Rousseau C

References (2)

Title : Efficacy Assessment of an Uncharged Reactivator of NOP-Inhibited Acetylcholinesterase Based on Tetrahydroacridine Pyridine-Aldoxime Hybrid in Mouse Compared to Pralidoxime - Calas_2020_Biomolecules_10_
Author(s) : Calas AG , Hanak AS , Jaffre N , Nervo A , Dias J , Rousseau C , Courageux C , Brazzolotto X , Villa P , Obrecht A , Goossens JF , Landry C , Hachani J , Gosselet F , Dehouck MP , Yerri J , Kliachyna M , Baati R , Nachon F
Ref : Biomolecules , 10 : , 2020
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. This breathing assessment could help define the No Observed Adverse Effect Level (NOAEL) dose of new oximes which would have a maximum therapeutic effect without any toxic side effects.
ESTHER : Calas_2020_Biomolecules_10_
PubMedSearch : Calas_2020_Biomolecules_10_
PubMedID: 32512884

Title : An easy method for the determination of active concentrations of cholinesterase reactivators in blood samples: Application to the efficacy assessment of non quaternary reactivators compared to HI-6 and pralidoxime in VX-poisoned mice - Calas_2017_Chem.Biol.Interact_267_11
Author(s) : Calas AG , Dias J , Rousseau C , Arboleas M , Touvrey-Loiodice M , Mercey G , Jean L , Renard PY , Nachon F
Ref : Chemico-Biological Interactions , 267 :11 , 2017
Abstract : Organophosphorus nerve agents, like VX, are highly toxic due to their strong inhibition potency against acetylcholinesterase (AChE). AChE inhibited by VX can be reactivated using powerful nucleophilic molecules, most commonly oximes, which are one major component of the emergency treatment in case of nerve agent intoxication. We present here a comparative in vivo study on Swiss mice of four reactivators: HI-6, pralidoxime and two uncharged derivatives of 3-hydroxy-2-pyridinaldoxime that should more easily cross the blood-brain barrier and display a significant central nervous system activity. The reactivability kinetic profile of the oximes is established following intraperitoneal injection in healthy mice, using an original and fast enzymatic method based on the reactivation potential of oxime-containing plasma samples. HI-6 displays the highest reactivation potential whatever the conditions, followed by pralidoxime and the two non quaternary reactivators at the dose of 50 mg/kg bw. But these three last reactivators display equivalent reactivation potential at the same dose of 100 mumol/kg bw. Maximal reactivation potential closely correlates to surviving test results of VX intoxicated mice.
ESTHER : Calas_2017_Chem.Biol.Interact_267_11
PubMedSearch : Calas_2017_Chem.Biol.Interact_267_11
PubMedID: 26972668