Two novel, putative mechanisms of action for citalopram-induced platelet inhibition

Roweth, Harvey G.; Cook, Aaron A.; Moroi, Masaaki; Bonna, Arkadiusz; Jung, Stéphanie; Bergmeier, Wolfgang; Sage, Stewart O.; Jarvis, Gavin E.

doi:10.1038/s41598-018-34389-5

Cited by 14 publications

(9 citation statements)

References 52 publications

(67 reference statements)

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“…The collapse of the U46619 response at 200 µM is also consistent with this hypothesis. Preliminary data that support these hypotheses have recently been presented 48 .…”

Section: Discussionmentioning

confidence: 88%

Citalopram inhibits platelet function independently of SERT-mediated 5-HT transport

Roweth

Yan

Bedwani

et al. 2018

Sci Rep

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Citalopram prevents serotonin (5-HT) uptake into platelets by blocking the serotonin reuptake transporter (SERT). Although some clinical data suggest that selective serotonin reuptake inhibitors (SSRIs) may affect haemostasis and thrombosis, these poorly-characterised effects are not well understood mechanistically and useful in vitro data is limited. We sought to determine whether the inhibitory effects of citalopram on platelets are mediated via its pharmacological inhibition of 5-HT transport. We quantified the inhibitory potency of (RS)-, (R)- and (S)-citalopram on platelet function. If SERT blockade is the primary mechanism for citalopram-mediated platelet inhibition, these potencies should show quantitative congruence with inhibition of 5-HT uptake. Our data show that citalopram inhibits platelet aggregation, adhesion and thromboxane production with no difference in potency between (R)- and (S)-isomers. By contrast, citalopram had a eudysmic ratio of approximately 17 (S > R) for SERT blockade. Furthermore, nanomolar concentrations of citalopram inhibited 5-HT uptake into platelets but had no effect on other platelet functions, which were inhibited by micromolar concentrations. Our data indicate that citalopram-induced inhibition of platelets in vitro is not mediated by blockade of 5-HT transport. This raises a new question for future investigation: by what mechanism(s) does citalopram inhibit platelets?

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“…The collapse of the U46619 response at 200 µM is also consistent with this hypothesis. Preliminary data that support these hypotheses have recently been presented 48 .…”

Section: Discussionmentioning

confidence: 88%

Citalopram inhibits platelet function independently of SERT-mediated 5-HT transport

Roweth

Yan

Bedwani

et al. 2018

Sci Rep

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“…Together, these data suggest that R5421 may inhibit αIIbβ 3 activation by acting distal to receptor signalling, perhaps on Rap1b activation, though the precise target remains to be identified. Interestingly, CalDAG‐GEFI has been recently identified as a target of the antidepressant, citalopram (Roweth et al, 2018), indicating that it is possible for this protein to be inhibited by small molecules. Another possible target of R5421, a carbamate, is arylacetamide deacetylase‐like 1 (AADACL1), a lipid deacetylase that regulates Rap1b activity in platelets.…”

Section: Discussionmentioning

confidence: 99%

Ethaninidothioic acid (R5421) is not a selective inhibitor of platelet phospholipid scramblase activity

Millington‐Burgess

Bonna²,

Rahman

et al. 2020

British J Pharmacology

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Background and Purpose Ethaninidothioic acid (R5421) has been used as a scramblase inhibitor to determine the role of phospholipid scrambling across a range of systems including platelet procoagulant activity. The selectivity of R5421 has not been thoroughly studied. Here, we characterised the effects of R5421 on platelet function and its suitability for use as a scramblase inhibitor. Experimental Approach Human platelet activation was measured following pretreatment with R5421 and stimulation with a range of agonists. Phosphatidylserine exposure was measured using annexin V binding. Integrin αIIbβ3 activation and α‐granule release were measured by flow cytometry. Cytosolic Ca2+ signals were measured using Cal520 fluorescence. An in silico ligand‐based screen identified 16 compounds which were tested in these assays. Key Results R5421 inhibited A23187‐induced phosphatidylserine exposure in a time‐ and temperature‐dependent manner. R5421 inhibited Ca2+ signalling from the PAR1, PAR4 and glycoprotein VI receptors as well as platelet αIIbβ3 integrin activation and α‐granule release. R5421 is therefore not a selective inhibitor of platelet scramblase activity. An in silico screen identified the pesticide thiodicarb as similar to R5421. It also inhibited platelet phosphatidylserine exposure, Ca2+ signalling from the PAR1 and glycoprotein VI, αIIbβ3 activation and α‐granule release. Thiodicarb additionally disrupted Ca2+ homeostasis in unstimulated platelets. Conclusion and Implications R5421 is not a selective inhibitor of platelet scramblase activity. We have identified the pesticide thiodicarb, which had similar effects on platelet function to R5421 as well as additional disruption of Ca2+ signalling which may underlie some of thiodicarb's toxicity.

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“…It is likely not a consequence of its canonic function as an SSRI. However, citalopram has additional targets and inhibits platelet activation independent of SERT, possibly via inhibition of Rap1 activation (Roweth et al ). Interestingly, it has been reported that Rap1 deletion increases exocytosis in mouse cortical neurons, possibly by regulating calcium channel expression (Subramanian et al ).…”

Section: Discussionmentioning

confidence: 99%

Drug testing complementary metal‐oxide‐semiconductor chip reveals drug modulation of transmitter release for potential therapeutic applications

Huang

Rathore

Lindau

2019

Journal of Neurochemistry

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Neurodegenerative diseases, such as Parkinson’s disease, Alzheimer’s disease, and Huntington’s disease, are considered incurable and significantly reduce the quality of life of the patients. A variety of drugs that modulate neurotransmitter levels have been used for the treatment of the neurodegenerative diseases but with limited efficacy. In this work, an amperometric complementary metal‐oxide‐semiconductor (CMOS) chip is used for high‐throughput drug testing with respect to the modulation of transmitter release from single vesicles using chromaffin cells prepared from bovine adrenal glands as a model system. Single chromaffin cell amperometry was performed with high efficiency on the surface‐modified CMOS chip and follow‐up whole‐cell patch‐clamp experiments were performed to determine the readily releasable pool sizes. We show that the antidepressant drug bupropion significantly increases the amount of neurotransmitter released in individual quantal release events. The antidepressant drug citalopram accelerates rapid neurotransmitter release following stimulation and follow‐up patch‐clamp experiments reveal that this is because of the increase in the pool of readily releasable vesicles. These results shed light on the mechanisms by which bupropion and citalopram may be potentially effective in the treatment of neurodegenerative diseases. These results demonstrate that the CMOS amperometry chip technology is an excellent tool for drug testing to determine the specific mechanisms by which they modulate neurotransmitter release.

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Two novel, putative mechanisms of action for citalopram-induced platelet inhibition

Cited by 14 publications

References 52 publications

Citalopram inhibits platelet function independently of SERT-mediated 5-HT transport

Citalopram inhibits platelet function independently of SERT-mediated 5-HT transport

Ethaninidothioic acid (R5421) is not a selective inhibitor of platelet phospholipid scramblase activity

Drug testing complementary metal‐oxide‐semiconductor chip reveals drug modulation of transmitter release for potential therapeutic applications

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