Sulfone Metabolite of Fipronil Blocks γ-Aminobutyric Acid- and Glutamate-Activated Chloride Channels in Mammalian and Insect Neurons

Abstract

Fipronil sulfone, a major metabolite of fipronil in both insects and mammals, binds strongly to GABA receptors and is thought to play a significant role in poisoning by fipronil. To better understand the mechanism of selective insecticidal action of fipronil, we examined the effects of its sulfone metabolite on GABA-and glutamate-activated chloride channels (GluCls) in cockroach thoracic ganglion neurons and on GABA A receptors in rat dorsal root ganglion neurons using the whole-cell patch-clamp technique. Fipronil sulfone blocked both desensitizing and nondesensitizing GluCls in the cockroach. Activation was required for block and unblock of desensitizing GluCls. In contrast, activation was not prerequisite for block and unblock of nondesensitizing channels. After repetitive activation of the receptors, the IC 50 of fipronil sulfone to block the desensitizing GluCls was reduced from 350 to 25 nM and that for blocking nondesensitizing GluCls was reduced from 31.2 to 8.8 nM. This use-dependent block may be explained by its slow unbinding rate. In cockroach and rat neurons, fipronil sulfone blocked GABA receptors in both activated and resting states, with IC 50 values ranging from 20 to 70 nM. In conclusion, although fipronil sulfone is a potent inhibitor of cockroach GABA receptors, desensitizing and nondesensitizing GluCls, and rat GABA A receptors, its selective toxicity in insects over mammals appears to be associated with its potent blocking action on both desensitizing and nondesensitizing GluCls, which are lacking in mammals.

Rhipicephalus(Boophilus) microplus resistant to acaricides and ivermectin in cattle farms of Mexico

“…Orr et al (2009) chloride channels in insects (ZHAO et al, 2005). Also, it acts in the reproductive process by altering both the structure and function of germinative cells of R. sanguineus females (OLIVEIRA et al, 2009).…”

Lactational Exposure to Fipronil Pesticide in Low Dose Impairs Memory in Rat Offspring

“…The fact of chemical injury to the CNS can change the phases of acquisition, consolidation and recall of the memory [11] contributes to raise questions about GABAergic system involvement. In this sense it was recently demonstrated that reduction of GABA in the prefrontal cortex caused a delay in the activities done by monkeys [12][13][14].…”

Use of non-mammalian alternative models for neurotoxicological study

“…However, it was unlear whether the conversion of fipronil to its sulfone represented detoxication in mammals and insects. Fipronil sulfone blocked both slowand fast-desensitizing GluCls (Zhao et al, 2005). The IC 50 for slow-and fast-desensitizing currents were calculated to be 8.5 ± 0.4 nM (n = 4) and 25 ± 2 nM (n = 4), respectively.…”