Efficacy Assessment of an Uncharged Reactivator of NOP-Inhibited Acetylcholinesterase Based on Tetrahydroacridine Pyridine-Aldoxime Hybrid in Mouse Compared to Pralidoxime
(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 a...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-06-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/10/6/858 |
| _version_ | 1797566114661662720 |
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| author | André-Guilhem Calas Anne-Sophie Hanak Nina Jaffré Aurélie Nervo José Dias Catherine Rousseau Charlotte Courageux Xavier Brazzolotto Pascal Villa Adeline Obrecht Jean-François Goossens Christophe Landry Johan Hachani Fabien Gosselet Marie-Pierre Dehouck Jagadeesh Yerri Maria Kliachyna Rachid Baati Florian Nachon |
| author_facet | André-Guilhem Calas Anne-Sophie Hanak Nina Jaffré Aurélie Nervo José Dias Catherine Rousseau Charlotte Courageux Xavier Brazzolotto Pascal Villa Adeline Obrecht Jean-François Goossens Christophe Landry Johan Hachani Fabien Gosselet Marie-Pierre Dehouck Jagadeesh Yerri Maria Kliachyna Rachid Baati Florian Nachon |
| author_sort | André-Guilhem Calas |
| collection | DOAJ |
| description | (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. |
| first_indexed | 2024-03-10T19:22:09Z |
| format | Article |
| id | doaj.art-c8ad1bdb8ca0419e90bec0584f145514 |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-10T19:22:09Z |
| publishDate | 2020-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-c8ad1bdb8ca0419e90bec0584f1455142023-11-20T02:52:34ZengMDPI AGBiomolecules2218-273X2020-06-0110685810.3390/biom10060858Efficacy Assessment of an Uncharged Reactivator of NOP-Inhibited Acetylcholinesterase Based on Tetrahydroacridine Pyridine-Aldoxime Hybrid in Mouse Compared to PralidoximeAndré-Guilhem Calas0Anne-Sophie Hanak1Nina Jaffré2Aurélie Nervo3José Dias4Catherine Rousseau5Charlotte Courageux6Xavier Brazzolotto7Pascal Villa8Adeline Obrecht9Jean-François Goossens10Christophe Landry11Johan Hachani12Fabien Gosselet13Marie-Pierre Dehouck14Jagadeesh Yerri15Maria Kliachyna16Rachid Baati17Florian Nachon18Département de Toxicologie et Risques Chimiques, Institut de Recherche Biomédicale des Armées, F-91220 Brétigny-sur-Orge, FranceDépartement de Toxicologie et Risques Chimiques, Institut de Recherche Biomédicale des Armées, F-91220 Brétigny-sur-Orge, FranceDépartement de Toxicologie et Risques Chimiques, Institut de Recherche Biomédicale des Armées, F-91220 Brétigny-sur-Orge, FranceDépartement de Toxicologie et Risques Chimiques, Institut de Recherche Biomédicale des Armées, F-91220 Brétigny-sur-Orge, FranceDépartement de Toxicologie et Risques Chimiques, Institut de Recherche Biomédicale des Armées, F-91220 Brétigny-sur-Orge, FranceDépartement de Toxicologie et Risques Chimiques, Institut de Recherche Biomédicale des Armées, F-91220 Brétigny-sur-Orge, FranceDépartement de Toxicologie et Risques Chimiques, Institut de Recherche Biomédicale des Armées, F-91220 Brétigny-sur-Orge, FranceDépartement de Toxicologie et Risques Chimiques, Institut de Recherche Biomédicale des Armées, F-91220 Brétigny-sur-Orge, FranceCNRS, Université de Strasbourg, PCBIS Plate-forme de Chimie Biologique Intégrative de Strasbourg UMS 3286, F-67412 Illkirch, FranceCNRS, Université de Strasbourg, PCBIS Plate-forme de Chimie Biologique Intégrative de Strasbourg UMS 3286, F-67412 Illkirch, FranceUniversité de Lille, ULR-7365—GRITA Groupe de Recherche sur les Formes Injectables et Technologies Associées, F-59000, Lille, FranceUniversité d’Artois (UArtois), UR 2465, LBHE Laboratoire de la Barrière Hémato-Encéphalique, F-62307 Lens, FranceUniversité d’Artois (UArtois), UR 2465, LBHE Laboratoire de la Barrière Hémato-Encéphalique, F-62307 Lens, FranceUniversité d’Artois (UArtois), UR 2465, LBHE Laboratoire de la Barrière Hémato-Encéphalique, F-62307 Lens, FranceUniversité d’Artois (UArtois), UR 2465, LBHE Laboratoire de la Barrière Hémato-Encéphalique, F-62307 Lens, FranceUMR CNRS 7515, ICPEES Institut de Chimie et Procédés pour l’Énergie, l’Environnement et la Santé, F-67087 Strasbourg, FranceUMR CNRS 7515, ICPEES Institut de Chimie et Procédés pour l’Énergie, l’Environnement et la Santé, F-67087 Strasbourg, FranceUMR CNRS 7515, ICPEES Institut de Chimie et Procédés pour l’Énergie, l’Environnement et la Santé, F-67087 Strasbourg, FranceDépartement de Toxicologie et Risques Chimiques, Institut de Recherche Biomédicale des Armées, F-91220 Brétigny-sur-Orge, France(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.https://www.mdpi.com/2218-273X/10/6/858organophosphorus nerve agentsoximecholinesterasereactivationventilationpharmacodynamics |
| spellingShingle | André-Guilhem Calas Anne-Sophie Hanak Nina Jaffré Aurélie Nervo José Dias Catherine Rousseau Charlotte Courageux Xavier Brazzolotto Pascal Villa Adeline Obrecht Jean-François Goossens Christophe Landry Johan Hachani Fabien Gosselet Marie-Pierre Dehouck Jagadeesh Yerri Maria Kliachyna Rachid Baati Florian Nachon Efficacy Assessment of an Uncharged Reactivator of NOP-Inhibited Acetylcholinesterase Based on Tetrahydroacridine Pyridine-Aldoxime Hybrid in Mouse Compared to Pralidoxime Biomolecules organophosphorus nerve agents oxime cholinesterase reactivation ventilation pharmacodynamics |
| title | Efficacy Assessment of an Uncharged Reactivator of NOP-Inhibited Acetylcholinesterase Based on Tetrahydroacridine Pyridine-Aldoxime Hybrid in Mouse Compared to Pralidoxime |
| title_full | Efficacy Assessment of an Uncharged Reactivator of NOP-Inhibited Acetylcholinesterase Based on Tetrahydroacridine Pyridine-Aldoxime Hybrid in Mouse Compared to Pralidoxime |
| title_fullStr | Efficacy Assessment of an Uncharged Reactivator of NOP-Inhibited Acetylcholinesterase Based on Tetrahydroacridine Pyridine-Aldoxime Hybrid in Mouse Compared to Pralidoxime |
| title_full_unstemmed | Efficacy Assessment of an Uncharged Reactivator of NOP-Inhibited Acetylcholinesterase Based on Tetrahydroacridine Pyridine-Aldoxime Hybrid in Mouse Compared to Pralidoxime |
| title_short | Efficacy Assessment of an Uncharged Reactivator of NOP-Inhibited Acetylcholinesterase Based on Tetrahydroacridine Pyridine-Aldoxime Hybrid in Mouse Compared to Pralidoxime |
| title_sort | efficacy assessment of an uncharged reactivator of nop inhibited acetylcholinesterase based on tetrahydroacridine pyridine aldoxime hybrid in mouse compared to pralidoxime |
| topic | organophosphorus nerve agents oxime cholinesterase reactivation ventilation pharmacodynamics |
| url | https://www.mdpi.com/2218-273X/10/6/858 |
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