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Research ArticleTOXICOLOGY

Effects of Pharmacological Agents upon a Transgenic Model of Parkinson's Disease in Drosophila melanogaster

Robert G. Pendleton, Feroz Parvez, Marwa Sayed and Ralph Hillman
Journal of Pharmacology and Experimental Therapeutics January 2002, 300 (1) 91-96; DOI: https://doi.org/10.1124/jpet.300.1.91
Robert G. Pendleton
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Feroz Parvez
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Marwa Sayed
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Ralph Hillman
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Abstract

The human gene that codes for the protein α-synuclein has been transferred into the Drosophila melanogaster genome. The transgenic flies recapitulate some of the essential features of Parkinson's disease. These include the degeneration of certain dopaminergic neurons in the brain accompanied by the appearance of age-dependent abnormalities in locomotor activity. In the present study, we tested the locomotor response of these transgenic flies to prototypes of the major classes of drugs currently used to treat this disorder. A time course study was first conducted to determine when impaired locomotor activity appeared relative to normal “wild-type” flies. A climbing or negative geotaxis assay measuring the ability of the organisms to climb up the walls of a plastic vial was used. Based on the results obtained, normal and transgenic flies were treated with each of the drugs in their food for 13 days and then assayed. The activity of transgenic flies treated with l-DOPA was restored to normal. Similarly, the dopamine agonists pergolide, bromocriptine, and 2,3,4,5-tetrahydro-7,8-dihydroxy- 1-phenyl-1H-3-benzazepine (SK&F 38393) were substantially effective. Atropine, the prototypical muscarinic cholinergic receptor antagonist, was also effective but to a lesser extent than the other antiparkinson compounds. p-Chlorophenylalanine, an inhibitor of serotonin synthesis, was without beneficial effect as was α-methyl-p-tyrosine, an inhibitor of tyrosine hydroxylase, the rate-limiting step in catecholamine biosynthesis. This behavioral study further demonstrates the utility of this model in studying Parkinson's disease and reinforces the concept that inhibition of the action of α-synuclein may be useful in its treatment as may dopamine D1 receptor agonists.

Footnotes

  • Support for this research was provided by a grant from the Howard Hughes Medical Institute through the Undergraduate Biological Science Education Program.

  • Abbreviations

    GAL4
    protein transcription factor with four DNA binding sites that normally activates galactose metabolism in yeast
    UAS
    upstream activating system
    elav
    neuronal locus
    SK&F 38393
    2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine
    αMT
    α-methyl-p-tyrosine
    PCPA
    p-chlorophenylalanine
    • Received August 20, 2001.
    • Accepted October 16, 2001.
    • The American Society for Pharmacology and Experimental Therapeutics
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    Journal of Pharmacology and Experimental Therapeutics: 300 (1)
    Journal of Pharmacology and Experimental Therapeutics
    Vol. 300, Issue 1
    1 Jan 2002
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    Research ArticleTOXICOLOGY

    Effects of Pharmacological Agents upon a Transgenic Model of Parkinson's Disease in Drosophila melanogaster

    Robert G. Pendleton, Feroz Parvez, Marwa Sayed and Ralph Hillman
    Journal of Pharmacology and Experimental Therapeutics January 1, 2002, 300 (1) 91-96; DOI: https://doi.org/10.1124/jpet.300.1.91

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    Research ArticleTOXICOLOGY

    Effects of Pharmacological Agents upon a Transgenic Model of Parkinson's Disease in Drosophila melanogaster

    Robert G. Pendleton, Feroz Parvez, Marwa Sayed and Ralph Hillman
    Journal of Pharmacology and Experimental Therapeutics January 1, 2002, 300 (1) 91-96; DOI: https://doi.org/10.1124/jpet.300.1.91
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