The monoamine oxidase-B (MAO-B) inhibitor rasagaline reduced motor symptoms in patients with early Parkinson's disease, but it is not clear that it slows neurodegeneration, according to a study published last week in the Archives of Neurology.

MAO B and its isoform, MAO A, help to produce toxic oxygen free radicals. The enzyme is elevated threefold in aged human brain tissue, and there is experimental evidence that MAO inhibitors could be neuroprotective in neurodegenerative diseases including Alzheimer's (see ARF related news story).

The MAO-B inhibitor selegiline (sold as Eldepryl, Atapryl, or Carbex) has been used in Parkinson's disease for more than a decade. It does have a modest effective on symptoms when used alone in the early stages of the disease, but its effectiveness as a neuroprotectant is still a matter of debate. It has primarily found a niche as an adjunct that allows a reduction in L-dopa dosage without sacrificing motor function. Among the alternatives to selegiline, rasagiline has been considered especially promising because it is a more selective inhibitor of MAO and does not metabolize to amphetamine, as some portion of the oral selegiline does.

Rasagiline has still not been approved by the US Food and Drug Administration for PD, and the current study was undertaken to determine the safety and efficacy of the drug. The Parkinson Study Group conducted a multicenter, 26-week, parallel-group, randomized, double-blind, placebo-controlled study of 404 patients with early PD who were not undergoing L-dopa therapy (the TEMPO study). Both dosages used in the trial (1 mg/day and 2 mg/day) proved effective at reducing symptoms relative to placebo (-4.20 units and -3.56 units, respectively, on the Unified Parkinson's Disease Rating Scale). This was comparable to the benefit demonstrated by selegiline and lazabemide, another MAO-B inhibitor.

The most likely mechanism of action for rasagaline, as with the other MAO-B inhibitors, is through the slowing of endogenous dopamine catabolism. However the authors point out that in animal models, rasagaline has shown anti-apoptotic and neuroprotective qualities. Since this study indicated the safety and efficacy of the drug, they suggest longer studies to determine whether there is a neuroprotective effect of rasagiline that could delay the need for L-dopa in Parkinson's patients.-Hakon Heimer.

References:
Parkinson Study Group. A controlled trial of rasagiline in early Parkinson Disease: The TEMPO study. Arch Neurol. 2002 Dec;59:1937-43. Abstract

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  1. This study from the Parkinson’s Study Group indicates rasagiline should benefit persons with very early Parkinson’s disease. These benefits seem modest, and are similar to those observed with another MAO-B inhibitor, selegiline. The impact that rasagiline has on symptoms, as quantified by the UPDRS rating scale, was not greater than that reported from studies of L-dopa/carbidopa and dopamine agonists. Thus, although rasagiline could prove helpful to particular individuals with very mild Parkinson’s disease, it seems on the basis of this trial alone that rasagiline will not have a marked impact on how Parkinson’s disease is currently treated in these patients. It probably won’t affect the debate over whether treatment initiation should emphasize L-dopa/carbidopa or a dopamine agonist. Still, in the study rasagiline was well tolerated, and the question of whether there is a neuroprotective benefit remains unanswered. If longer term studies show its benefits to persist over time in the Parkinson’s patient, it would likely then have a more influential role on Parkinson’s management, and spur interest in its evaluation for other neurodegenerative disorders, in particular Alzheimer’s disease. Also, it is still possible that niche uses will be found for rasagiline in which it turns out to be quite useful.

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References

News Citations

  1. Building Blocks for Neurodegenerative Disease Therapy

Paper Citations

  1. A controlled trial of rasagiline in early Parkinson disease: the TEMPO Study. Arch Neurol. 2002 Dec;59(12):1937-43. PubMed.

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Papers

  1. A controlled trial of rasagiline in early Parkinson disease: the TEMPO Study. Arch Neurol. 2002 Dec;59(12):1937-43. PubMed.

Primary Papers

  1. A controlled trial of rasagiline in early Parkinson disease: the TEMPO Study. Arch Neurol. 2002 Dec;59(12):1937-43. PubMed.