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

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Abstract

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.

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Abbreviations

ACh:

Acetylcholine

AChE:

Acetylcholinesterase

GABA:

γ-aminobutyric acid

NMDA:

N-methyl-d-aspartate

NMJ:

Neuromuscular junction

OP:

Organophosphorus agents

POX:

Paraoxon

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Funding

Muscle contraction studies in this research were supported by Russian Science Foundation project no. 17-14-01097 for P.M. Toxicological studies were supported by the Program for “Basic Research for Biomedical Technologies” for KP.

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Authors and Affiliations

  1. Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center of RAS, Arbuzov str. 8, Kazan, Russia, 420088

    O. A. Lenina & K. A. Petrov

  2. Kazan Federal University, 18 Kremlyovskaya str, Kazan, Russia, 420008

    P. Masson & K. A. Petrov

  3. Kazan Institute of Biochemistry and Biophysics, FRC Kazan Scientific Center of RAS, Lobachevsky str. 2/31, Kazan, Russia, 420111

    K. A. Petrov

Authors
  1. O. A. Lenina
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  2. P. Masson
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Corresponding author

Correspondence to K. A. Petrov.

Ethics declarations

All experiments involving animals were performed in accordance with the guidelines set forth by the European Communities Council Directive of November 24, 1986 (86/609/EEC) and the protocol of experiments approved by the Animal Care and Use Committee of Kazan Federal University.

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Lenina, O.A., Masson, P. & Petrov, K.A. Blockade of Metabotropic GABA-B Receptors as an Approach to Reduce Toxic Peripheral Effects of Cholinesterase Inhibitors. BioNanoSci. 9, 38–43 (2019). https://doi.org/10.1007/s12668-018-0572-x

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