Analogues of Marine Guanidine Alkaloids Are in Vitro Effective against Trypanosoma cruzi and Selectively Eliminate Leishmania (L.) infantum Intracellular Amastigotes

Synthetic analogues of marine sponge guanidine alkaloids showed in vitro antiparasitic activity against Leishmania (L.) infantum and Trypanosoma cruzi. Guanidines 10 and 11 presented the highest selectivity index when tested against Leishmania. The antiparasitic activity of 10 and 11 was investigated in host cells and in parasites. Both compounds induced depolarization of mitochondrial membrane potential, upregulation of reactive oxygen species levels, and increased plasma membrane permeability in Leishmania parasites. Immunomodulatory assays suggested an NO-independent effect of guanidines 10 and 11 on macrophages. The same compounds also promoted anti-inflammatory activity in L. (L.) infantum-infected macrophages cocultived with splenocytes, reducing the production of cytokines MCP-1 and IFN-γ. Guanidines 10 and 11 affect the bioenergetic metabolism of Leishmania, with selective elimination of parasites via a host-independent mechanism

Cyclobenzaprine Raises ROS Levels in Leishmania infantum and Reduces Parasite Burden in Infected Mice

Submitted by Sandra Infurna ([email protected]) on 2017-05-04T11:55:40Z No. of bitstreams: 1 edesio_cunhajr_etal_IOC_2017.pdf: 1518221 bytes, checksum: 6be150919adf4e381a7886f6406acc7b (MD5)Approved for entry into archive by Sandra Infurna ([email protected]) on 2017-05-04T12:14:58Z (GMT) No. of bitstreams: 1 edesio_cunhajr_etal_IOC_2017.pdf: 1518221 bytes, checksum: 6be150919adf4e381a7886f6406acc7b (MD5)Made available in DSpace on 2017-05-04T12:14:58Z (GMT). No. of bitstreams: 1 edesio_cunhajr_etal_IOC_2017.pdf: 1518221 bytes, checksum: 6be150919adf4e381a7886f6406acc7b (MD5) Previous issue date: 2017Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Bioquímica de Tripanosomatídeos. Rio de Janeiro, RJ. Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Bioquímica de Tripanosomatídeos. Rio de Janeiro, RJ. Brasil.Universidade de São Paulo. Instituto de Medicina Tropical. São Paulo, SP, Brasil / Instituto Adolfo Lutz. Centro de Parasitologia e Micologia. São Paulo, SP, Brasil.Instituto Adolfo Lutz. Centro de Parasitologia e Micologia. São Paulo, SP, Brasil.Universidade de São Paulo. Instituto de Medicina Tropical. São Paulo, SP, Brasil.Centro de Investigaciones BioloÂgicas (CSIC). Unidad Asociada Interacciones, Metabolismo y Bioanálisis CSIC-CEU. Madrid, Spain.Universidad CEU San Pablo. Faculty of Pharmacy. Center for Metabolomics and Bioanalysis (CEMBIO. Madrid, Spain.Centro de Investigaciones BioloÂgicas (CSIC). Unidad Asociada Interacciones, Metabolismo y Bioanálisis CSIC-CEU. Madrid, Spain.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Bioquímica de Tripanosomatídeos. Rio de Janeiro, RJ. Brasil.Instituto Adolfo Lutz. Centro de Parasitologia e Micologia. São Paulo, SP, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Bioquímica de Tripanosomatídeos. Rio de Janeiro, RJ. Brasil.The leishmanicidal action of tricyclic antidepressants has been studied and evidences have pointed that their action is linked to inhibition of trypanothione reductase, a key enzyme in the redox metabolism of pathogenic trypanosomes. Cyclobenzaprine (CBP) is a tricyclic structurally related to the antidepressant amitriptyline, differing only by the presence of a double bond in the central ring. This paper describes the effect of CBP in experimental visceral leishmaniasis, its inhibitory effect in trypanothione reductase and the potential immunomodulatory activity

<i>In vitro</i> activity of CBP.

<p>(A) Promastigotes of <i>L</i>. <i>infantum</i> were incubated with CBP for 72 h. The growth inhibition was measured using resazurin. (n = 3) (B) Peritoneal macrophages were infected with <i>L</i>. <i>infantum</i> and treated with CBP for 72 h. The slides were stained and the results were expressed as an infection index^# [II = % infected cells × (number of amastigotes/total number of macrophages)]. The inset shows representative photos from the slides. (n = 3).</p

Effect of CBP on TryR and ROS production.

<p>(a) <i>TryR assay</i>. Soluble extract of promastigotes of <i>L</i>. <i>infantum</i> using oxidized trypanothione as substrate and clomipramine (50 μM) as positive control (PC) of inhibition. Reading was initiated after adding 100 μM of DTNB at 410nm (n = 3). (b) <i>ROS production</i>. Promastigotes of <i>L</i>. <i>infantum</i> were incubated with CBP and ROS generation was measured with H₂DCFDA reagent. Antimycin A 10 μM was used as positive control (PC). (n = 3) *p<0.05, ** p<0.01 and ***p<0.001.</p

Increase of Nitric Oxide levels in macrophages treated with CBP.

<p>The production of nitric oxide (NO) by macrophages was measured after 24 h incubation with cyclobenzaprine (12 μM). The nitric oxide content was colorimetrically determined by the Griess reaction in the culture supernatants. Lipopolysaccharide (LPS) was used as positive control (1 μg/mL) (C). (n = 3) *p<0.05.</p

Analogues of Marine Guanidine Alkaloids Are in Vitro Effective against Trypanosoma cruzi and Selectively Eliminate Leishmania (L.) infantum Intracellular Amastigotes.

Synthetic analogues of marine sponge guanidine alkaloids showed in vitro antiparasitic activity against Leishmania (L.) infantum and Trypanosoma cruzi. Guanidines 10 and 11 presented the highest selectivity index when tested against Leishmania. The antiparasitic activity of 10 and 11 was investigated in host cells and in parasites. Both compounds induced depolarization of mitochondrial membrane potential, upregulation of reactive oxygen species levels, and increased plasma membrane permeability in Leishmania parasites. Immunomodulatory assays suggested an NO-independent effect of guanidines 10 and 11 on macrophages. The same compounds also promoted anti-inflammatory activity in L. (L.) infantum-infected macrophages cocultived with splenocytes, reducing the production of cytokines MCP-1 and IFN-γ. Guanidines 10 and 11 affect the bioenergetic metabolism of Leishmania, with selective elimination of parasites via a host-independent mechanism

Analogues of Marine Guanidine Alkaloids Are <i>in</i> <i>Vitro</i> Effective against <i>Trypanosoma cruzi</i> and Selectively Eliminate <i>Leishmania</i> (<i>L</i>.) <i>infantum</i> Intracellular Amastigotes

Synthetic analogues of marine sponge guanidine alkaloids showed <i>in vitro</i> antiparasitic activity against <i>Leishmania</i> (<i>L.</i>) <i>infantum</i> and <i>Trypanosoma cruzi.</i> Guanidines <b>10</b> and <b>11</b> presented the highest selectivity index when tested against <i>Leishmania</i>. The antiparasitic activity of <b>10</b> and <b>11</b> was investigated in host cells and in parasites. Both compounds induced depolarization of mitochondrial membrane potential, upregulation of reactive oxygen species levels, and increased plasma membrane permeability in <i>Leishmania</i> parasites. Immunomodulatory assays suggested an NO-independent effect of guanidines <b>10</b> and <b>11</b> on macrophages. The same compounds also promoted anti-inflammatory activity in <i>L.</i> (<i>L.</i>) <i>infantum</i>-infected macrophages cocultived with splenocytes, reducing the production of cytokines MCP-1 and IFN-γ. Guanidines <b>10</b> and <b>11</b> affect the bioenergetic metabolism of <i>Leishmania</i>, with selective elimination of parasites via a host-independent mechanism

NEOTROPICAL XENARTHRANS: a data set of occurrence of xenarthran species in the Neotropics

Xenarthrans—anteaters, sloths, and armadillos—have essential functions for ecosystem maintenance, such as insect control and nutrient cycling, playing key roles as ecosystem engineers. Because of habitat loss and fragmentation, hunting pressure, and conflicts with domestic dogs, these species have been threatened locally, regionally, or even across their full distribution ranges. The Neotropics harbor 21 species of armadillos, 10 anteaters, and 6 sloths. Our data set includes the families Chlamyphoridae (13), Dasypodidae (7), Myrmecophagidae (3), Bradypodidae (4), and Megalonychidae (2). We have no occurrence data on Dasypus pilosus (Dasypodidae). Regarding Cyclopedidae, until recently, only one species was recognized, but new genetic studies have revealed that the group is represented by seven species. In this data paper, we compiled a total of 42,528 records of 31 species, represented by occurrence and quantitative data, totaling 24,847 unique georeferenced records. The geographic range is from the southern United States, Mexico, and Caribbean countries at the northern portion of the Neotropics, to the austral distribution in Argentina, Paraguay, Chile, and Uruguay. Regarding anteaters, Myrmecophaga tridactyla has the most records (n = 5,941), and Cyclopes sp. have the fewest (n = 240). The armadillo species with the most data is Dasypus novemcinctus (n = 11,588), and the fewest data are recorded for Calyptophractus retusus (n = 33). With regard to sloth species, Bradypus variegatus has the most records (n = 962), and Bradypus pygmaeus has the fewest (n = 12). Our main objective with Neotropical Xenarthrans is to make occurrence and quantitative data available to facilitate more ecological research, particularly if we integrate the xenarthran data with other data sets of Neotropical Series that will become available very soon (i.e., Neotropical Carnivores, Neotropical Invasive Mammals, and Neotropical Hunters and Dogs). Therefore, studies on trophic cascades, hunting pressure, habitat loss, fragmentation effects, species invasion, and climate change effects will be possible with the Neotropical Xenarthrans data set. Please cite this data paper when using its data in publications. We also request that researchers and teachers inform us of how they are using these data