Involvement of the GABAA receptor α subunit in the mode of action of etifoxine

Mattei, César; Taly, Antoine; Soualah, Zineb; Saulais, Ophélie; Henrion, Daniel; Guérineau, Nathalie C.; Verleye, Marc; Legros, Christian

doi:10.1016/j.phrs.2019.04.034

Cited by 24 publications

(18 citation statements)

References 69 publications

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“…Oocytes were harvested and injected as previously described [ 88 ]. Briefly, ovarian lobes were taken from female Xenopus ( Xenopus laevis ) anesthetized in Tricaine (0.15% in ice-cold water) for 20 min.…”

Section: Methodsmentioning

confidence: 99%

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Partial Agonist Activity of Neonicotinoids on Rat Nicotinic Receptors: Consequences over Epinephrine Secretion and In Vivo Blood Pressure

Park

Taly

Bourreau

et al. 2021

IJMS

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Neonicotinoid insecticides are nicotine-derived molecules which exert acute neurotoxic effects over the insect central nervous system by activating nicotinic acetylcholine receptors (nAChRs). However, these receptors are also present in the mammalian central and peripheral nervous system, where the effects of neonicotinoids are faintly known. In mammals, cholinergic synapses are crucial for the control of vascular tone, blood pressure and skeletal muscle contraction. We therefore hypothesized that neonicotinoids could affect cholinergic networks in mammals and sought to highlight functional consequences of acute intoxication in rats with sub-lethal concentrations of the highly used acetamiprid (ACE) and clothianidin (CLO). In this view, we characterized their electrophysiological effects on rat α3β4 nAChRs, knowing that it is predominantly expressed in ganglia of the vegetative nervous system and the adrenal medulla, which initiates catecholamine secretion. Both molecules exhibited a weak agonist effect on α3β4 receptors. Accordingly, their influence on epinephrine secretion from rat adrenal glands was also weak at 100 M, but it was stronger at 500 M. Challenging ACE or CLO together with nicotine (NIC) ended up with paradoxical effects on secretion. In addition, we measured the rat arterial blood pressure (ABP) in vivo by arterial catheterization. As expected, NIC induced a significant increase in ABP. ACE and CLO did not affect the ABP in the same conditions. However, simultaneous exposure of rats to both NIC and ACE/CLO promoted an increase of ABP and induced a biphasic response. Modeling the interaction of ACE or CLO on α3β4 nAChR is consistent with a binding site located in the agonist pocket of the receptor. We present a transversal experimental approach of mammal intoxication with neonicotinoids at different scales, including in vitro, ex vivo, in vivo and in silico. It paves the way of the acute and chronic toxicity for this class of insecticides on mammalian organisms

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Section: Methodsmentioning

confidence: 99%

“…The technique was previously described [ 88 , 90 ]. The expression of nAChR in oocytes was tested at a holding potential of ™60 mV using a TEV-200 amplifier (Dagan Corporation, Minneapolis, USA).…”

Section: Methodsmentioning

confidence: 99%

Partial Agonist Activity of Neonicotinoids on Rat Nicotinic Receptors: Consequences over Epinephrine Secretion and In Vivo Blood Pressure

Park

Taly

Bourreau

et al. 2021

IJMS

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“…Xenopus oocytes were prepared as previously described ( Mattei et al, 2019 ). Briefly, adult female Xenopus laevis were purchased from Centre de Ressources Biologiques Xénopes (Rennes, France) and were bred in the laboratory according to the recommendations of the Guide for the Care and Use of Laboratory Animals of the European Community.…”

Section: Methodsmentioning

confidence: 99%

“…The cDNAs encoding the α6 and δ subunits used in this work were cloned in mouse as previously described ( Mattei et al, 2019 ). pGW1 (= pRK5) plasmids containing cDNAs encoding mouse β3 and γ2S subunits were provided by Steven J. Moss (Department of Neuroscience, Tufts University, Boston, United States).…”

Section: Methodsmentioning

confidence: 99%

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GABAA Receptor Subunit Composition Drives Its Sensitivity to the Insecticide Fipronil

et al. 2021

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Fipronil (FPN) is a worldwide-used neurotoxic insecticide, targeting, and blocking GABAA receptors (GABAARs). Beyond its efficiency on insect GABAARs, FPN causes neurotoxic effects in humans and mammals. Here, we investigated the mode of action of FPN on mammalian α6-containing GABAARs to understand its inhibitory effects on GABA-induced currents, as a function of the synaptic or extrasynaptic localization of GABAARs. We characterized the effects of FPN by electrophysiology using Xenopus oocytes which were microtransplanted with cerebellum membranes or injected with α6β3, α6β3γ2S (synaptic), and α6β3δ (extrasynaptic) cDNAs. At micromolar concentrations, FPN dose-dependently inhibited cerebellar GABA currents. FPN acts as a non-competitive antagonist on ternary receptors. Surprisingly, the inhibition of GABA-induced currents was partial for extra-synaptic (α6β3δ) and binary (α6β3) receptors, while synaptic α6β3γ2S receptors were fully blocked, indicating that the complementary γ or δ subunit participates in FPN-GABAAR interaction. FPN unexpectedly behaved as a positive modulator on β3 homopentamers. These data show that FPN action is driven by the subunit composition of GABAARs—highlighting the role of the complementary subunit—and thus their localization within a physiological synapse. We built a docking model of FPN on GABAARs, which reveals two putative binding sites. This is consistent with a double binding mode of FPN on GABAARs, possibly one being of high affinity and the other of low affinity. Physiologically, the γ/δ subunit incorporation drives its inhibitory level and has important significance for its toxicity on the mammalian nervous system, especially in acute exposure.

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Beneficial effects of tannic acid on comorbid anxiety in cecal ligation and puncture-induced sepsis in rats and potential underlying mechanisms

Ranjbaran

Kianian

Ashabi

et al. 2023

Naunyn-Schmiedeberg's Arch Pharmacol

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Sepsis-associated encephalopathy (SAE), a neurological dysfunction caused by sepsis, is the most common complication among septic ICU patients. Given the major role of in ammation in the pathophysiology of sepsis-induced anxiety, an extreme and early manifestation of SAE, the present study examined whether tannic acid, as an anti-in ammatory agent, has anxiolytic effects in cecal ligation and puncture (CLP)-induced sepsis.Forty male Wistar rats were assigned to four groups: 1) Sham; 2) Sham + Tannic acid; 3) Sepsis and 4) Sepsis + Tannic acid. Sepsis was induced by cecal ligation and puncture model. Animals in the Sham + Tannic acid and Sepsis + Tannic acid groups received tannic acid (20 mg/kg, i.p.), 6, 12 and 18 h after the sepsis induction. Twenty four hours after the sepsis induction, systolic blood pressure and sepsis score were assessed. Anxiety-related behaviors were evaluated using elevated plus-maze and dark-light transition tests. Moreover, in ammatory markers (TNF-α and IL-6), oxidative stress parameters (MDA and SOD) and protein levels (GABAA receptors and IL-1β) were measured in the brain tissue samples.Administration of tannic acid signi cantly improved sepsis score and hypotension which induced by sepsis. Anxiety-related behaviors showed a signi cant decrease in the Sepsis + Tannic acid group compared to the Sepsis group. Tannic acid caused a signi cant decrease in the brain in ammatory markers and a remarkable improvement in the brain oxidative status compared to the septic rats. Tannic acid prevented animals from decreasing GABAA receptors and increasing IL-1β protein levels in the brain tissue samples compared to the Sepsis group. This study indicated that tannic acid mitigated anxietyrelated behaviors through decreasing in ammation and oxidative stress and positive modifying IL-1β/GABAA receptors pathway. Therefore, tannic acid shows promise as an e cacious treatment for comorbid anxiety in septic patients. HighlightsSepsis-associated encephalopathy (SAE) is de ned as an acute brain dysfunction secondary to sepsis without overt infection of the central nervous system and is characterized by neurological symptoms of varying severity, from sickness behavior and delirium to coma. Anxiety is a manifestation of sickness behavior caused by sepsis, which based on the available evidence, occurs signi cantly in 47% of the patients.The present study demonstrated that anxiety comorbidity with sepsis may occur due to increased in ammation and oxidative stress in the brain, and negative modifying IL-1β/GABAA receptors pathway in the hippocampus.Treatment with tannic acid was able to ameliorate all the mentioned parameters almost close to the levels measured before the induction of sepsis. Therefore, tannic acid administration may be considered as a potential therapeutic strategy in the context of comorbid anxiety during sepsis.However, further investigations are needed to elucidate the exact mechanisms underlying the bene cial effects of tannic acid.

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Involvement of the GABAA receptor α subunit in the mode of action of etifoxine

Cited by 24 publications

References 69 publications

Partial Agonist Activity of Neonicotinoids on Rat Nicotinic Receptors: Consequences over Epinephrine Secretion and In Vivo Blood Pressure

Partial Agonist Activity of Neonicotinoids on Rat Nicotinic Receptors: Consequences over Epinephrine Secretion and In Vivo Blood Pressure

GABAA Receptor Subunit Composition Drives Its Sensitivity to the Insecticide Fipronil

Beneficial effects of tannic acid on comorbid anxiety in cecal ligation and puncture-induced sepsis in rats and potential underlying mechanisms

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