
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D. S. Wimalasena
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K. Wimalasena
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Abstract

We have recently characterized a series of 3-amino-2-phenyl-propene (APP) derivatives as reversible inhibitors for the bovine adrenal chromaffin granule vesicular monoamine transporter (VMAT) that have been previously characterized as potent irreversible dopamine-β-monooxygenase (DβM) and monoamine oxidase (MAO) inhibitors. Halogen substitution on the 4′-position of the aromatic ring gradually increases VMAT inhibition potency from 4′-F to 4′-I, parallel to the hydrophobicity of the halogen. We show that these derivatives are taken up into both neuronal and non-neuronal cells, and into resealed chromaffin granule ghosts efficiently through passive diffusion. Uptake rates increased according to the hydrophobicity of the 4′-substituent. More importantly, these derivatives are highly toxic to human neuroblastoma SH-SY5Y but not toxic to M-1, Hep G2, or human embryonic kidney 293 non-neuronal cells at similar concentrations. They drastically perturb dopamine (DA) uptake and metabolism in SH-SY5Y cells under sublethal conditions and are able to deplete both vesicular and cytosolic catecholamines in a manner similar to that of amphetamines. In addition, 4′-IAPP treatment significantly increases intracellular reactive oxygen species (ROS) and decreases glutathione (GSH) levels in SH-SY5Y cells, and cell death is significantly attenuated by the common antioxidants α-tocopherol, N-acetyl-l-cysteine and GSH, but not by the nonspecific caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone. DNA fragmentation analysis further supports that cell death is probably due to a caspase-independent ROS-mediated apoptotic pathway. Based on these and other findings, we propose that drastic perturbation of DA metabolism in SH-SY5Y cells by 4′-halo APP derivatives causes increased oxidative stress, leading to apoptotic cell death.

Footnotes

  • This work was supported by National Institutes of Health grant NS39423 and a United States Department of Education Graduate Assistance in Areas of National Need Fellowship.

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

  • doi:10.1124/mol.107.035873.

  • ABBREVIATIONS: DA, dopamine; NE, norepinephrine; E, epinephrine; ROS, reactive oxygen species; b561, cytochrome b561; V-H+, vesicular H+; DβM, dopamine-β-monooxygenase; VMAT, vesicular monoamine transporter; Asc, ascorbic acid; DAT, dopamine transporter; MPP+, 1-methyl-4-phenylpyridinium; APP, 3-amino-2-phenylpropene; OHAPP, hydroxy-3-amino-2-phenylpropene; MAO, monoamine oxidase; GSH, reduced glutathione; GBR 12909, vanoxerine; Z-VAD-FMK, N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone; FBS, fetal bovine serum; HPLC, high-performance liquid chromatography; HPLC-EC, HPLC with electrochemical detection; HPLC-UV, HPLC with UV detection; DMEM, Dulbecco's modified Eagle's medium; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; NAC, N-acetyl-cysteine; KRB, Krebs-Ringer buffer; DOPAC, 3,4-dihydroxyphenylacetic acid; HVA, homovanillic acid; DCF-DA, 2′,7′-dichlorofluorescein diacetate; DCF, 2′,7′-dichlorofluorescein; MCB, monochlorobimane.

    • Received March 7, 2007.
    • Accepted June 14, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 72 (3)
Molecular Pharmacology
Vol. 72, Issue 3
1 Sep 2007
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Research ArticleArticle

Perturbation of Dopamine Metabolism by 3-Amino-2-(4′-halophenyl)propenes Leads to Increased Oxidative Stress and Apoptotic SH-SY5Y Cell Death

Warren C. Samms, Rohan P. Perera, D. S. Wimalasena and K. Wimalasena
Molecular Pharmacology September 1, 2007, 72 (3) 744-752; DOI: https://doi.org/10.1124/mol.107.035873

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Research ArticleArticle

Perturbation of Dopamine Metabolism by 3-Amino-2-(4′-halophenyl)propenes Leads to Increased Oxidative Stress and Apoptotic SH-SY5Y Cell Death

Warren C. Samms, Rohan P. Perera, D. S. Wimalasena and K. Wimalasena
Molecular Pharmacology September 1, 2007, 72 (3) 744-752; DOI: https://doi.org/10.1124/mol.107.035873
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