Synergistic actions of P-glycoprotein inhibitors on the activity of tacrine anticholinesterases towards vector mosquitoes

Mosquitoes affect human health worldwide as a result of their ability to vector multiple diseases.  Widespread insecticide resistance limits the use of current mosquitocidal chemistries to reduce the risk of mosquito-vectored diseases. Thus, mosquitocide resistance is a serious public health challenge that warrants the development of improved mosquitocide control strategies for these disease vectors.  P-glycoprotein(s) are efflux transporters that assist in maintaining the blood-brain barrier interface of mosquitoes and may serve as a first line of defense to mosquitocide exposures.  Our studies have demonstrated the blood-brain barrier of mosquitoes to interfere with the target-site delivery and action of anticholinesterase (anti-ChEs) chemistries; however, knowledge of these anti-ChEs interacting with mosquito P-glycoproteins is limited.  Here, I will summarize a toxicological, biochemical, and molecular examination of P-glycoprotein(s) transport substrates and inhibitory ligands for the yellow fever mosquito, Aedes aegypti (Liverpool Strain).  These data will be discussed with regard to the use of chemomodulators for increased target-site delivery and action of mosquitocides.