Abstract
In this study, we delineate the human monoamine oxidase (hMAO) inhibitory potential of natural Diels–Alder type adducts, mulberrofuran G (1), kuwanon G (2), and albanol B (3), from Morus alba root bark to characterize their role in Parkinson’s disease (PD) and depression, focusing on their ability to modulate dopaminergic receptors (D1R, D2LR, D3R, and D4R). In hMAO-A inhibition, 1–3 showed mild effects (50% inhibitory concentration (IC50): 54‒114 μM). However, 1 displayed moderate inhibition of the hMAO-B isozyme (IC50: 18.14 ± 1.06 μM) followed by mild inhibition by 2 (IC50: 57.71 ± 2.12 μM) and 3 (IC50: 90.59 ± 1.72 μM). Our kinetic study characterized the inhibition mode, and the in silico docking predicted that the moderate inhibitor 1 would have the lowest binding energy. Similarly, cell-based G protein-coupled receptors (GPCR) functional assays in vector-transfected cells expressing dopamine (DA) receptors characterized 1–3 as D1R/D2LR antagonists and D3R/D4R agonists. The half-maximum effective concentration (EC50) of 1–3 on DA D3R/D4R was 15.13/17.19, 20.18/21.05, and 12.63/‒ µM, respectively. Similarly, 1–3 inhibited 50% of the DA response on D1R/D2LR by 6.13/2.41, 16.48/31.22, and 7.16/18.42 µM, respectively. A computational study revealed low binding energy for the test ligands. Interactions with residues Asp110, Val111, Tyr365, and Phe345 at the D3R receptor and Asp115 and His414 at the D4R receptor explain the high agonist effect. Likewise, Asp187 at D1R and Asp114 at D2LR play a crucial role in the antagonist effects of the ligand binding. Our overall results depict 1–3 from M. alba root bark as good inhibitors of hMAO and potent modulators of DA function as D1R/D2LR antagonists and D3R/D4R agonists. These active constituents in M. alba deserve in-depth study for their potential to manage neurodegenerative disorders (NDs), particularly PD and psychosis.
Highlights
Monoamine oxidase (MAO) is a flavoenzyme in the outer mitochondrial membrane of neuronal and non-neuronal cells that has a vital role in the etiology of age-regulated neurodegenerative disorders (NDs)
The in vitro human monoamine oxidase (hMAO) inhibition potentials of 1–3 and the reference compound selegiline was evaluated via a chemiluminescent assay in a white, opaque, 96-well plate using the MAO-Glo kit (Promega, Madison, WI)
The test compounds of the present study showed a unique profile, i.e., moderate hMAO inhibition with good D1R/D2LR antagonist and D3R/D4R agonist effect
Summary
Monoamine oxidase (MAO) is a flavoenzyme in the outer mitochondrial membrane of neuronal and non-neuronal cells that has a vital role in the etiology of age-regulated neurodegenerative disorders (NDs). MAO catalyzes the oxidative deamination of monoamine neurotransmitters, dietary amines, and xenobiotics and regulates their levels and functions in the brain. MAO liberates hydrogen peroxide, the reactive oxygen species (ROS) most potent in causing oxidative stress and mitochondrial dysfunction [1]. Though the etiology of NDs remains unclear, apoptosis, oxidative stress, mitochondrial dysfunction, inflammation, an impaired ubiquitin-proteasome system, and excitotoxicity are common disease-modifying factors [2]. MAO-A inhibition prevents the deamination of neurotransmitters, reduces oxidative stress, and increases the availability of neurotransmitters within noradrenergic and serotonergic neurons of the CNS to regulate neuron signaling via their respective receptors [4,7]. MAO inhibitors function as neuroprotective agents against age-related NDs
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