Entacapone enhances levodopa-induced reversal of motor disability in MPTP-treated common marmosets

Authors

  • Lance A. Smith,

    1. Neurodegenerative Diseases Research Centre, Pharmacology Group, Biomedical Sciences Division, King's College, London, England; Orion-Farmos
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  • Ariel Gordin,

    1. Neurodegenerative Diseases Research Centre, Pharmacology Group, Biomedical Sciences Division, King's College, London, England; Orion-Farmos
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  • Dr. Peter Jenner,

    Corresponding author
    1. Orion Research Center, Espoo, Finland
    • Pharmacology Group, Biomedical Sciences Division, King's College London, Manresa Road, London SW3 6LX, U.K.
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  • C. David Marsden

    1. University Department of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London, England
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Abstract

Oral administration of levodopa (L-dopa) (2.5–25.0 mg/kg) plus carbidopa (12.5 mg/kg p.o.) to MPTP-treated common marmosets produced a dose-related increase in locomotor activity and a corresponding decrease in motor disability. Pretreatment with the peripheral COMT inhibitor entacapone (12.5 mg/kg p.o.) enhanced the intensity and duration of the increase in locomotor activity and the reversal of motor disability produced by a threshold dose of L-dopa (2.5 mg/kg p.o.) plus carbidopa. By contrast, entacapone pretreatment did not potentiate the increased locomotor activity or reversal of motor disability produced by a near-maximal dose of L-dopa (12.5 mg/kg p.o.) plus carbidopa. The effects of entacapone (5.0–25.0 mg/kg p.o.) were dose related, with doses of >12.5 mg/kg tending to produce less potentiation of L-dopa's effects compared to lower doses. Pretreatment with entacapone (12.5 mg/kg p.o.) without carbidopa caused a short-lasting enhancement of L-dopa's (12.5 mg/kg p.o.) action, whereas pretreatment with carbidopa (12.5 mg/kg p.o.) alone had a more dramatic effect. However, pretreatment with both carbidopa and entacapone produced the greatest overall motor response. In conclusion, entacapone enhances the motor response produced by a low threshold dose of L-dopa plus carbidopa. However, optimization of both the dose of L-dopa and entacapone appears necessary to obtain the maximal therapeutic response.

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