Monoamine Oxidase Inhibitor (MAO-I)-Mediated Neuroprotection for Treating Parkinson’s Disease

Monoamine oxidases (MAO)-A andMAO-B catalyze the oxidative deamination of monoamine neurotransmitters, such as dopamine (DA), noradrenaline, and serotonin, in the central and peripheral nervous system. Parkinson’s disease (PD) is an aging-related movement disorder, caused by a deficiency of the neurotransmitter DA in the striatum of the brain, caused by degeneration of the nigrostriatal DA neurons. During the1960s, L-DOPA, a direct precursor of DA, which is synthesized in vivo from tyrosine in DA neurons by tyrosine hydroxylase and is converted to DA by aromatic L-amino acid decarboxylase, was introduced to treat this DA deficiency in the striatum. In addition to L-DOPA as a treatment, MAO-B inhibitors (MAO-B-Is) have been used since the 1970s, first selegiline (L-(-)-deprenyl), then rasagiline, and more recently safinamide, as an effective therapy for PD by preventing the degradation of DA. Furthermore, monotherapy with MAO-B-I, selegiline, rasagiline, or safinamide has been proved to be effective in the case of early PD. Accumulating data suggest thatMAO-B-Is may also have neuroprotective efficacy due to several mechanisms that may or may not be related to MAO inhibition. DA oxidation and formation of misfolded α-synuclein oligomers may be linked to dysfunctions of mitochondria, the autophagy-lysosomal system, and ubiquitin-proteasome system, resulting in DA neuron death in PD; and MAO-I may prevent these processes to afford neuroprotection. However, many clinical and basic studies have suggested, but not yet convincingly proved, neuroprotective effects of MAO-I in PD. It remains to be proved if the administration of MAO-B-I several decades before the onset of PD could prevent the occurrence of PD based on neuroprotection and, if so, to confirm the molecular mechanism involved.