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New piperazine multi-effect drugs prevent neurofibrillary degeneration and amyloid deposition, and preserve memory in animal models of Alzheimer's disease
Nicolas Sergeant
1
Valérie Vingtdeux
1
Sabiha Eddarkaoui
1
Marion Gay
1
Caroline Evrard
1
Nicolas Le Fur
1
Cyril Laurent
1
Raphaëlle Caillierez
1
Hélène Obriot
1
Paul-Emmanuel Larchanché
1
Amaury Farce
2
Mathilde Coevoet
1
Pascal Carato
1
Mostafa Kouach
3
Amandine Descat
3
Patrick Dallemagne
4
Valérie Buée-Scherrer
1
David Blum
1
Malika Hamdane
1
Luc Buee
1, *
Patricia Melnyk
1, *
*
Corresponding author
Caroline Evrard 1
Mail :
Author
Nicolas Le Fur 1
Author
Cyril Laurent 1
Author
Raphaëlle Caillierez 1
Author
Hélène Obriot 1
Author
Paul-Emmanuel Larchanché 1
Author
Amaury Farce 2
Author
Mathilde Coevoet 1
Mail :
Author Employer institution : Université de Lille
Pascal Carato 1
Author
Mostafa Kouach 3
Author
Amandine Descat 3
Author
Patrick Dallemagne 4
Mail :
Author IdHAL : patrick-dallemagne ResearcherId : http://www.researcherid.com/rid/D-3237-2013 ORCID : https://orcid.org/0000-0002-4845-615X
Valérie Buée-Scherrer 1
Author
David Blum 1
Mail :
Author IdHAL : david-blum ORCID : https://orcid.org/0000-0001-5691-431X
Malika Hamdane 1
Author
Luc Buee 1
Mail :
Correspondent author IdHAL : luc-buee ResearcherId : http://www.researcherid.com/rid/B-3126-2010 ORCID : https://orcid.org/0000-0002-6261-4230
Patricia Melnyk 1
Mail :
Correspondent author IdHAL : patricia-melnyk ORCID : https://orcid.org/0000-0002-9555-3446
1
JPArc - U1172 Inserm - Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (Faculté de Médecine Henri Warembourg - Pôle Recherche - 1 place de verdun 59045 Lille cedex. - France)
- Université Lille Nord de France (COMUE) (365 bis, rue Jules Guesde BP 50458 - 59658 Villeneuve d’Ascq Cedex - France)
- INSERM - Institut National de la Santé et de la Recherche Médicale : U1172 (101, rue de Tolbiac, 75013 Paris - France)
- CHRU Lille - Centre Hospitalier Régional Universitaire [Lille] (2, avenue Oscar Lambret - 59037 Lille Cedex - France)
- Université Lille 2 - Faculté de Médecine (1, place de Verdun 59045 Lille Cédex - France)
2
LIRIC - Lille Inflammation Research International Center (Faculté de médecine
Pôle recherche-4ème étage
Place de Verdun
F-59045 Lille Cedex - France)
- Institut Pasteur de Lille : U995 (1 Rue du Professeur Calmette - Lille Cedex - 59019 - France)
- RIIP - Réseau International des Instituts Pasteur (25, rue du Dr Roux 75724 Paris Cedex 15 - France)
- INSERM - Institut National de la Santé et de la Recherche Médicale : U995 (101, rue de Tolbiac, 75013 Paris - France)
- Université de Lille (Lille - France)
- CHRU Lille - Centre Hospitalier Régional Universitaire [Lille] : U995 (2, avenue Oscar Lambret - 59037 Lille Cedex - France)
3
CUMA - Centre Universitaire de Mesures et d'Analyses [UNIV Lille] (France)
- Université de Lille (Lille - France)
4
CERMN - Centre d'Etudes et de Recherche sur le Médicament de Normandie (Boulevard Becquerel 14032 Caen cedex - France)
- UNICAEN - Université de Caen Normandie : EA 4258 (Esplanade de la Paix - CS 14032 - 14032 CAEN Cedex 5 - France)
- NU - Normandie Université (Esplanade de la Paix - CS 14032 - 14032 Caen Cedex 5 - France)
Abstract : Alzheimer's Disease is a devastating dementing disease involving amyloid deposits, neurofibrillary tangles, progressive and irreversible cognitive impairment. Today, only symptomatic drugs are available and therapeutic treatments, possibly acting at a multiscale level, are thus urgently needed. To that purpose, we designed multi-effects compounds by synthesizing drug candidates derived by substituting a novel N,N'-disubstituted piperazine anti-amyloid scaffold and adding acetylcholinesterase inhibition property. Two compounds were synthesized and evaluated. The most promising hybrid molecule reduces both the amyloid pathology and the Tau pathology as well as the memory impairments in a preclinical model of Alzheimer's disease. In vitro also, the compound reduces the phosphorylation of Tau and inhibits the release of Aβ peptides while preserving the processing of other metabolites of the amyloid precursor protein. We synthetized and tested the first drug capable of ameliorating both the amyloid and Tau pathology in animal models of AD as well as preventing the major brain lesions and associated memory impairments. This work paves the way for future compound medicines against both Alzheimer's-related brain lesions development and the associated cognitive impairments.
Document type :
Journal articles
Complete list of metadatas
https://www.hal.inserm.fr/inserm-02350071
Contributor : David Blum <>
Submitted on : Tuesday, November 5, 2019 - 10:09:14 PM
Last modification on : Saturday, February 29, 2020 - 4:00:06 PM
Document(s) archivé(s) le : Friday, February 7, 2020 - 1:36:22 PM
Contributor : David Blum <>
Submitted on : Tuesday, November 5, 2019 - 10:09:14 PM
Last modification on : Saturday, February 29, 2020 - 4:00:06 PM
Document(s) archivé(s) le : Friday, February 7, 2020 - 1:36:22 PM
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Identifiers
- HAL Id : inserm-02350071, version 1
- DOI : 10.1016/j.nbd.2019.03.028
- PUBMED : 30928644
Collections
RIIP | RIIP_LILLE | UNIV-LILLE | CERMN | UNICAEN | COMUE-NORMANDIE
Citation
Nicolas Sergeant, Valérie Vingtdeux, Sabiha Eddarkaoui, Marion Gay, Caroline Evrard, et al.. New piperazine multi-effect drugs prevent neurofibrillary degeneration and amyloid deposition, and preserve memory in animal models of Alzheimer's disease. Neurobiology of Disease, Elsevier, 2019, 129, pp.217-233. ⟨10.1016/j.nbd.2019.03.028⟩. ⟨inserm-02350071⟩
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