The antimalarial drug quinine interferes with serotonin biosynthesis and action

Islahudin, Farida; Tindall, Sarah M.; Mellor, Ian R.; Swift, K M; Christensen, Hans Erik Mølager; Fone, Kevin C. F.; Pleass, Richard J.; Ting, Kang Nee; Avery, Simon V.

doi:10.1038/srep03618

Cited by 18 publications

(12 citation statements)

References 38 publications

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“…In contrast, endogenous serotonin metabolism appeared able to proceed, as evidenced by the detection of 5-HIAA in the cell culture medium. This suggests that serotonin precursors are available under basal conditions and is consistent with the reported ability of these cells to synthesise serotonin (Islahudin et al, 2014). In order to model the partial complex I deficiency reported in PD, cells were pre-treated with the established complex I inhibitor, rotenone.…”

Section: Discussionsupporting

confidence: 66%

Inhibition of neuronal mitochondrial complex I or lysosomal glucocerebrosidase is associated with increased dopamine and serotonin turnover

Fuente¹,

Burke

Eaton³

et al. 2017

Neurochemistry International

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Parkinson's disease (PD) is a neurodegenerative disorder caused by loss of dopaminergic and serotoninergic signalling. A number of pathogenic mechanisms have been implicated including loss of mitochondrial function at the level of complex I, and lysosomal metabolism at the level of lysosomal glucocerebrosidase (GBA1). In order to investigate further the potential involvement of complex I and GBA1 in PD, we assessed the impact of loss of respective enzyme activities upon dopamine and serotonin turnover. Using SH-SY5Y cells, complex I deficiency was modelled by using rotenone whilst GBA1 deficiency was modelled by the use of conduritol B epoxide (CBE). Dopamine, its principal metabolites, and the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the extracellular medium were quantified by HPLC. Inhibition of complex I significantly increased extracellular concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC) and 5-HIAA. Comparable results were observed with CBE. These results suggest increased monoamine oxidase activity and provide evidence for involvement of impaired complex I or GBA1 activity in the dopamine/serotonin deficiency seen in PD. Use of extracellular media may also permit relatively rapid assessment of dopamine/serotonin metabolism and permit screening of novel therapeutic agents.

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Section: Discussionsupporting

confidence: 66%

Inhibition of neuronal mitochondrial complex I or lysosomal glucocerebrosidase is associated with increased dopamine and serotonin turnover

Fuente¹,

Burke

Eaton³

et al. 2017

Neurochemistry International

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“…With strong conservation of function between yeast and Plasmodium spp., yeast has been widely used for heterologous expression of functional Plasmodium sp. proteins ( 11 – 14 ) and for studies elucidating antimalarial drug modes of action ( 15 – 19 ) or resistance ( 20 – 22 ). Findings from such yeast studies have been successfully extrapolated to malaria patients ( 23 ).…”

Section: Introductionmentioning

confidence: 99%

The Candidate Antimalarial Drug MMV665909 Causes Oxygen-Dependent mRNA Mistranslation and Synergizes with Quinoline-Derived Antimalarials

Vallières

Avery

2017

Antimicrob Agents Chemother

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To cope with growing resistance to current antimalarials, new drugs with novel modes of action are urgently needed. Molecules targeting protein synthesis appear to be promising candidates. We identified a compound (MMV665909) from the Medicines for Malaria Venture (MMV) Malaria Box of candidate antimalarials that could produce synergistic growth inhibition with the aminoglycoside antibiotic paromomycin, suggesting a possible action of the compound in mRNA mistranslation. This mechanism of action was substantiated with a Saccharomyces cerevisiae model using available reporters of mistranslation and other genetic tools. Mistranslation induced by MMV665909 was oxygen dependent, suggesting a role for reactive oxygen species (ROS). Overexpression of Rli1 (a ROS-sensitive, conserved FeS protein essential in mRNA translation) rescued inhibition by MMV665909, consistent with the drug's action on translation fidelity being mediated through Rli1. The MMV drug also synergized with major quinoline-derived antimalarials which can perturb amino acid availability or promote ROS stress: chloroquine, amodiaquine, and primaquine. The data collectively suggest translation fidelity as a novel target of antimalarial action and support MMV665909 as a promising drug candidate.

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“…Such strong synergies are not very common, but their detection is facilitated by screening approaches (chemical or biological) and/or the use of a good model system. The yeast Saccharomyces cerevisiae is widely adopted as a eukaryotic cell model of choice and has been applied to characterize the actions of antifungal drugs 10 11 as well as a diverse range of other therapeutic compounds 12 13 14 15 .…”

mentioning

confidence: 99%

Novel, Synergistic Antifungal Combinations that Target Translation Fidelity

Moreno-Martinez

Vallières

Holland

et al. 2015

Sci Rep

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There is an unmet need for new antifungal or fungicide treatments, as resistance to existing treatments grows. Combination treatments help to combat resistance. Here we develop a novel, effective target for combination antifungal therapy. Different aminoglycoside antibiotics combined with different sulphate-transport inhibitors produced strong, synergistic growth-inhibition of several fungi. Combinations decreased the respective MICs by ≥8-fold. Synergy was suppressed in yeast mutants resistant to effects of sulphate-mimetics (like chromate or molybdate) on sulphate transport. By different mechanisms, aminoglycosides and inhibition of sulphate transport cause errors in mRNA translation. The mistranslation rate was stimulated up to 10-fold when the agents were used in combination, consistent with this being the mode of synergistic action. A range of undesirable fungi were susceptible to synergistic inhibition by the combinations, including the human pathogens Candida albicans, C. glabrata and Cryptococcus neoformans, the food spoilage organism Zygosaccharomyces bailii and the phytopathogens Rhizoctonia solani and Zymoseptoria tritici. There was some specificity as certain fungi were unaffected. There was no synergy against bacterial or mammalian cells. The results indicate that translation fidelity is a promising new target for combinatorial treatment of undesirable fungi, the combinations requiring substantially decreased doses of active components compared to each agent alone.

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The antimalarial drug quinine interferes with serotonin biosynthesis and action

Cited by 18 publications

References 38 publications

Inhibition of neuronal mitochondrial complex I or lysosomal glucocerebrosidase is associated with increased dopamine and serotonin turnover

Inhibition of neuronal mitochondrial complex I or lysosomal glucocerebrosidase is associated with increased dopamine and serotonin turnover

The Candidate Antimalarial Drug MMV665909 Causes Oxygen-Dependent mRNA Mistranslation and Synergizes with Quinoline-Derived Antimalarials

Novel, Synergistic Antifungal Combinations that Target Translation Fidelity

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