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Diethylcarbamazine activates TRP channels including TRP-2 in filaria, Brugia malayi

Diethylcarbamazine is an important classic drug used for prevention and treatment of lymphatic filariasis and loiasis, diseases caused by filarial nematodes. Despite many studies, its site of action has not been established. Until now, the consensus has been that diethylcarbamazine works by activati...

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Autores principales: Verma, Saurabh, Kashyap, Sudhanva S., Robertson, Alan P., Martin, Richard J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387335/
https://www.ncbi.nlm.nih.gov/pubmed/32724078
http://dx.doi.org/10.1038/s42003-020-01128-4
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author Verma, Saurabh
Kashyap, Sudhanva S.
Robertson, Alan P.
Martin, Richard J.
author_facet Verma, Saurabh
Kashyap, Sudhanva S.
Robertson, Alan P.
Martin, Richard J.
author_sort Verma, Saurabh
collection PubMed
description Diethylcarbamazine is an important classic drug used for prevention and treatment of lymphatic filariasis and loiasis, diseases caused by filarial nematodes. Despite many studies, its site of action has not been established. Until now, the consensus has been that diethylcarbamazine works by activating host immune systems, not by a direct action on the parasites. Here we show that low concentrations of diethylcarbamazine have direct and rapid (<30 s) temporary spastic paralyzing effects on the parasites that lasts around 4 h, which is produced by diethylcarbamazine opening TRP channels in muscle of Brugia malayi involving TRP-2 (TRPC-like channel subunits). GON-2 and CED-11, TRPM-like channel subunits, also contributed to diethylcarbamazine responses. Opening of these TRP channels produces contraction and subsequent activation of calcium-dependent SLO-1K channels. Recovery from the temporary paralysis is consistent with inactivation of TRP channels. Our observations elucidate mechanisms for the rapid onset and short-lasting therapeutic actions of diethylcarbamazine.
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spelling pubmed-73873352020-08-12 Diethylcarbamazine activates TRP channels including TRP-2 in filaria, Brugia malayi Verma, Saurabh Kashyap, Sudhanva S. Robertson, Alan P. Martin, Richard J. Commun Biol Article Diethylcarbamazine is an important classic drug used for prevention and treatment of lymphatic filariasis and loiasis, diseases caused by filarial nematodes. Despite many studies, its site of action has not been established. Until now, the consensus has been that diethylcarbamazine works by activating host immune systems, not by a direct action on the parasites. Here we show that low concentrations of diethylcarbamazine have direct and rapid (<30 s) temporary spastic paralyzing effects on the parasites that lasts around 4 h, which is produced by diethylcarbamazine opening TRP channels in muscle of Brugia malayi involving TRP-2 (TRPC-like channel subunits). GON-2 and CED-11, TRPM-like channel subunits, also contributed to diethylcarbamazine responses. Opening of these TRP channels produces contraction and subsequent activation of calcium-dependent SLO-1K channels. Recovery from the temporary paralysis is consistent with inactivation of TRP channels. Our observations elucidate mechanisms for the rapid onset and short-lasting therapeutic actions of diethylcarbamazine. Nature Publishing Group UK 2020-07-28 /pmc/articles/PMC7387335/ /pubmed/32724078 http://dx.doi.org/10.1038/s42003-020-01128-4 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Verma, Saurabh
Kashyap, Sudhanva S.
Robertson, Alan P.
Martin, Richard J.
Diethylcarbamazine activates TRP channels including TRP-2 in filaria, Brugia malayi
title Diethylcarbamazine activates TRP channels including TRP-2 in filaria, Brugia malayi
title_full Diethylcarbamazine activates TRP channels including TRP-2 in filaria, Brugia malayi
title_fullStr Diethylcarbamazine activates TRP channels including TRP-2 in filaria, Brugia malayi
title_full_unstemmed Diethylcarbamazine activates TRP channels including TRP-2 in filaria, Brugia malayi
title_short Diethylcarbamazine activates TRP channels including TRP-2 in filaria, Brugia malayi
title_sort diethylcarbamazine activates trp channels including trp-2 in filaria, brugia malayi
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387335/
https://www.ncbi.nlm.nih.gov/pubmed/32724078
http://dx.doi.org/10.1038/s42003-020-01128-4
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