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Promising selective MAO-B inhibition by sesamin, a lignan from Zanthoxylum flavum stems.

ABSTRACT: Monoamine oxidase inhibition is an important therapeutic approach for various neurodegenerative disorders. Reversible MAO inhibitors selectively targeting only one isoform possess substantial merit in terms of safety, efficacy, and side effect profile. This study aimed to isolate the secondary metabolites of Zanthoxylum flavum stems and evaluate their recombinant human MAO inhibition, antimicrobial, and antiprotozoal activities. As a result, fourteen compounds were isolated and identified (nine of them were reported from Z. flavum for the first time). Compound 3 (sesamin) exhibited potent selective MAO-B inhibition (IC50 value of 1.45 ± 0.05 µM) which reported herein for the first time. Compound 2 showed selective MAO-A inhibition activity, compound 5 exhibited good trypanocidal activity, and compound 7 displayed moderate antibacterial activity. The promising MAO-B inhibitory activity of sesamin provoked us to further explore the kinetic properties, the binding mode, and the underlying mechanism of MAO-B inhibition by this lignan. This detailed investigation substantiated a reversible binding and mixed MAO-B catalytic function inhibition via sesamin (Ki: 0.473 ± 0.076 ?M). Selectivity and reversibility of sesamin on MAO-B provide exciting prerequisites for further in vivo investigation to confirm its therapeutic potentiality.

SUBMITTER: Mohamed SM

PROVIDER: S-EPMC7132610 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Promising selective MAO-B inhibition by sesamin, a lignan from <i>Zanthoxylum flavum</i> stems.

Mohamed Shaymaa M SM Chaurasiya Narayan D ND Mohamed Nesma M NM Bayoumi Soad A L SAL Tekwani Babu L BL Ross Samir A SA

Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society 20200213 4

Monoamine oxidase inhibition is an important therapeutic approach for various neurodegenerative disorders. Reversible MAO inhibitors selectively targeting only one isoform possess substantial merit in terms of safety, efficacy, and side effect profile. This study aimed to isolate the secondary metabolites of <i>Zanthoxylum flavum</i> stems and evaluate their recombinant human MAO inhibition, antimicrobial, and antiprotozoal activities. As a result, fourteen compounds were isolated and identified ...[more]

PMID: 32273799

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Project description:Sesamin (SSM) and sesamolin (SesA) are the two major furofuran lignans of sesame oil and they have been previously noticed to exert various biological actions. However, their modulatory actions on different types of ionic currents in electrically excitable cells remain largely unresolved. The present experiments were undertaken to explore the possible perturbations of SSM and SesA on different types of ionic currents, e.g., voltage-gated Na+ currents (INa), erg-mediated K+ currents (IK(erg)), M-type K+ currents (IK(M)), delayed-rectifier K+ currents (IK(DR)) and hyperpolarization-activated cation currents (Ih) identified from pituitary tumor (GH3) cells. The exposure to SSM or SesA depressed the transient and late components of INa with different potencies. The IC50 value of SSM needed to lessen the peak or sustained INa was calculated to be 7.2 or 0.6 μM, while that of SesA was 9.8 or 2.5 μM, respectively. The dissociation constant of SSM-perturbed inhibition on INa, based on the first-order reaction scheme, was measured to be 0.93 μM, a value very similar to the IC50 for its depressant action on sustained INa. The addition of SSM was also effective at suppressing the amplitude of resurgent INa. The addition of SSM could concentration-dependently inhibit the IK(M) amplitude with an IC50 value of 4.8 μM. SSM at a concentration of 30 μM could suppress the amplitude of IK(erg), while at 10 μM, it mildly decreased the IK(DR) amplitude. However, the addition of neither SSM (10 μM) nor SesA (10 μM) altered the amplitude or kinetics of Ih in response to long-lasting hyperpolarization. Additionally, in this study, a modified Markovian model designed for SCN8A-encoded (or NaV1.6) channels was implemented to evaluate the plausible modifications of SSM on the gating kinetics of NaV channels. The model demonstrated herein was well suited to predict that the SSM-mediated decrease in peak INa, followed by increased current inactivation, which could largely account for its favorable decrease in the probability of the open-blocked over open state of NaV channels. Collectively, our study provides evidence that highlights the notion that SSM or SesA could block multiple ion currents, such as INa and IK(M), and suggests that these actions are potentially important and may participate in the functional activities of various electrically excitable cells in vivo.

Dataset Information

Promising selective MAO-B inhibition by sesamin, a lignan from Zanthoxylum flavum stems.

Publications

Promising selective MAO-B inhibition by sesamin, a lignan from <i>Zanthoxylum flavum</i> stems.

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