Avermectin B_la Modulation of γ‐Aminobutyric Acid/Benzodiazepine Receptor Binding in Mammalian Brain

Abstract

The anthelminthic natural product avermectin B1a (AVM) modulates the binding of gamma-aminobutyric acid (GABA) and benzodiazepine (BZ) receptor ligands to membrane homogenates of mammalian brain. The potent (EC50 = 40 nM) enhancement by AVM of [3H]diazepam binding to rat or bovine brain membranes resembled that of barbiturates and pyrazolopyridines in being inhibited (partially) by the convulsants picrotoxin, bicuculline, and strychnine, and by the anticonvulsants phenobarbital and chlormethiazole. The maximal effect of AVM was not increased by pentobarbital or etazolate. However, AVM affected BZ receptor subpopulations or conformational states in a manner different from pentobarbital. Further, unlike pentobarbital and etazolate, AVM did not inhibit allosterically the binding of the BZ receptor inverse agonist [3H]beta-carboline-3-carboxylate methyl ester, nor did it inhibit, but rather enhanced, the binding of the cage convulsant [35S]t-butyl bicyclophosphorothionate to picrotoxin receptor sites. AVM at submicromolar concentrations had the opposite effect of pentobarbital and etazolate on GABA receptor binding, decreasing by half the high-affinity binding of [3H]GABA and related agonist ligands, and increasing by over twofold the binding of the antagonist [3H]bicuculline methochloride, an effect that was potentiated by picrotoxin. AVM also reversed the enhancement of GABA agonists and inhibition of GABA antagonist binding by barbiturates and pyrazolopyridines. These overall effects of AVM are unique and require the presence of another separate drug receptor site on the GABA/BZ receptor complex.

Pentylenetetrazol‐Induced Seizures Decrease γ‐Aminobutyric Acid‐Mediated Recurrent Inhibition and Enhance Adenosine‐Mediated Depression

“…Animals were decapitated 24 h after the second and last PTZ injection. Toffano et al, 1978;Olsen and Snowman, 1985). Maximal density of binding sites of the high-affinity component (Bmaxl) was clearly lower in cortex as well as in hippocampus of PTZ-treated mice.…”

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

“…There is agreement only with regard to the enhancement of [3H]diazepam or [3H]flunitrazepam (Flu) binding by AVM (12)(13)(14)(15). On the other hand, AVM can either enhance (16,17) or have no effect on (14) binding of the inverse agonist [3H]P-carboline carboxylate, and it potentiates (18), has no effect on (19), or inhibits [3H]GABA or [3H]muscimol binding (15,20). It also inhibits [3H]muscimol binding to honey bee brain (21).…”

Mutational Analysis at Intersubunit Interfaces of an Anionic Glutamate Receptor Reveals a Key Interaction Important for Channel Gating by Ivermectin

“…Other functional studies showed that, the susceptibility of amino acids in M1 to various chemical modifications is changed following the transition of resting ACh- and GABA-gated Cys-loop receptors to their active state (Akabas and Karlin, 1995; Yu et al, 2003; Arevalo et al, 2005; Li et al, 2006; Pandhare et al, 2012). It is of interest to note that IVM activates mammalian GABA-gated chloride channels as well (Williams and Risley, 1982; Olsen and Snowman, 1985; Sigel and Baur, 1987; Krůsek and Zemková, 1994; Adelsberger et al, 2000; Lynagh and Lynch, 2012b; Ménez et al, 2012), possibly by binding to a pocket between M1 and M3 of adjacent subunits akin to the GluClRs. So, this potential IVM-binding pocket might overlap the well-characterized binding site of GABA A Rs for the intravenous anesthetic agent etomidate (Li et al, 2006, 2010; Olsen and Li, 2011; Chiara et al, 2012; Stewart et al, 2013a,b, reviewed in Olsen et al, 2014).…”

“…Notably, IVM activates and/or potentiates a few vertebrate Cys-loop receptors, like GABA-, and Gly-gated Cl − channels (Williams and Risley, 1982; Olsen and Snowman, 1985; Sigel and Baur, 1987; Krůsek and Zemková, 1994; Adelsberger et al, 2000; Shan et al, 2001; Zheng et al, 2002; Pless and Lynch, 2009b; Lynagh and Lynch, 2012a; Ménez et al, 2012; Wang and Lynch, 2012) and the α7 cationic ACh-gated channel (Krause et al, 1998; Collins and Millar, 2010), though with much higher drug concentrations than in GluClRs. IVM can also activate the P2X ATP-gated ion channel belonging to a different family of ligand-gated ion channels (Khakh et al, 1999; Priel and Silberberg, 2004; Silberberg et al, 2007; Habermacher et al, 2016).…”