Monoamine oxidase B inhibitors for the treatment of Parkinson's disease: a review of symptomatic and potential disease-modifying effects

Abstract

Parkinson's disease is a disorder characterized pathologically by progressive neurodegeneration of the dopaminergic cells of the nigrostriatal pathway. Although the resulting dopamine deficiency is the cause of the typical motor features of Parkinson's disease (bradykinesia, rigidity, tremor), additional non-motor symptoms appear at various timepoints and are the result of non-dopamine nerve degeneration. Monoamine oxidase B (MAO-B) inhibitors are used in the symptomatic treatment of Parkinson's disease as they increase synaptic dopamine by blocking its degradation. Two MAO-B inhibitors, selegiline and rasagiline, are currently licensed in Europe and North America for the symptomatic improvement of early Parkinson's disease and to reduce off-time in patients with more advanced Parkinson's disease and motor fluctuations related to levodopa. A third MAO-B inhibitor (safinamide), which also combines additional non-dopaminergic properties of potential benefit to Parkinson's disease, is currently under development in phase III clinical trials as adjuvant therapy to either a dopamine agonist or levodopa. MAO-B inhibitors have also been studied extensively for possible neuroprotective or disease-modifying actions. There is considerable laboratory evidence that MAO-B inhibitors do exert some neuroprotective properties, at least in the Parkinson's disease models currently available. However, these models have significant limitations and caution is required in assuming that such results may easily be extrapolated to clinical trials. Rasagiline 1 mg/day has been shown to provide improved motor control in terms of Unified Parkinson's Disease Rating Scale (UPDRS) score at 18 months in those patients with early disease who began the drug 9 months before a second group. There are a number of possible explanations for this effect that may include a disease-modifying action; however, the US FDA recently declined an application for the licence of rasagiline to be extended to cover disease modification.