Toxicity and mode of action of the aporphine plant alkaloid liriodenine on the insect GABA receptor. (15th October 2021)

• Record Type: Journal Article
• Authors: Coquerel, Quentin R.R.; Démares, Fabien; Geldenhuys, Werner J.; Le Ray, Anne-Marie; Bréard, Dimitri; Richomme, Pascal; Legros, Christian; Norris, Edmund; Bloomquist, Jeffrey R.
• Is Part Of: Toxicon. Volume 201(2021)
• Page Start: 141
• Page End: 147
• Publication Date: 2021-10-15
• Subjects: Anopheles gambiae -- Bicuculline -- Drosophila melanogaster -- GABA antagonist -- Insecticide; Area under the curve (AUC) -- Central nervous system (CNS) -- Piperonyl butoxide (PBO); Toxins -- Periodicals; Venom -- Periodicals; 615.9
• DOI: 10.1016/j.toxicon.2021.08.019
• Languages: English
• ISSNs: 0041-0101

Abstract

Abstract: Liriodenine is a biologically active plant alkaloid with multiple effects on mammals, fungi, and bacteria, but has never been evaluated for insecticidal activity. Accordingly, liriodenine was applied topically in ethanolic solutions to adult female Anopheles gambiae, and found to be mildly toxic. Its lethality was synergized in mixtures with dimethyl sulfoxide and piperonyl butoxide. Recordings from the ventral nerve cord of larval Drosophila melanogaster showed that liriodenine was neuroexcitatory and reversed the inhibitory effect of 1 mM GABA at effective concentrations of 20–30 μM. GABA antagonism on the larval nervous system was equally expressed on both susceptible and cyclodiene-resistant rdl preparations. Acutely isolated neurons from Periplaneta americana were studied under patch clamp and inhibition of GABA-induced currents with an IC50 value of about 1 μM were observed. In contrast, bicuculline did not reverse the effects of GABA on cockroach neurons, as expected. In silico molecular models suggested reasonable structural concordance of liriodenine and bicuculline and isosteric hydrogen bond acceptor sites. This study is the first assessing of the toxicology of liriodenine on insects and implicates the GABA receptor as one likely neuronal target, where liriodenine might be considered an active chemical analog of bicuculline. Graphical abstract: Image 1 Highlights: Liriodenine had low insecticidal activity, synergized by DMSO & PBO. It excited Drosophila ventral cord and reversed GABA blocking effects. It blocked GABAA receptors in patch clamped cockroach neurons. Molecular modeling shows some similarity in structure to bicuculline. The results suggest it could be an active analog of bicuculline in insects.