Dataset Information

Probing Multi-Target Action of Phlorotannins as New Monoamine Oxidase Inhibitors and Dopaminergic Receptor Modulators with the Potential for Treatment of Neuronal Disorders.

ABSTRACT: Modulation of multiple protein targets with a single compound is essential for the effective treatment of central nervous system disorders. In our previous G protein-coupled receptor (GPCR) cell-based study, a selective human monoamine oxidase (hMAO)-A inhibitor, eckol, stimulated activity of dopamine D3 and D4 receptors. This result led to our interest in marine phlorotannin-mediated modulation of hMAO enzymes and related GPCRs in neuronal disorders. Here, we evaluate the multi-target effects of phloroglucinol, phlorofucofuroeckol-A (PFF-A), and dieckol by screening their modulatory activity against hMAO-A and -B and various neuronal GPCRs. Among the tested phlorotannins, PFF-A showed the strongest inhibitory activity against both hMAO isoforms, with higher selectivity toward hMAO-B than hMAO-A. Enzyme kinetics and docking data revealed that PFF-A noncompetitively acts on hMAOs into the alternative binding pocket of enzymes with allosteric functions. In a functional assay for GPCR screening, dieckol and PFF-A exhibited a multi-target combination of D3R/D4R agonism and D1/5HT1A/NK1 antagonism. In particular, they effectively stimulated D3R and D4R, compared to other GPCRs. Docking analysis confirmed that dieckol and PFF-A successfully docked into the conserved active sites of D3R and D4R and interacted with aspartyl and serine residues in the orthosteric binding pockets of the respective receptors. Based on our experimental and computational data, we established the structure-activity relationship between tested phlorotannins and target proteins, including hMAOs and GPCRs. Our current findings suggest that hMAO inhibitors dieckol and PFF-A, major phlorotannins of edible brown algae with multi-action on GPCRs, are potential agents for treatment of psychological disorders and Parkinson's disease.

SUBMITTER: Seong SH

PROVIDER: S-EPMC6627067 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Probing Multi-Target Action of Phlorotannins as New Monoamine Oxidase Inhibitors and Dopaminergic Receptor Modulators with the Potential for Treatment of Neuronal Disorders.

Seong Su Hui SH Paudel Pradeep P Choi Jeong-Wook JW Ahn Dong Hyun DH Nam Taek-Jeong TJ Jung Hyun Ah HA Choi Jae Sue JS

Marine drugs 20190624 6

Modulation of multiple protein targets with a single compound is essential for the effective treatment of central nervous system disorders. In our previous G protein-coupled receptor (GPCR) cell-based study, a selective human monoamine oxidase (hMAO)-A inhibitor, eckol, stimulated activity of dopamine D3 and D4 receptors. This result led to our interest in marine phlorotannin-mediated modulation of hMAO enzymes and related GPCRs in neuronal disorders. Here, we ...[more]

PMID: 31238535

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Project description:See Jellinger (doi:10.1093/awx190) for a scientific commentary on this article. The enzyme monoamine oxidases (B and A subtypes, encoded by MAOB and MAOA, respectively) are drug targets in the treatment of Parkinson's disease. Inhibitors of MAOB are used clinically in Parkinson's disease for symptomatic purposes whereas the potential disease-modifying effect of monoamine oxidase inhibitors is debated. As astroglial cells express high levels of MAOB, the enzyme has been proposed as a brain imaging marker of astrogliosis, a cellular process possibly involved in Parkinson's disease pathogenesis as elevation of MAOB in astrocytes might be harmful. Since brain monoamine oxidase status in Parkinson's disease is uncertain, our objective was to measure, by quantitative immunoblotting in autopsied brain homogenates, protein levels of both monoamine oxidases in three different degenerative parkinsonian disorders: Parkinson's disease (n = 11), multiple system atrophy (n = 11), and progressive supranuclear palsy (n = 16) and in matched controls (n = 16). We hypothesized that if MAOB is 'substantially' localized to astroglial cells, MAOB levels should be generally associated with standard astroglial protein measures (e.g. glial fibrillary acidic protein). MAOB levels were increased in degenerating putamen (+83%) and substantia nigra (+10%, non-significant) in multiple system atrophy; in caudate (+26%), putamen (+27%), frontal cortex (+31%) and substantia nigra (+23%) of progressive supranuclear palsy; and in frontal cortex (+33%), but not in substantia nigra of Parkinson's disease, a region we previously reported no increase in astrocyte protein markers. Although the magnitude of MAOB increase was less than those of standard astrocytic markers, significant positive correlations were observed amongst the astrocyte proteins and MAOB. Despite suggestions that MAOA (versus MAOB) is primarily responsible for metabolism of dopamine in dopamine neurons, there was no loss of the enzyme in the parkinsonian substantia nigra; instead, increased nigral levels of a MAOA fragment and 'turnover' of the enzyme were observed in the conditions. Our findings provide support that MAOB might serve as a biochemical imaging marker, albeit not entirely specific, for astrocyte activation in human brain. The observation that MAOB protein concentration is generally increased in degenerating brain areas in multiple system atrophy (especially putamen) and in progressive supranuclear palsy, but not in the nigra in Parkinson's disease, also distinguishes astrocyte behaviour in Parkinson's disease from that in the two 'Parkinson-plus' conditions. The question remains whether suppression of either MAOB in astrocytes or MAOA in dopamine neurons might influence progression of the parkinsonian disorders.

Dataset Information

Probing Multi-Target Action of Phlorotannins as New Monoamine Oxidase Inhibitors and Dopaminergic Receptor Modulators with the Potential for Treatment of Neuronal Disorders.

Publications

Probing Multi-Target Action of Phlorotannins as New Monoamine Oxidase Inhibitors and Dopaminergic Receptor Modulators with the Potential for Treatment of Neuronal Disorders.

Similar Datasets

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