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OtherNEUROPHARMACOLOGY

Deprenyl and Desmethylselegiline Protect Mesencephalic Neurons from Toxicity Induced by Glutathione Depletion

Catherine Mytilineou, Efthimia Kototos Leonardi, Pheona Radcliffe, Esa H. Heinonen, Shan-Kuo Han, Peter Werner, Gerald Cohen and C. Warren Olanow
Journal of Pharmacology and Experimental Therapeutics February 1998, 284 (2) 700-706;
Catherine Mytilineou
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Efthimia Kototos Leonardi
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Pheona Radcliffe
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Esa H. Heinonen
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Shan-Kuo Han
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Peter Werner
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Gerald Cohen
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C. Warren Olanow
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Abstract

Oxidative stress is thought to play an important role in the pathogenesis of Parkinson’s disease (PD). Glutathione (GSH), a major cellular antioxidant, is decreased in the substantia nigra pars compacta of PD patients. The aim of the present study was to investigate whether deprenyl and its desmethyl metabolite, putative neuroprotective agents in the treatment of PD, could protect cultured rat mesencephalic neurons from cell death caused by GSH depletion due to treatment with l-buthionine-(S,R)-sulfoximine (BSO). BSO (10 μM) caused extensive cell death after 48 hr, as demonstrated by disruption of cellular integrity and release of lactate dehydrogenase into the culture medium. Both deprenyl and desmethylselegiline, at concentrations of 5 and 50 μM, significantly protected dopaminergic neurons from toxicity without preventing the BSO-induced loss in GSH. Protection was not associated with monoamine oxidase type B inhibition in that pargyline, a potent MAO inhibitor, was ineffective and pretreatment with pargyline did not prevent the protective effects of deprenyl. Protection was not associated with inhibition of dopamine uptake by deprenyl because the dopamine uptake inhibitor mazindol did not diminish BSO toxicity. The antioxidant ascorbic acid (200 μM) also protected against BSO-induced cell death, suggesting that oxidative events were involved. This study demonstrates that deprenyl and its desmethyl metabolite can diminish cell death associated with GSH depletion.

Footnotes

  • Send reprint requests to: Catherine Mytilineou, Ph.D., Department of Neurology, Box 1137, Mount Sinai School of Medicine, 1 Gustave L. Levy Place, New York, NY 10029.

  • ↵1 This work was supported by National Institutes of Health Grants NS-23017 and NS-34354, the Lowenstein Foundation and Somerset Pharmaceuticals.

  • Abbreviations:
    BSO
    l-buthionine-(S,R)-sulfoximine
    DA
    dopamine
    DMS
    R-(−)-desmethylselegiline
    GSH
    reduced glutathione
    6-OHDA
    6-hydroxydopamine
    LDH
    lactate dehydrogenase
    MAO
    monoamine oxidase
    NMDA
    N-methyl-d-aspartate
    PD
    Parkinson’s disease
    TH
    tyrosine hydroxylase
    MEM
    minimal essential medium
    PBS
    phosphate-buffered saline
    SOD
    superoxide dismutase
    SNc
    substantia nigra pars compacta
    • Received May 14, 1997.
    • Accepted September 8, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 284, Issue 2
1 Feb 1998
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OtherNEUROPHARMACOLOGY

Deprenyl and Desmethylselegiline Protect Mesencephalic Neurons from Toxicity Induced by Glutathione Depletion

Catherine Mytilineou, Efthimia Kototos Leonardi, Pheona Radcliffe, Esa H. Heinonen, Shan-Kuo Han, Peter Werner, Gerald Cohen and C. Warren Olanow
Journal of Pharmacology and Experimental Therapeutics February 1, 1998, 284 (2) 700-706;

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OtherNEUROPHARMACOLOGY

Deprenyl and Desmethylselegiline Protect Mesencephalic Neurons from Toxicity Induced by Glutathione Depletion

Catherine Mytilineou, Efthimia Kototos Leonardi, Pheona Radcliffe, Esa H. Heinonen, Shan-Kuo Han, Peter Werner, Gerald Cohen and C. Warren Olanow
Journal of Pharmacology and Experimental Therapeutics February 1, 1998, 284 (2) 700-706;
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