Does selegiline (Eldepryl, Zelapar) have neuroprotective effects in patients with Parkinson disease (PD)?

Updated: Jan 24, 2019
  • Author: Robert A Hauser, MD, MBA; Chief Editor: Selim R Benbadis, MD  more...
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Answer

Selegiline (Eldepryl, Zelapar) is an irreversible inhibitor of MAO-B. In humans, brain dopamine is metabolized by MAO-B, and the blockade of this enzyme will reduce the metabolism of dopamine. Selegiline was shown conclusively to delay the need for levodopa therapy in early Parkinson disease, in the DATATOP (Deprenyl And Tocopherol Antioxidative Therapy Of Parkinsonism) study. [64, 65] The Parkinson Study Group evaluated the ability of selegiline and tocopherol to delay progression of clinical disability in early Parkinson disease by randomizing 800 patients to receive selegiline (10 mg/day) or placebo and tocopherol (2000 IU/day) or placebo. Patients who received selegiline, with placebo or with tocopherol, experienced a significant delay in the need for levodopa therapy. Patients who received placebo required levodopa at a projected median of 15 months from enrollment, whereas those who received selegiline required levodopa ataprojectedmedianof24monthsafterenrollment.Tocopherolhadnoeffectonprogression of disability. [64, 65]

Because selegiline was observed to provide a small but statistically significant symptomatic (early) benefit, it is not possible to determine whether a neuroprotective effect contributed to the delay in need for levodopa in the DATATOP study. [64, 65]

In another study, patients with early Parkinson disease who received selegiline over a 7-year period experienced less clinical progression and required less levodopa than patients receiving placebo. [66] In this study, patients with early Parkinson disease were randomized to selegiline or placebo, and levodopa was added as needed. After 5 years, patients who were treated with placebo had Unified Parkinson Disease Rating Scale (UPDRS) scores that were 35% higher (worse) than those treated with selegiline, even as they were receiving 19% higher doses of levodopa. [66] This is a striking finding, considering that as monotherapy in early disease, selegiline provides only modest symptomatic improvement.

Selegiline is the medication that first garnered wide interest as a possible neuroprotective agent for Parkinson disease. Laboratory investigations continue to provide evidence that selegiline affords a neuroprotective effect for dopamine neurons independent of MAO-B inhibition. Selegiline was reported to protect dopamine cells in mice from MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) toxicity, even when the agent was administered after a delay sufficient to allow the oxidation of MPTP to MPP+ (1-methyl-4-phenylpyridinium), [67] an effect that cannot be attributed to MAO-B inhibition.

In cell-culture systems, selegiline's neuroprotective effect is mediated by new protein synthesis. Selegiline induces transcriptional events that result in increased synthesis of antioxidant and antiapoptotic proteins. Evidence indicates that one of selegiline's metabolites, desmethylselegiline, is the active agent for neuroprotection. It is possible that selegiline's amphetamine metabolites may interfere with its neuroprotective actions.


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