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Title: | Inhibition of tryptophan hydroxylases and monoamino oxidase-A by the proton pump inhibitor, omeprazole - in vitro and in vivo investigations |
Author: | Betari, Nibal Sahlholm, Kristoffer Morató Arús, Xavier Godoy-Marín, Héctor Jáuregui Pallarés, Olga Teigen, Knut Ciruela Alférez, Francisco Haavik, Jan |
Keywords: | Enzims al·lostèrics Serotonina Anàlisi Enzimoimmunoassaig sobre fase sòlida Allosteric enzymes Serotonin Assaying Enzyme-linked immunosorbent assay |
Issue Date: | 26-Nov-2020 |
Publisher: | Frontiers Media |
Abstract: | Serotonin (5-HT) is a hormone and neurotransmitter that modulates neural activity as well as a wide range of other physiological processes including cardiovascular function, bowel motility, and platelet aggregation. 5-HT synthesis is catalyzed by tryptophan hydroxylase (TPH) which exists as two distinct isoforms; TPH1 and TPH2, which are responsible for peripheral and central 5-HT, respectively. Due to the implication of 5-HT in a number of pathologies, including depression, anxiety, autism, sexual dysfunction, irritable bowel syndrome, inflammatory bowel disease, and carcinoid syndrome, there has been a growing interest in finding modulators of these enzymes in recent years. We thus performed high-throughput screening (HTS) using a fluorescence-based thermal shift assay (DSF) to search the Prestwick Chemical Library containing 1,280 compounds, mostly FDA-approved drugs, for TPH1 binders. We here report the identification of omeprazole, a proton pump inhibitor, as an inhibitor of TPH1 and TPH2 with low micromolar potency and high selectivity over the other aromatic amino acid hydroxylases. The S-enantiomer of omeprazole, esomeprazole, has recently also been described as an inhibitor of monoamine oxidase-A (MAO-A), the main enzyme responsible for 5-HT degradation, albeit with lower potency compared to the effect on TPH1 and TPH2. In order to investigate the net effect of simultaneous inhibition of TPH and MAO-A in vivo, we administered high-dose (100 mg/kg) omeprazole to CD-1 mice for 4 days, after which the animals were subjected to the tail suspension test. Finally, central (whole brain) and peripheral (serum) 5-HT content was measured using liquid chromatography-mass spectrometry (LC-MS). Omeprazole treatment significantly increased 5-HT concentrations, both in brain and in serum, and reduced the time spent immobile in the tail suspension test relative to vehicle control. Thus, the MAO-A inhibition afforded by high-dose omeprazole appears to overcome the opposing effect on 5-HT produced by inhibition of TPH1 and TPH2. Further modification of proton pump inhibitor scaffolds may yield more selective modulators of 5-HT metabolism. |
Note: | Reproducció del document publicat a: https://doi.org/10.3389/fphar.2020.593416 |
It is part of: | Frontiers in Pharmacology, 2020, vol. 11, p. 593416 |
URI: | http://hdl.handle.net/2445/173564 |
Related resource: | https://doi.org/10.3389/fphar.2020.593416 |
ISSN: | 1663-9812 |
Appears in Collections: | Articles publicats en revistes (Patologia i Terapèutica Experimental) Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL)) |
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