Abstract
BackgroundMonoamine oxidase-B (MAO-B) inhibitors are widely used in the treatment of Parkinson’s disease. They increase vital monoamine neurotransmitters in the brain. However, there is a need for safer natural reversible MAO inhibitors with MAO-B selectivity. Our previous studies showed that Psoralea corylifolia seeds (PCS) extract contains compounds that inhibit monoamine oxidase-B.MethodsIn this study, six of PCS constituents sharing a benzopyrone structure were investigated. The compounds Biochanin-A (BIO-A), isopsoralen, 6-prenylnaringenin, neobavaisoflavone, psoralen, and psoralidin, were tested for their ability to inhibit recombinant human MAO-A and B (hMAO-A and hMAO-B) isozymes. The ability of these compounds to inhibit MAO-A and MAO-B were compared to that of PCS ethanolic extract (PCSEE) using spectrophotometric assays and confirmed by luminescence assays. The highly potent and selective MAO-B inhibitor, BIO-A, was further investigated for both isozymes reversibility and enzyme kinetics. Molecular docking studies were used to predict the bioactive conformation and molecular interactions of BIO-A with both isozymes.ResultsThe data obtained indicate that benzopyrones inhibited hMAO-A and hMAO-B with different degrees as confirmed with the luminescence assay. BIO-A inhibited hMAO-B with high potency and selectivity in the present study (IC50 = 0.003 μg/mL) and showing 38-fold more selectivity than PCSEE (hMAO-B IC50 = 3.03 μg/mL, 17-fold selectivity) without affecting hydrogen peroxide. Furthermore, BIO-A reversibly and competitively inhibited both hMAOs with significantly lower inhibitory constant (Ki) in hMAO-B (3.8 nM) than hMAO-A (99.3 nM). Our docking studies indicated that the H-bonds and hydrophobic interactions at the human MAO-A and MAO-B active sites contributed to the reversibility and selectivity of BIO-A.ConclusionsThe data obtained indicate that BIO-A is a potent, reversible and selective MAO-B inhibitor and may be recommended for further investigation in its possible use in the therapeutic management of Parkinson’s and Alzheimer’s diseases.
Highlights
Monoamine oxidase-B (MAO-B) inhibitors are widely used in the treatment of Parkinson’s disease
The left shifted BIO-A curves compared to PCS ethanolic extract (PCSEE) curves display BIO-A significantly higher potency and RS in favor to inhibit hMAO-B (RSB) than PCSEE (Fig. 3 b)
BIO-A-induced changes of Recombinant human MAO (hMAO)-A and hMAO-B Michaelis-Menten parameters To determine the mode of BIO-A reversible inhibition on both MAOs, we investigated BIO-A effects on Michaelis-Menten kinetics of hMAO-A and hMAO-B at their initial velocities (Fig. 5)
Summary
Monoamine oxidase-B (MAO-B) inhibitors are widely used in the treatment of Parkinson’s disease. They increase vital monoamine neurotransmitters in the brain. Human monoamine oxidases A and B isozymes (MAO-A and MAO-B) regulate neurotransmitters such as dopamine (DA), norepinephrine (NE), and serotonin (5-HT) [1] These metabolizing isozymes belong to the family of flavincontaining amine oxidoreductases and are in the mitochondrial membranes of brain neurons and glia, in addition to other peripheral cells. The non-selective and selective inhibitors of MAO-A (MAO-AIs) are used primarily for patients who have not responded to other antidepressants therapy [1]. Some of these therapeutic agents such as moclobemide and pirlindole are currently in use
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