Actions of avermectin B<sub>1a</sub> on the γ‐aminobutyric Acid<sub>A</sub> receptor and chloride channels in rat brain

Abalis, Ibrahim M.; Eldefrawi, Amira T.; Eldefrawi, Mohyee E.

doi:10.1002/jbt.2570010108

Cited by 47 publications

(22 citation statements)

References 34 publications

(38 reference statements)

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“…Abamectin stimulates radiochloride efflux from mammalian brain vesicular preparations that is sensitive to block by DIDS (Fig. 4), an established blocker of voltage-depen- December 2003 dent chloride channels (Abalis et al, 1986). Similar results were observed for abamectin-dependent efflux from mouse brain vesicles (Payne and Soderlund, 1991), and structure-activity studies found that seven abamectin analogs stimulated efflux with half maximal potencies of around 1 mM (Payne and Soderlund, 1993).…”

Section: Voltage-gated Chloride Channels As Insecticide Targetsmentioning

confidence: 57%

Chloride channels as tools for developing selective insecticides

Bloomquist

2003

Arch Insect Biochem Physiol

231

112

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Ligand-gated chloride channels underlie inhibition in excitable membranes and are proven target sites for insecticides. The gamma-aminobutyric acid (GABA(1)) receptor/chloride ionophore complex is the primary site of action for a number of currently used insecticides, such as lindane, endosulfan, and fipronil. These compounds act as antagonists by stabilizing nonconducting conformations of the chloride channel. Blockage of the GABA-gated chloride channel reduces neuronal inhibition, which leads to hyperexcitation of the central nervous system, convulsions, and death. We recently investigated the mode of action of the silphinenes, plant-derived natural compounds that structurally resemble picrotoxinin. These materials antagonize the action of GABA on insect neurons and block GABA-mediated chloride uptake into mouse brain synaptoneurosomes in a noncompetitive manner. In mammals, avermectins have a blocking action on the GABA-gated chloride channel consistent with a coarse tremor, whereas at longer times and higher concentrations, activation of the channel suppresses neuronal activity. Invertebrates display ataxia, paralysis, and death as the predominant signs of poisoning, with a glutamate-gated chloride channel playing a major role. Additional target sites for the avermectins or other chloride channel-directed compounds might include receptors gated by histamine, serotonin, or acetylcholine.The voltage-sensitive chloride channels form another large gene family of chloride channels. Voltage-dependent chloride channels are involved in a number of physiological processes including: maintenance of electrical excitability, chloride ion secretion and resorption, intravesicular acidification, and cell volume regulation. A subset of these channels is affected by convulsants and insecticides in mammals, although the role they play in acute lethality in insects is unclear. Given the wide range of functions that they mediate, these channels are also potential targets for insecticide development.

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Section: Voltage-gated Chloride Channels As Insecticide Targetsmentioning

confidence: 57%

Chloride channels as tools for developing selective insecticides

Bloomquist

2003

Arch Insect Biochem Physiol

231

112

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“…Ivermectin has also been demonstrated to have effects on other vertebrate receptors. Avermectin B1a in vitro opens the GABA A -receptor Cl channel by binding to the GABA recognition site and acting as a partial receptor agonist, but also opens a voltage-dependent Cl channel [1]. Additionally, the fact that ivermectin dosedependently blocks convulsions caused by strychnine indicates a potential action on the chloride channels opened by glycine [41].…”

Section: Discussionmentioning

confidence: 99%

“…It is difficult to explain why proven in vitro antagonists of different types of chloride channel (picrotoxin, DIDS, strychnine, etc.) have no therapeutic value in treatment for poisoning with ivermectin [1,39]. Alternatively, as we have noted previously, there is substantial evidence that ivermectin interacts with the binding sites of benzodiazepines on the GABA receptor-ionophore complex chloride channel [25,45].…”

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confidence: 95%

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Central and Peripheral Neurotoxic Effects of Ivermectin in Rats

Trailovic

Nedeljković

2011

The Journal of Veterinary Medical Science

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ABSTRACT. Ivermectin is considered a very safe drug; however, there are reports of toxic effects in particularly sensitive populations or due to accidental overdose. The aim of this study was (1) to further characterize the central and peripheral toxic effects of ivermectin in animals and (2) to determine possible therapeutic strategies for use in cases of ivermectin poisoning. We tested the effects of experimental doses of ivermectin previously reported to cause various intensities of CNS depression. However, in our study, ivermectin at 2.5, 5.0 and 7.5 mg/kg i.v. did not produce visible CNS depression in rats and 10 mg/kg resulted in sleepiness and staggering 10 to 40 min after application, while a dose of 15 mg/kg caused CNS depression very similar to general anesthesia. Ivermectin dose-dependently potentiates thiopentone-induced sleeping time in rats. Flumazenil (0.2 mg/kg), the benzodiazepine antagonist, did not affect the action of thiopentone; however, it significantly reduced sleeping time in rats treated with a combination of ivermectin (10 mg/kg) and thiopentone (25 mg/kg; from 189.86  45.28 min to 83.13  32.22 min; mean  SD). Ivermectin causes an increase in the tonus (EC 50 =50.18 M) and contraction amplitude (EC 50 =59.32 M) of isolated guinea pig ileum, very similar to GABA, but without the initial relaxation period. These effects are dose-dependent and sensitive to atropine. Our results confirm the central and peripheral GABAergic properties of ivermectin in mammals and also indicate involvement of the cholinergic system in its toxicity. In addition, the results suggest that flumazenil and atropine have potential clinical roles in the treatment of ivermectin toxicity.

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“…However, effects of ivermectin on other ion channels are known and may contribute to the drug's efficacy. Most noticeably, ivermectin binds to and interacts with insect ␥-aminobutyric acid (GABA)-gated chloride channels (7,8). Together with glycine-gated channels, GABA-gated channels are the closest homologues of GluCl channels and are likely to be sites of ivermectin toxicity.…”

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confidence: 99%

Drug-resistant Drosophila indicate glutamate-gated chloride channels are targets for the antiparasitics nodulisporic acid and ivermectin

Kane

Hirschberg

Qian

et al. 2000

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

170

146

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The fruit fly Drosophila melanogaster was used to examine the mode of action of the novel insecticide and acaricide nodulisporic acid. Flies resistant to nodulisporic acid were selected by stepwise increasing the dose of drug in the culture media. The resistant strain, glc 1 , is at least 20-fold resistant to nodulisporic acid and 3-fold cross-resistant to the parasiticide ivermectin, and exhibited decreased brood size, decreased locomotion, and bang sensitivity. Binding assays using glc 1 head membranes showed a marked decrease in the affinity for nodulisporic acid and ivermectin. A combination of genetics and sequencing identified a proline to serine mutation (P299S) in the gene coding for the glutamategated chloride channel subunit DmGluCl␣. To examine the effect of this mutation on the biophysical properties of DmGluCl␣ channels, it was introduced into a recombinant DmGluCl␣, and RNA encoding wild-type and mutant subunits was injected into Xenopus oocytes. Nodulisporic acid directly activated wild-type and mutant DmGluCl␣ channels. However, mutant channels were Ϸ10-fold less sensitive to activation by nodulisporic acid, as well as ivermectin and the endogenous ligand glutamate, providing direct evidence that nodulisporic acid and ivermectin act on DmGluCl␣ channels.

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Actions of avermectin B_1a on the γ‐aminobutyric Acid_A receptor and chloride channels in rat brain

Cited by 47 publications

References 34 publications

Chloride channels as tools for developing selective insecticides

Chloride channels as tools for developing selective insecticides

Central and Peripheral Neurotoxic Effects of Ivermectin in Rats

Drug-resistant Drosophila indicate glutamate-gated chloride channels are targets for the antiparasitics nodulisporic acid and ivermectin

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Actions of avermectin B1a on the γ‐aminobutyric AcidA receptor and chloride channels in rat brain

Cited by 47 publications

References 34 publications

Chloride channels as tools for developing selective insecticides

Chloride channels as tools for developing selective insecticides

Central and Peripheral Neurotoxic Effects of Ivermectin in Rats

Drug-resistant Drosophila indicate glutamate-gated chloride channels are targets for the antiparasitics nodulisporic acid and ivermectin

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Actions of avermectin B_1a on the γ‐aminobutyric Acid_A receptor and chloride channels in rat brain