The Benzopyrone Biochanin-A as a reversible, competitive, and selective monoamine oxidase B inhibitor

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.

Acetylcholinesterase and monoamine oxidase-B inhibitory activities by ellagic acid derivatives isolated from Castanopsis cuspidata var. sieboldii

“…3 , 4 , and 5 inhibited AChE in a competitive but partially mixed manner, whereas 3 and 5 inhibited MAO-B in a competitive manner. The majority of AChE inhibitors described to date are mixed or partially mixed inhibitors 22 , 26 , 57 , whereas the MAO-B inhibitors described are usually competitive type 58 – 60 .…”

Perspectives Regarding the Role of Biochanin A in Humans

“…BCA also exerts a neuroprotective effect against L-glutamate-induced cytotoxicity, which plays a crucial role in neuronal cell death in various neurodegenerative diseases and reduces glutathione levels (Tan et al, 2013; Biradar et al, 2014). BCA is a potent, reversible, and selective oxidase-B (MAO-B) inhibitor because of the hydrophobic interactions between BCA and MAO-B, and MAO-B inhibitors are widely used in the treatment of PD and have potential in the future treatment of AD (Zarmouh et al, 2017). BCA effectively inhibits the activity of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) not only via a mitochondria-dependent apoptosis pathway but also by binding the allosteric site of BACE1; BACE1 accumulation is among the major histological hallmarks of AD (Youn et al, 2016).…”

Isothiocyanate from Moringa oleifera seeds mitigates hydrogen peroxide-induced cytotoxicity and preserved morphological features of human neuronal cells

“…Interestingly, the role of reported plant sourced natural compounds with promising antioxidant and anti-inflammatory activities that prevent or delay the occurrence and progression of NDDs, has been pursuing the interest of many researchers in the quest for additional candidates with better potentials [ 16 – 18 ]. Having said that, Glucomoringin-isothiocyanate (GMG-ITC) was reported to have wide range of biological activities such as anti-inflammatory, anti-oxidant, antimicrobial and antiulcer [ 19 – 22 ].…”