5HT1A Serotonin Receptor Agonists Inhibit<i>Plasmodium falciparum</i>by Blocking a MembraneChannel

Locher, Christopher P.; Ruben, Peter C.; Gut, Jiří; Rosenthal, Philip J.

doi:10.1128/aac.47.12.3806-3809.2003

Cited by 13 publications

(8 citation statements)

References 38 publications

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“…Apicidin is a potent inhibitor of histone deacetylase [HDA; of which the P. falciparum ortholog PfHDA2 exists (Coleman et al, 2014 )] and this mechanism of inhibition is responsible for the antiprotozoal properties of the drug (Darkin-Rattray et al, 1996 ; Engel et al, 2015 ). Dihydroergotamine is a known inhibitor of P. falciparum (Weisman et al, 2006 ), which may target a serotonin 5-HT1a-like receptor in the parasite thought to be a nutrient channel critical for parasite development (Hanoun et al, 2003 ; Locher et al, 2003 ). Ergotamine, the structural analog of dihydroergotamine was one compound involved in a docking study looking for competitive inhibitors for the enzyme P. falciparum lactate dehydrogenase ( Pf LDH), upon which the parasite is dependent for energy production where it achieved a reasonably good docking score (Penna-Coutinho et al, 2011 ).…”

Section: Resultsmentioning

confidence: 99%

Using Machine Learning to Predict Synergistic Antimalarial Compound Combinations With Novel Structures

et al. 2018

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The parasite Plasmodium falciparum is the most lethal species of Plasmodium to cause serious malaria infection in humans, and with resistance developing rapidly novel treatment modalities are currently being sought, one of which being combinations of existing compounds. The discovery of combinations of antimalarial drugs that act synergistically with one another is hence of great importance; however an exhaustive experimental screen of large drug space in a pairwise manner is not an option. In this study we apply our machine learning approach, Combination Synergy Estimation (CoSynE), which can predict novel synergistic drug interactions using only prior experimental combination screening data and knowledge of compound molecular structures, to a dataset of 1,540 antimalarial drug combinations in which 22.2% were synergistic. Cross validation of our model showed that synergistic CoSynE predictions are enriched 2.74 × compared to random selection when both compounds in a predicted combination are known from other combinations among the training data, 2.36 × when only one compound is known from the training data, and 1.5 × for entirely novel combinations. We prospectively validated our model by making predictions for 185 combinations of 23 entirely novel compounds. CoSynE predicted 20 combinations to be synergistic, which was experimentally validated for nine of them (45%), corresponding to an enrichment of 1.70 × compared to random selection from this prospective data set. Such enrichment corresponds to a 41% reduction in experimental effort. Interestingly, we found that pairwise screening of the compounds CoSynE individually predicted to be synergistic would result in an enrichment of 1.36 × compared to random selection, indicating that synergy among compound combinations is not a random event. The nine novel and correctly predicted synergistic compound combinations mainly (where sufficient bioactivity information is available) consist of efflux or transporter inhibitors (such as hydroxyzine), combined with compounds exhibiting antimalarial activity alone (such as sorafenib, apicidin, or dihydroergotamine). However, not all compound synergies could be rationalized easily in this way. Overall, this study highlights the potential for predictive modeling to expedite the discovery of novel drug combinations in fight against antimalarial resistance, while the underlying approach is also generally applicable.

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Section: Resultsmentioning

confidence: 99%

Using Machine Learning to Predict Synergistic Antimalarial Compound Combinations With Novel Structures

et al. 2018

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“…Serotonin results in increased vascular permeability and smooth muscle contraction and has been shown to activate dendritic cells (DCs). It might also influence the IE directly; serotonin receptor agonists and tryptophan catabolites are known to modulate the parasite life cycle and inhibit parasite growth in culture [17,18]. (3) Recent analysis of the secreted platelet proteome have detected numerous chemokines including CXCL4, CXCL7 and regulated upon activation normal T-cell expressed and secreted (RANTES, or CCL5) that have important roles in the phased arrival of leukocytes and natural killer (NK) cells and granulocytes (eosinophils, or Eos), polymorphonuclear neutrophils (PMNs) and mast cells (Mast) [15].…”

Section: Discussionmentioning

confidence: 99%

“…Another possibility is that platelets clumped around an infected erythrocyte might starve the parasite of key metabolites by blocking nutrient uptake through parasite or host transporter proteins located within the erythrocyte plasma membrane (Figure 1). Given that serotonin is found in platelet dense granules, the observation that serotonin receptor agonists and other products of tryptophan catabolism inhibit P. falciparum by blocking membrane channels [17] and modulating the parasite cell cycle [18] is very exciting. It will now be important to throw some of these platelet mediators directly into parasite cultures to determine what effect they have on inducing apoptosis in the authors' TUNEL assays.…”

Section: To Die Upon a Platelet's Kissmentioning

confidence: 99%

Platelet power: sticky problems for sticky parasites?

Pleass

2009

Trends in Parasitology

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Platelets might have a crucial role in the pathogenesis of both human and rodent malarias by assisting in the sequestration of infected erythrocytes within the cerebral vasculature. However, recent elegant work by McMorran et al. suggests that they are also involved in innate protection during the early stages of infection. Here, we discuss the implications of their important findings in the context of immunity to malaria. Platelet: friend or foe?The platelet, traditionally known for its role in blood clotting, is also known for its putative involvement in malaria pathology [1,2]. However, a recent study using C57BL6 mice genetically deficient in the megakaryocyte growth and differentiation factor C-mpl (encoded by the Mpl gene), and resulting in mice with 90% fewer platelets, showed that these animals were significantly more susceptible to death when infected with Plasmodium chabaudi [3]. Furthermore, the authors went on to show that purified human platelets killed Plasmodium falciparum parasites within red blood cells when added to in vitro cultures and that various platelet antagonists, including aspirin, reversed this antiparasitic activity both in vitro and in vivo. This result raises concerns over the use of aspirin as an antipyretic in patients with malaria. Using specific receptor antagonists, the authors demonstrated that killing and control of parasite growth in P. falciparum cultures was dependent on platelet activation via P2Y1, an ADP-dependent metabotrophic puronergic receptor (Figure 1).These results in animals seem counterintuitive, in that platelets are believed to be involved in pathological disease states that hasten death, such as cerebral malaria [1,2]. For example, mice with significantly compromised platelet function (CXCL4 or CXCR3 deficient) have been shown to survive longer than their wild-type counterparts [4]. By contrast, platelet depletion by anti-CD41 monoclonal antibody injection early, but not late, in the course of disease is known to protect C57BL6 mice from Plasmodium berghei ANKA-induced severe experimental cerebral malaria (ECM) by altering levels of pathogenic cytokines [5]. Unfortunately, the study by McMorran et al. used P. chabaudi, a rodent malaria thatalthough capable of sequestering to a number of organs -is not known to develop ECM. It should also be noted that non-sequestering Plasmodium species also give rise to ECM in some inbred mouse strains, Plasmodium yoelii 17XL in BALB/c mice being a good example Europe PMC Funders Group A cornucopia of receptorsThe first of these questions is easier to explain for P. falciparum than for Plasmodium vivax or the murine malarias. Platelet-mediated clumping is common in P. falciparum field isolates, is distinctive from other adhesive phenotypes and involves the host receptors CD36[7] and gC1qR/HABP1/p32 [8]. Whether these are the only platelet receptors involved is debatable and worth exploring. Although GPIIb/IIIa (CD41/CD61) and GPIb/IX (CD42a/ CD42b)-deficient platelets still clump to infected erythrocytes [7], the...

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“…[ 31 ] Serotonergic system activation is involved in hyperpyretic states as demonstrated by hyperthermia during episodes of serotonergic syndrome,[ 32 ] and by the temperature lowering effect of 5HT1A agonist on patients infected by Plasmodium falciparum . [ 33 ] It has been speculated that migraine attacks are caused by dysregulation of brain temperature, possibly as a defense mechanism. [ 34 ]…”

Section: Discussionmentioning

confidence: 99%

Headache in the presentation of noncephalic acute illness

Tzadok

Toledano

Fuchs

et al. 2015

Journal of Neurosciences in Rural Practice

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Background:Headache is a frequent symptom of many systemic diseases that do not involve cranial structures. In this observational study, we assessed factors associated with headache in the acute presentation of systemic conditions in a nonsurgical emergency department (ED).Methods:Consecutive patients, admitted to Soroka University Medical Center ED due to noncephalic illness, were prospectively surveyed using a structured questionnaire focused on the prevalence and characteristics of headache symptoms. Medical data were extracted from the patient's charts.Results:Between 1 and 6/2012, 194 patients aged 64.69 ± 19.52 years, were evaluated. Headache was reported by 83 (42.7%) patients and was more common among patients with febrile illness (77.5% vs. 22.5%, P < 0.001). Respiratory illness and level of O2 saturation were not associated with headache. Headache in the presentation of a noncephalic illness was associated with younger age (58 vs. 69, P < 0.001) and with suffering from a primary headache disorder (48.2% vs. 10.8%, P < 0.001). Headache was also associated with higher body temperature and lower platelets count.Conclusions:Headache is a common symptom in acute noncephalic conditions and was found to be associated with younger age and febrile disease on presentation. Patients who present with primary headache disorders are more prone to have headache during acute illness. Acute obstructive respiratory disease, hypercarbia or hypoxemia were not associated with headache.

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5HT1A Serotonin Receptor Agonists InhibitPlasmodium falciparumby Blocking a MembraneChannel

Cited by 13 publications

References 38 publications

Using Machine Learning to Predict Synergistic Antimalarial Compound Combinations With Novel Structures

Using Machine Learning to Predict Synergistic Antimalarial Compound Combinations With Novel Structures

Platelet power: sticky problems for sticky parasites?

Headache in the presentation of noncephalic acute illness

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