Different Generations of Type-B Monoamine Oxidase Inhibitors in Parkinson’s Disease: From Bench to Bedside

Three inhibitors of type-B monoamine oxidase (MAOB), selegiline, rasagiline, and safinamide, are used for the treatment of Parkinson’s disease (PD). All three drugs improve motor signs of PD, and are effective in reducing motor fluc-tuations in patients undergoing long-term L-DOPA treatment. The effect of MAOB inhibitors on non-motor symptoms is not uniform and may not be class-related. Selegiline and rasagiline are irreversible inhibitors forming a covalent bond within the active site of MAOB. In contrast, safinamide is a reversible MAOB inhibitor, and also inhibits voltage-sensitive sodium channels and glutamate release. Safinamide is the prototype of a new generation of multi-active MAOB inhibitors, which in-cludes the antiepileptic drug, zonisamide. Inhibition of MAOB-mediated dopamine metabolism largely accounts for the an-tiparkinsonian effect of the three drugs. Dopamine metabolism by MAOB generates reactive oxygen species, which contrib-ute to nigro-striatal degeneration. Among all antiparkinsonian agents, MAOB inhibitors are those with the greatest neuropro-tective potential because of inhibition of dopamine metabolism, induction of neurotrophic factors, and, in the case of safina-mide, inhibition of glutamate release. The recent development of new experimental animal models that more closely mimic the progressive neurodegeneration associated with PD will allow to test the hypothesis that MAOB inhibitors may slow the progression of PD.