Study of the nematode putative GABA type‐A receptor subunits: evidence for modulation by ivermectin

Feng, Xiao-Peng; Hayashi, Jon H.; Beech, Robin N.; Prichard, Roger K.

doi:10.1046/j.1471-4159.2002.01199.x

Cited by 117 publications

(96 citation statements)

References 22 publications

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“…It has been commonly observed that IVM does not affect mf motility or viability at pharmacologically relevant concentrations in culture (5,9), which is consistent with the apparent absence of GluCl expression in regions associated with somatic muscle function. Recently, it has been reported that IVM concentrations >1 μM affect mf motility (29); this may be associated with drug effects on GABA-gated chloride channels, which are secondary targets for the ML class (30). These effects may partially account for the concentration-dependence of the drug effect on secretion seen at the later time-point.…”

Section: Discussionmentioning

confidence: 99%

Ivermectin disrupts the function of the excretory-secretory apparatus in microfilariae of Brugia malayi

Moreno

Nabhan

Solomon

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

148

141

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Ivermectin (IVM) is a broad-spectrum anthelmintic used in filariasis control programs. By binding to nematode glutamate-gated chloride channels (GluCls), IVM disrupts neurotransmission processes regulated by GluCl activity. IVM treatment of filarial infections is characterized by an initial dramatic drop in the levels of circulating microfilariae, followed by long-term suppression of their production, but the drug has little direct effect on microfilariae in culture at pharmacologically relevant concentrations. We localized Brugia malayi GluCl expression solely in a muscle structure that surrounds the microfilarial excretory-secretory (ES) vesicle, which suggests that protein release from the ES vesicle is regulated by GluCl activity. Consistent with this hypothesis, exposure to IVM in vitro decreased the amount of protein released from microfilariae. To better understand the scope of IVM effects on protein release by the parasite, three different expression patterns were identified from immunolocalization assays on a representative group of five microfilarial ES products. Patterns of expression suggest that the ES apparatus is the main source of regulated ES product release from microfilariae, as it is the only compartment that appears to be under neuromuscular control. Our results show that IVM treatment of microfilariae results in a marked reduction of protein release from the ES apparatus. Under in vivo conditions, the rapid microfilarial clearance induced by IVM treatment is proposed to result from suppression of the ability of the parasite to secrete proteins that enable evasion of the host immune system. filarial nematode | macrocyclic lactone | glutamate-gated chloride channels

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Section: Discussionmentioning

confidence: 99%

Ivermectin disrupts the function of the excretory-secretory apparatus in microfilariae of Brugia malayi

Moreno

Nabhan

Solomon

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

148

141

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“…In addition to nematode acetylcholine receptors, these targets also include P2X receptors of Schistosoma [32] and of mouse ( [33]) and histamine-gated chloride channels of Drosophila [34], as well as nematode [35][36][37][38] and insect [39,40] glutamate-gated chloride channels, GABA receptors from nematodes to vertebrates [41][42][43][44] and human glycine receptors [45]. There is also evidence for an action of IVM on an intracellular ligand-gated ion channel, the ryanodine receptor [46].…”

Section: Ivermectin Can Have Allosteric and Agonist Effects On Ligandmentioning

confidence: 99%

Comparative pharmacology and computational modelling yield insights into allosteric modulation of human α7 nicotinic acetylcholine receptors

Sattelle

Akamatsu²,

Matsuda³

et al. 2009

Biochemical Pharmacology

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HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L'archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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“…In addition, long-term use and repeated dosing with these drugs may result in parasite resistance, as already observed in veterinary settings (Kaplan 2004) and some indication in the field (Awadzi et al 2004;Bourguinat et al 2007). Genetic basis for such phenomenon has been demonstrated (Feng et al 2002;Prichard 2007). There is thus a need for new effective and well-tolerated drugs.…”

Section: Introductionmentioning

confidence: 99%

In vitro activities of plant extracts on human Loa loa isolates and cytotoxicity for eukaryotic cells

et al. 2010

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Loa loa, a filarial worm, can cause fatal encephalitis in humans. In an attempt to find alternatives to the standard treatments (ivermectin and diethylcarbamazine citrate), we tested 12 methanolic extracts of nine traditional plant remedies. The extracts (100-0.09 microg/ml) were incubated with 20 Loa loa microfilariae isolated from patients at 37 degrees C with 5% CO(2) in modified Eagle's medium supplemented with 10% fetal serum and antibiotics. Activity was evaluated 120 h later by counting live microfilariae under a microscope. Cytotoxicity for eukaryotic cells was estimated by measuring 3-[4,5-dimethylthiazol-2-yl]-2-5 diphenyl tetrazolium bromide transformation to formazan at 450 nM in a spectrophotometer. The plants tested were Lophira alata, Greenwayodendron suaveolens, Uapaca togoensis, Zanthoxylum heitzii, Peperomia pellucida, Piptadeniastrum africanum, Petersianthus macrocarpus, Vernonia conferta, and Vernonia hymenolepis. Chemical screening showed that most of the extracts contained reducing sugars, tannin or polyphenols, sterols or triterpenes, saponosides, and alkaloids. None contained carotinoids and few contained flavonoids. The 50% lethal concentration ranged from 0.22 to 70.28 microg/ml, while the 50% inhibitory concentration for eukaryotic cells (IC(50)) ranged from 8.52 to 119.52 microg/ml. Extracts of P. macrocarpus (selectivity index = 72.16), P. africanum (13.69), Z. heitzii (12.11), and L. alata (9.26) were highly selective for L. loa.

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Study of the nematode putative GABA type‐A receptor subunits: evidence for modulation by ivermectin

Cited by 117 publications

References 22 publications

Ivermectin disrupts the function of the excretory-secretory apparatus in microfilariae of Brugia malayi

Ivermectin disrupts the function of the excretory-secretory apparatus in microfilariae of Brugia malayi

Comparative pharmacology and computational modelling yield insights into allosteric modulation of human α7 nicotinic acetylcholine receptors

In vitro activities of plant extracts on human Loa loa isolates and cytotoxicity for eukaryotic cells

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