Abstract
Monoamine oxidase-B (MAO-B) is a well-established therapeutic target for Parkinson’s disease (PD); however, previous clinical studies on currently available irreversible MAO-B inhibitors have yielded disappointing neuroprotective effects. Here, we tested the therapeutic potential of KDS2010, a recently synthesized potent, selective, and reversible MAO-B inhibitor in multiple animal models of PD. We designed and synthesized a series of α-aminoamide derivatives and found that derivative KDS2010 exhibited the highest potency, specificity, reversibility, and bioavailability (> 100%). In addition, KDS2010 demonstrated significant neuroprotective and anti-neuroinflammatory efficacy against nigrostriatal pathway destruction in the mouse MPTP model of parkinsonism. Treatment with KDS2010 also alleviated parkinsonian motor dysfunction in 6-hydroxydopamine-induced and A53T mutant α-synuclein overexpression rat models of PD. Moreover, KDS2010 showed virtually no toxicity or side effects in non-human primates. KDS2010 could be a next-generation therapeutic candidate for PD.
Highlights
Parkinson’s disease (PD) is a neurodegenerative disorder primarily affecting the nigrostriatal dopaminergic pathway and manifesting with prominent motor deficits such as rigidity, bradykinesia, resting tremor, and gait disturbance [1]
Recent studies have demonstrated that monoamine oxidase-B (MAO-B) expression is dramatically elevated in reactive astrocytes and that MAO-B is responsible for astrocytic GABA synthesis through the putrescine degradation pathway [8,9,10,11]
We synthesized a series of α-aminoamide derivatives by introducing biphenyl groups with various substituents as potential novel MAO-B inhibitors [14] and demonstrated that introduction of an electronwithdrawing group at the para-position is key to potent MAO-B inhibition
Summary
Parkinson’s disease (PD) is a neurodegenerative disorder primarily affecting the nigrostriatal dopaminergic pathway and manifesting with prominent motor deficits such as rigidity, bradykinesia, resting tremor, and gait disturbance [1]. Recent studies have demonstrated that MAO-B expression is dramatically elevated in reactive astrocytes and that MAO-B is responsible for astrocytic GABA synthesis through the putrescine degradation pathway [8,9,10,11]. A recent study revealed that GABA from reactive astrocytes in the substantia nigra pars compacta (SNpc) tonically inhibits neighboring dopaminergic (DAergic) neurons, thereby suppressing the synthesis and release of dopamine [8]. These findings suggest that excessive MAO-B-mediated astrocytic GABA synthesis is critically involved in PD pathology and that MAO-B inhibitors may reduce PD symptoms by suppressing astrocytic GABA synthesis and disinhibiting nigral DAergic neurons
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