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Research Project: Integrated Pest Management of Mosquitoes and Biting Flies

Location: Mosquito and Fly Research

Title: Toxicity and mode of action of the aporphine plant alkaloid liriodenine on the insect GABA receptor

Author
item COQUEREL, QUENTIN - University Of Florida
item DEMARES, FABIEN - University Of Florida
item GELDENHUYS, WERNER - West Virginia University
item LE RAY, ANNE-MARIE - University Of Angers
item BREARD, DIMITRI - University Of Angers
item RICHOMME, PASCAL - University Of Angers
item LEGROS, CHRISTIAN - University Of Angers
item Norris, Edmund
item BLOOMQUIST, JEFFREY - University Of Florida

Submitted to: Toxicon
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/23/2021
Publication Date: 9/7/2021
Citation: Coquerel, Q.R., Demares, F., Geldenhuys, W.J., Le Ray, A., Breard, D., Richomme, P., Legros, C., Norris, E.J., Bloomquist, J.R. 2021. Toxicity and mode of action of the aporphine plant alkaloid liriodenine on the insect GABA receptor. Toxicon. 201:141-147. https://doi.org/10.1016/j.toxicon.2021.08.019.
DOI: https://doi.org/10.1016/j.toxicon.2021.08.019

Interpretive Summary: In this study, we screened a novel plant compound, liriodenine, for its toxicity against mosquitoes and its activity directly on the insect nervous system. Liriodenine was applied topically on African malaria mosquito females but was observed to be only moderately toxic. We demonstrated that applying this compound in combination with a synergist did increase its toxicity, suggesting that its lower insecticidal activity may be due to rapid metabolism within the insect. Furthermore, applying the compound directly on the Drosophila melanogaster central nervous system demonstrated that liriodenine was capable of exciting the nervous system. In fact, it was capable of reversing the block produced by GABA, a neurotransmitter that produces neuroinhibition, at micromolar concentrations. Furthermore, these results were validated by showing that liriodenine reversed the effects of GABA on American cockroach central nervous system neurons in patch clamp experiments. The IC50 of this reversal was approximately 1 micromolar. These studies in concert with molecular modeling suggests that liriodenine acts as an analog of bicuculline (a drug that reverses GABA in mammalian systems, but not insects) that is significantly active on the insect nervous system. The importance of this finding for the field of insect control is further discussed.

Technical Abstract: Liriodenine has been shown to be biologically active with multiple effects on mammals, fungi and bacteria, but has never been evaluated for insecticidal activity. In this study, liriodenine was applied topically to adults Anopheles gambiae, and found to be mildly toxic. Its lethality was synergized with both dimethyl sulfoxide (DMSO) and piperonyl butoxide (PBO). In recordings of the ventral nerve cord of larval Drosophila melanogaster, liriodenine was neuroexcitatory and reversed the inhibitory effect of 3 mM GABA at effective concentrations of 20-30 µM. GABAA receptors in Periplaneta americana acutely isolated neurons were studied under patch clamp and inhibitory effects with an IC50 value of about 1 µM were observed. In contrast, as expected bicuculline did not reverse the effects of GABA on either the DmCNS or cockroach neurons. In silico molecular models highlighted novel docking poses for liriodenine and bicuculline on the GABA receptor. This study is the first assessing of the toxicology of liriodenine on insects, and suggests the GABA as a target, with liriodenine acting as an active analog of bicuculline in insects.