Mosquitoes are responsible for the highest mortality induced by an animal to human in any given year. They are deadly by transmitting various diseases, such as malaria, or more recently the zika virus. To prevent these pathologies, the best strategy remains control of the vectors, especially if no disease vaccine exists. Insecticides are so far the most effective way of both population control, and individual protection from biting insects. The neurotoxic insecticides represent the major part of the commercialized compounds, and are targeting mostly the cholinergic system, voltage-sensitive sodium channel or the GABAergic system. Resistance to insecticides is a global issue, and finding new modes of action is a good way to diversify their targets, reducing the risk of resistance. In this context, we assessed liriodenine, a natural aporphine alkaloid isolated from Stephania venosa (Menispermaceae), but also found in Annona glabra or Fissistigma glaucescens (Annonaceae) plants. Liriodenine has many distinct forms of biological activity, including antimicrobial, antineoplastic, and trypanocidal activity, as well as cardioregulatory actions on mammals. These effects have been associated with different modes of action, such as sodium, calcium, and potassium channel blockers, or as a muscarinic antagonist. In this study, we assessed the effect of liriodenine on the insect through different model systems. Our results indicate that liriodenine increases neuronal excitation on the central nervous system of Drosophila melanogaster, before blocking its firing. Moreover, on the same model, it was able to reverse transiently (EC50 = 18 µM) the inhibition induced by a high concentration of GABA (1 mM). When tested on the peripheral neuromuscular junction of Musca domestica, excitatory post-synaptic potentials were not altered significantly by concentrations of liriodenine up to 70 µM. Thus, it would appear to have little effect on insect ion channels, beside the GABA antagonist properties. When injected into female Aedes aegypti (50 ng/mosquito) liriodenine caused little mortality, but the mosquitoes collected at the bottom of the cup and did not fly when disturbed, indicating impaired behavior consistent with overall reduced CNS activity. These results suggest that its poor activity in vivo, will need to be overcome through either co-administration with a synergist, or pharmacodynamic enhancement by altering liriodenine structure to make it more potent.

Liriodenine, a natural plant alkaloid, as a tool to explore new targets for mosquitocidal activity

2019 Fall National Meeting

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