Blockade of Metabotropic GABA-B Receptors as an Approach to Reduce Toxic Peripheral Effects of Cholinesterase Inhibitors

The application of organophosphate (OP) pesticides in agriculture, in addition to the existence of chemical warfare nerve agents and their possible use in terrorist acts is a significant threat to populations all over the world. Moreover, treatment of OP poisoning is still imperfect. Here, we studied the effect of blockade of metabotropic GABA-B receptors by compound CGP55845 (10 μM) on the force of muscle contractions when cholinesterases are inhibited by paraoxon. It was shown that CGP55845 prevented the decrease in the force of diaphragm muscle contractions caused by paraoxon ex vivo . Moreover, for in vivo experiments, GABA-B receptor blocker CGP36742 at the doses 30 and 100 mg/kg was used. It was shown that CGP36742 is able to reduce the lethality of mice after OP challenge . Thus, GABA-B receptor blockers can be considered as additional medications, which can complement the current therapy of acute poisoning by cholinesterase inhibitors.