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

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  • Additional Information
    • Source:
      Publisher: MDPI Country of Publication: Switzerland NLM ID: 101596414 Publication Model: Electronic Cited Medium: Internet ISSN: 2218-273X (Electronic) Linking ISSN: 2218273X NLM ISO Abbreviation: Biomolecules Subsets: MEDLINE
    • Publication Information:
      Original Publication: Basel, Switzerland : MDPI, 2011-
    • Subject Terms:
      Acetylcholinesterase/*metabolism ; Cholinesterase Inhibitors/*pharmacology ; Pralidoxime Compounds/*pharmacology; Animals ; Blood-Brain Barrier/drug effects ; Cell Survival/drug effects ; Cells, Cultured ; Cholinesterase Inhibitors/administration & dosage ; Cholinesterase Inhibitors/chemistry ; Dose-Response Relationship, Drug ; Humans ; Injections, Intraperitoneal ; Male ; Mice ; Molecular Structure ; Pralidoxime Compounds/chemistry ; Recombinant Proteins/metabolism
    • 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.
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    • Grant Information:
      PDH-2-NRBC-4-C-4203 International Direction Générale de l'Armement; PDH-5-C-4210 International Direction Générale de l'Armement; ANR-17-CE39-0012 International Agence Nationale de la Recherche; LABEX ANR-10-LABX-0034_Medalis International Agence Nationale de la Recherche
    • Contributed Indexing:
      Keywords: blood-brain barrier crossing; cholinesterase; organophosphorus nerve agents; oxime; pharmacodynamics; reactivation; ventilation
    • Accession Number:
      0 (Cholinesterase Inhibitors)
      0 (Pralidoxime Compounds)
      0 (Recombinant Proteins)
      EC 3.1.1.7 (Acetylcholinesterase)
      P7MU9UTP52 (pralidoxime)
    • Publication Date:
      Date Created: 20200610 Date Completed: 20210413 Latest Revision: 20210413
    • Publication Date:
      20221213
    • Accession Number:
      PMC7355633
    • Accession Number:
      10.3390/biom10060858
    • Accession Number:
      32512884