Diethylcarbamazine mediated potentiation of emodepside induced paralysis requires TRP-2 in adult Brugia malayi

Kashyap, Sudhanva S.; McHugh, Mark; Robertson, Alan P.; Martin, R. J.

doi:10.1016/j.ijpddr.2022.10.002

Cited by 5 publications

(22 citation statements)

References 20 publications

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Section: Synthesis and Delivery Of Dsrnamentioning

confidence: 99%

“…Trp-2 target T7 promoter labeled primers were amplified using the primers trp-2f2, trp-2f2t7, trp-2r2 and trp-2r2t7 previously described (Supplementary Table 1) [4,15]. Nonspecific T7 labelled LacZ dsRNA constructs were amplified using the primers LacZf, LacZr, LacZft7, and LacZrt7 (Supplementary Table 1) [15]. Amplification was performed from sequence verified cDNA templates using a Techne TM PRIMEG cycler (Bibby Scientific Limited, UK) with the following cycling conditions: 95°C x 5 min, 35 x (95°C x 30 s, 55 °C x 30 s, 72 °C x 1 min), 72 °C x 10 min.…”

Section: Synthesis and Delivery Of Dsrnamentioning

confidence: 99%

“…cDNA from dsRNA-treated worms were amplified using the following target trp-2 and reference gene (Bma-gapdh) primers: trp-2f2, trp-2r2, SSK5F, and SSK5R (Supplementary Table 1) [4,15]. These genes were amplified in triplicate by quantitative real-time PCR (qPCR) using the CFX96 TouchTM Real-Time PCR Detection System and SsoAdvancedTM Universal SYBR® Green Supermix (Bio-Rad, USA).…”

Section: Analysis Of Transcript Levelsmentioning

confidence: 99%

“…The TRPC nematode orthologue channel, TRP-2, has been identified as a key channel in mediating diethylcarbamazine effects, particularly effects on muscle membrane currents and motility [4,15]. To test if the observed diethylcarbamazine Ca 2+ signal is mediated by Ca 2+ entering through TRP-2 channels, we treated dissected muscles with the TRPC specific antagonist SKF96365, a compound which we have previously used to inhibit TRP channel activity in both Brugia and the gastrointestinal parasite Ascaris was not certified by peer review) is the author/funder.…”

Section: Trp-2 Mediates the Diethylcarbamazine Induced Ca 2+ Signalmentioning

confidence: 99%

“…To further test if the diethylcarbamazine mediated Ca 2+ signal was due to TRP-2 activation, we used dsRNA to selectively knockdown trp-2 channels in Brugia. Knockdown of trp-2 by RNAi has previously demonstrated the key importance of TRP-2 in mediated diethylcarbamazine effects on motility as dsRNA trp-2 animals showed reduced diethylcarbamazine sensitivity [4,15]. We exposed dsRNA trp-2 treated animals to 30 µM diethylcarbamazine and measured the Ca 2+ signal.…”

Section: Trp-2 Mediates the Diethylcarbamazine Induced Ca 2+ Signalmentioning

confidence: 99%

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Diethylcarbamazine elicits Ca²⁺signals through TRP-2 channels that are potentiated by emodepside inBrugia malayimuscles

Williams

Kashyap

Robertson

et al. 2023

Preprint

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Filarial nematode infections are a major health concern in several countries. Lymphatic filariasis is caused by Wucheria bancrofti and Brugia spp. affecting over 120 million people. Heavy infections can lead to elephantiasis having serious effects on individuals' lives. Although current anthelmintics are effective at killing the microfilariae in the bloodstream, they have little to no effect against adult parasites found in the lymphatic system. The anthelmintic diethylcarbamazine is one of the central pillars of lymphatic filariasis control. Recent studies have reported that diethylcarbamazine can open Transient Receptor Potential (TRP) channels on the muscles of adult female Brugia malayi leading to contraction and paralysis. Diethylcarbamazine has synergistic effects in combination with emodepside on Brugia inhibiting motility: emodepside is an anthelmintic that has effects on filarial nematodes and is under trials for treatment of river blindness. Here we have studied the effects of diethylcarbamazine on single Brugia muscle cells by measuring the change in Ca2+fluorescence in the muscle using Ca2+-imaging techniques. Diethylcarbamazine interacts with the TRPC orthologue receptor TRP-2 to promote Ca2+entry into the Brugia muscle cells which can activate SLO-1 Ca2+activated K+channels, the putative target of emodepside. A combination of diethylcarbamazine and emodepside leads to a bigger Ca2+signal than when either compound is applied alone. Our study shows that diethylcarbamazine targets TRP channels to promote Ca2+entry that is increased by emodepside activation of SLO-1 channels.

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Section: Synthesis and Delivery Of Dsrnamentioning

confidence: 99%

Section: Synthesis and Delivery Of Dsrnamentioning

confidence: 99%

Section: Analysis Of Transcript Levelsmentioning

confidence: 99%

Section: Trp-2 Mediates the Diethylcarbamazine Induced Ca 2+ Signalmentioning

confidence: 99%

Section: Trp-2 Mediates the Diethylcarbamazine Induced Ca 2+ Signalmentioning

confidence: 99%

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Diethylcarbamazine elicits Ca²⁺signals through TRP-2 channels that are potentiated by emodepside inBrugia malayimuscles

Williams

Kashyap

Robertson

et al. 2023

Preprint

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The long and winding road towards new treatments against lymphatic filariasis and onchocerciasis

Risch,

Kazakov,

Specht

et al. 2024

Trends in Parasitology

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Diethylcarbamazine elicits Ca ²⁺ signals through TRP-2 channels that are potentiated by emodepside in Brugia malayi muscles

Williams,

Kashyap,

Robertson

et al. 2023

Antimicrob Agents Chemother

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Filarial nematode infections are a major health concern in several countries. Lymphatic filariasis is caused by Wuchereria bancrofti and Brugia spp. affecting over 120 million people. Heavy infections can lead to elephantiasis, which has serious effects on individuals’ lives. Although current anthelmintics are effective at killing microfilariae in the bloodstream, they have little to no effect against adult parasites found in the lymphatic system. The anthelmintic diethylcarbamazine is one of the central pillars of lymphatic filariasis control. Recent studies have reported that diethylcarbamazine can open transient receptor potential (TRP) channels in the muscles of adult female Brugia malayi, leading to contraction and paralysis. Diethylcarbamazine has synergistic effects in combination with emodepside on Brugia, inhibiting motility: emodepside is an anthelmintic that has effects on filarial nematodes and is under trial for the treatment of river blindness. Here, we have studied the effects of diethylcarbamazine on single Brugia muscle cells by measuring the change in Ca 2+ fluorescence in the muscle using Ca 2+ -imaging techniques. Diethylcarbamazine interacts with the transient receptor potential channel, C classification (TRPC) ortholog receptor TRP-2 to promote Ca 2+ entry into the Brugia muscle cells, which can activate Slopoke (SLO-1) Ca 2+ -activated K + channels, the putative target of emodepside. A combination of diethylcarbamazine and emodepside leads to a bigger Ca 2+ signal than when either compound is applied alone. Our study shows that diethylcarbamazine targets TRP channels to promote Ca 2+ entry that is increased by emodepside activation of SLO-1 K + channels.

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Diethylcarbamazine mediated potentiation of emodepside induced paralysis requires TRP-2 in adult Brugia malayi

Cited by 5 publications

References 20 publications

Diethylcarbamazine elicits Ca²⁺signals through TRP-2 channels that are potentiated by emodepside inBrugia malayimuscles

Diethylcarbamazine elicits Ca²⁺signals through TRP-2 channels that are potentiated by emodepside inBrugia malayimuscles

The long and winding road towards new treatments against lymphatic filariasis and onchocerciasis

Diethylcarbamazine elicits Ca ²⁺ signals through TRP-2 channels that are potentiated by emodepside in Brugia malayi muscles

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Diethylcarbamazine mediated potentiation of emodepside induced paralysis requires TRP-2 in adult Brugia malayi

Cited by 5 publications

References 20 publications

Diethylcarbamazine elicits Ca2+signals through TRP-2 channels that are potentiated by emodepside inBrugia malayimuscles

Diethylcarbamazine elicits Ca2+signals through TRP-2 channels that are potentiated by emodepside inBrugia malayimuscles

The long and winding road towards new treatments against lymphatic filariasis and onchocerciasis

Diethylcarbamazine elicits Ca 2+ signals through TRP-2 channels that are potentiated by emodepside in Brugia malayi muscles

Contact Info

Product

Resources

About

Diethylcarbamazine elicits Ca²⁺signals through TRP-2 channels that are potentiated by emodepside inBrugia malayimuscles

Diethylcarbamazine elicits Ca²⁺signals through TRP-2 channels that are potentiated by emodepside inBrugia malayimuscles

Diethylcarbamazine elicits Ca ²⁺ signals through TRP-2 channels that are potentiated by emodepside in Brugia malayi muscles