Dataset Information

The antimalarial drug quinine interferes with serotonin biosynthesis and action.

ABSTRACT: The major antimalarial drug quinine perturbs uptake of the essential amino acid tryptophan, and patients with low plasma tryptophan are predisposed to adverse quinine reactions; symptoms of which are similar to indications of tryptophan depletion. As tryptophan is a precursor of the neurotransmitter serotonin (5-HT), here we test the hypothesis that quinine disrupts serotonin function. Quinine inhibited serotonin-induced proliferation of yeast as well as human (SHSY5Y) cells. One possible cause of this effect is through inhibition of 5-HT receptor activation by quinine, as we observed here. Furthermore, cells exhibited marked decreases in serotonin production during incubation with quinine. By assaying activity and kinetics of the rate-limiting enzyme for serotonin biosynthesis, tryptophan hydroxylase (TPH2), we showed that quinine competitively inhibits TPH2 in the presence of the substrate tryptophan. The study shows that quinine disrupts both serotonin biosynthesis and function, giving important new insight to the action of quinine on mammalian cells.

SUBMITTER: Islahudin F

PROVIDER: S-EPMC3885885 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

The antimalarial drug quinine interferes with serotonin biosynthesis and action.

Islahudin Farida F Tindall Sarah M SM Mellor Ian R IR Swift Karen K Christensen Hans E M HE Fone Kevin C F KC Pleass Richard J RJ Ting Kang-Nee KN Avery Simon V SV

Scientific reports 20140109

The major antimalarial drug quinine perturbs uptake of the essential amino acid tryptophan, and patients with low plasma tryptophan are predisposed to adverse quinine reactions; symptoms of which are similar to indications of tryptophan depletion. As tryptophan is a precursor of the neurotransmitter serotonin (5-HT), here we test the hypothesis that quinine disrupts serotonin function. Quinine inhibited serotonin-induced proliferation of yeast as well as human (SHSY5Y) cells. One possible cause ...[more]

PMID: 24402577

Similar Datasets

Project description:BackgroundDespite the strides made in recent decades, the resistance observed in existing antimalarial drugs, and the intricate life cycle of the Plasmodium parasite underscore the pressing need to develop novel and effective therapeutic interventions. This article provides a comprehensive evaluation of the outcomes stemming from screening a library comprising 48 compounds (TCAMS) against Plasmodium falciparum.MethodsThis study focused on characterizing the IC50 values of compounds from the Tres Cantos Antimalarial Set (TCAMS) library via a double-labelling method of P. falciparum parasites with SYBR Green-I and MitoTracker Deep Red, which were evaluated via flow cytometry. Evaluation of the cytotoxicity of the best candidates in human embryonic kidney (HEK293) cells, chemoinformatic analysis, and exploration of the effects of the compounds on the action of serotonin and melatonin in the erythrocytic life cycle of the parasite.ResultsIC50 characterization confirmed that 93.75% of the compounds tested exhibited antimalarial activity at concentrations below 2 micromolar (µM), with 5 compounds showing IC50 values below 50 nM (nM) (15.21 ± 5.97 nM to 45.82 ± 5.11 nM). Furthermore, 12 compounds presented IC50 values between 50 and 100 nM (57.43 ± 12.25 nM to 100.6 ± 22.89 nM), highlighting their potent in vitro efficacy against P. falciparum. Cytotoxicity evaluation in HEK293 cells revealed that 12 from 17 compounds did not significantly reduce cell viability. Cheminformatics analysis clustered the compounds based on structural and physicochemical similarities, revealing distinct structural patterns. Exploration of hypothetical targets from the TCAMS library identified 27 compounds with potential targets, 15 specifically targeted serotonergic receptors. Subsequent serotonin and melatonin treatment experiments indicated that certain compounds could inhibit both effects on parasitaemia, suggesting a complex interaction with signaling in P. falciparum.ConclusionsThis study identifies promising antimalarial candidates with low IC50 values and highlights the significance of targeting serotonin receptors in the development of potential antimalarial drugs.

Dataset Information

The antimalarial drug quinine interferes with serotonin biosynthesis and action.

Publications

The antimalarial drug quinine interferes with serotonin biosynthesis and action.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets