Abstract
Isoliquiritigenin (= 4,2′,4′-Trihydroxychalcone) (ILG) is a major constituent of the Glycyrrhizae Rhizoma that has significant neuroprotective functions. In the present study, we re-examined the potential of ILG to inhibit human monoamine oxidase (hMAO) in vitro and established its mechanism of inhibition through a kinetics study and molecular docking examination. ILG showed competitive inhibition of hMAO-A and mixed inhibition of hMAO-B with IC50 values of 0.68 and 0.33 µM, respectively, which varied slightly from the reported IC50 values. Since ILG has been reported to reduce dopaminergic neurodegeneration and psychostimulant-induced toxicity (both of which are related to dopamine and vasopressin receptors), we investigated the binding affinity and modulatory functions of ILG on dopamine and vasopressin receptors. ILG was explored as an antagonist of the D1 receptor and an agonist of the D3 and V1A receptors with good potency. An in silico docking investigation revealed that ILG can interact with active site residues at target receptors with low binding energies. These activities of ILG on hMAO and brain receptors suggest the potential role of the compound to ameliorate dopaminergic deficits, depression, anxiety, and associated symptoms in Parkinson’s disease and other neuronal disorders.
Highlights
Isoliquiritigenin (= 4,2′,4′-Trihydroxychalcone) (ILG) is a major constituent of the Glycyrrhizae Rhizoma that has significant neuroprotective functions
Multiple mechanisms that provoke neurodegeneration have been proposed, such as complex molecular changes involving DA and non-dopamine neurons and non-neuronal cells, perturbed cell functions like mitochondrial dysfunction resulting from excessive reactive oxygen species (ROS) or either underexpression or mutation of protective genes like peroxisome proliferator-activated receptor-gamma activator-1α (PGC-1α) and parkin-associated proteins (PARK6, PARK7, and PARK8)
The results indicated that ILG can suppress the activity of human monoamine oxidase (hMAO)-B more efficiently than that of human MAO-A (hMAO-A) provided that a lower concentration is required to achieve the same level of activity (IC50 values); as Kic < Kiu, the compound has a greater affinity to inhibit unbound enzymes compared to substrate-bound enzymes
Summary
Isoliquiritigenin (= 4,2′,4′-Trihydroxychalcone) (ILG) is a major constituent of the Glycyrrhizae Rhizoma that has significant neuroprotective functions. An in silico docking investigation revealed that ILG can interact with active site residues at target receptors with low binding energies These activities of ILG on hMAO and brain receptors suggest the potential role of the compound to ameliorate dopaminergic deficits, depression, anxiety, and associated symptoms in Parkinson’s disease and other neuronal disorders. Levodopa (l-Dopa) often is combined with a DA receptor agonist, a monoamine oxidase-B (MAO-B) inhibitor, or a catechol-O-methyltransferase inhibitor to allay motor symptoms in advanced PD Such combination holds drawbacks, such as polypharmacology-related adverse drug reactions due to varying pharmacokinetic and pharmacodynamics profiles of each drug and medication non-adherence and noncompliance. Multiple studies have explored the promising effects of ILG as a neuroprotective and neurorescueing compound through inhibition of intracellular ROS generation; antioxidative action; attenuation of synaptic dysfunction, neuronal damage, and neuroinflammation, confirming its usefulness in neurodegenerative d iseases[11,12,13,14]
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