Efficacy Assessment of an Uncharged Reactivator of NOP-Inhibited Acetylcholinesterase Based on Tetrahydroacridine Pyridine-Aldoxime Hybrid in Mouse Compared to Pralidoxime.

Biomolecules
André-Guilhem CalasFlorian Nachon

Abstract

(1) Background: Human exposure to organophosphorus compounds employed as pesticides or as chemical warfare agents induces deleterious effects due to cholinesterase inhibition. One therapeutic approach is the reactivation of inhibited acetylcholinesterase by oximes. While currently available oximes are unable to reach the central nervous system to reactivate cholinesterases or to display a wide spectrum of action against the variety of organophosphorus compounds, we aim to identify new reactivators without such drawbacks. (2) Methods: This study gathers an exhaustive work to assess in vitro and in vivo efficacy, and toxicity of a hybrid tetrahydroacridine pyridinaldoxime reactivator, KM297, compared to pralidoxime. (3) Results: Blood-brain barrier crossing assay carried out on a human in vitro model established that KM297 has an endothelial permeability coefficient twice that of pralidoxime. It also presents higher cytotoxicity, particularly on bone marrow-derived cells. Its strong cholinesterase inhibition potency seems to be correlated to its low protective efficacy in mice exposed to paraoxon. Ventilatory monitoring of KM297-treated mice by double-chamber plethysmography shows toxic effects at the selected therapeutic dose. T...Continue Reading

References

May 1, 1992·Journal of Neurochemistry·M P DehouckJ P Tillement
Jul 1, 1987·Journal of Cellular Physiology·A Siflinger-BirnboimA B Malik
Mar 11, 1998·Journal of Clinical Gastroenterology·W G BlackardM B Fallon
Jan 1, 1997·Revista de medicina de la Universidad de Navarra·C DávilaP de Castro
Jun 6, 2000·Journal of Biomolecular Screening·J H ZhangK R Oldenburg
Aug 8, 2002·Neurotoxicology·Guy LallementFrédéric Dorandeu
Aug 27, 2003·Neurochemical Research·Koichi SakuradaTakehiko Takatori
Jul 1, 1961·Biochemical Pharmacology·G L ELLMANR M FEATHER-STONE
Sep 2, 2006·Journal of the Neurological Sciences·Kevin Cannard
Jun 20, 2007·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Sukyung Woo, William J Jusko
May 27, 2008·Chemico-biological Interactions·Zrinka KovarikBozica Radić
Nov 4, 2008·Journal of the American Chemical Society·Eugénie CarlettiFlorian Nachon
Jul 5, 2011·Neurotoxicology·Alessandra Antunes dos SantosMarcelo Farina
Mar 1, 2012·Accounts of Chemical Research·Guillaume MerceyPierre-Yves Renard
Jun 26, 2015·Arhiv za higijenu rada i toksikologiju·Suzana ŽunecAna Lucić Vrdoljak
Apr 30, 2016·Chemico-biological Interactions·Franz WorekTimo Wille
Sep 20, 2018·Annual Review of Pharmacology and Toxicology·Michael Eddleston
Nov 27, 2018·Molecular Informatics·Lars Carlsen
May 22, 2019·Toxicology·Tereza KobrlovaOndrej Soukup
Sep 27, 2019·Future Medicinal Chemistry·Lukas GoreckiJan Korabecny
Sep 29, 2019·Cellular and Molecular Life Sciences : CMLS·Guru Krishnakumar ViswanathanDaniel Segal
Feb 6, 2020·Fluids and Barriers of the CNS·Hideaki NishiharaBritta Engelhardt

❮ Previous
Next ❯

Methods Mentioned

BETA
size exclusion chromatography

Software Mentioned

Iox
AOT
GraphPad
LabChart
Prism
GraphPad Prism

Related Concepts

Related Feeds

Blood Brain Barrier

The blood brain barrier is a border that separates blood from cerebrospinal fluid. Discover the latest search on this highly selective semipermeable membrane here.

Blood Brain Barrier Chips

The blood brain barrier (BBB) is comprised of endothelial cells that regulate the influx and outflux of plasma concentrations. Lab-on-a-chip devices allow scientists to model diseases and mechanisms such as the passage of therapeutic antibodies across the BBB. Discover the latest research on BBB chips here.