title: Combining two repurposed drugs as a promising approach for Alzheimer's disease therapy.
abstract: Alzheimer disease (AD) represents a major medical problem where mono-therapeutic interventions demonstrated only a limited efficacy so far. We explored the possibility of developing a combinational therapy that might prevent the degradation of neuronal and endothelial structures in this disease. We argued that the distorted balance between excitatory (glutamate) and inhibitory (GABA/glycine) systems constitutes a therapeutic target for such intervention. We found that a combination of two approved drugs - acamprosate and baclofen - synergistically protected neurons and endothelial structures in vitro against amyloid-beta (Aβ) oligomers. The neuroprotective effects of these drugs were mediated by modulation of targets in GABA/glycinergic and glutamatergic pathways. In vivo, the combination alleviated cognitive deficits in the acute Aβ25-35 peptide injection model and in the mouse mutant APP transgenic model. Several patterns altered in AD were also synergistically normalised. Our results open up the possibility for a promising therapeutic approach for AD by combining repurposed drugs.
authors.affiliation: Pharnext, 11 rue des Peupliers, 92130 Issy-Les-Moulineaux, France.
authors.forename: Ilya
authors.initials: I
authors.lastname: Chumakov
authors.affiliation: Pharnext, 11 rue des Peupliers, 92130 Issy-Les-Moulineaux, France.
authors.forename: Serguei
authors.initials: S
authors.lastname: Nabirotchkin
authors.affiliation: Pharnext, 11 rue des Peupliers, 92130 Issy-Les-Moulineaux, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Cholet
authors.affiliation: Pharnext, 11 rue des Peupliers, 92130 Issy-Les-Moulineaux, France.
authors.forename: Aude
authors.initials: A
authors.lastname: Milet
authors.affiliation: Pharnext, 11 rue des Peupliers, 92130 Issy-Les-Moulineaux, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Boucard
authors.affiliation: Pharnext, 11 rue des Peupliers, 92130 Issy-Les-Moulineaux, France.
authors.forename: Damien
authors.initials: D
authors.lastname: Toulorge
authors.affiliation: Pharnext, 11 rue des Peupliers, 92130 Issy-Les-Moulineaux, France.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Pereira
authors.affiliation: Pharnext, 11 rue des Peupliers, 92130 Issy-Les-Moulineaux, France.
authors.forename: Esther
authors.initials: E
authors.lastname: Graudens
authors.affiliation: Pharnext, 11 rue des Peupliers, 92130 Issy-Les-Moulineaux, France.
authors.forename: Sory
authors.initials: S
authors.lastname: Traoré
authors.affiliation: Pharnext, 11 rue des Peupliers, 92130 Issy-Les-Moulineaux, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Foucquier
authors.affiliation: Pharnext, 11 rue des Peupliers, 92130 Issy-Les-Moulineaux, France.
authors.forename: Mickael
authors.initials: M
authors.lastname: Guedj
authors.affiliation: Pharnext, 11 rue des Peupliers, 92130 Issy-Les-Moulineaux, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Vial
authors.affiliation: Neuro/Sys, 410 CD 60, 13120 Gardanne, France.
authors.forename: Noëlle
authors.initials: N
authors.lastname: Callizot
authors.affiliation: Neuronexperts, 51 bd Pierre Dramard, 13916 Marseille, France.
authors.forename: Rémy
authors.initials: R
authors.lastname: Steinschneider
authors.affiliation: 1] Université de Montpellier 2, 34095 Montpellier, France; Inserm, U710, 34095 Montpellier, France; EPHE, 75017 Paris, France [2] Amylgen, 2196 bd de la Lironde, 34980 Montferrier-sur-Lez, France.
authors.forename: Tangui
authors.initials: T
authors.lastname: Maurice
authors.affiliation: Pharnext, 11 rue des Peupliers, 92130 Issy-Les-Moulineaux, France.
authors.forename: Viviane
authors.initials: V
authors.lastname: Bertrand
authors.affiliation: Pharnext, 11 rue des Peupliers, 92130 Issy-Les-Moulineaux, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Scart-Grès
authors.affiliation: Pharnext, 11 rue des Peupliers, 92130 Issy-Les-Moulineaux, France.
authors.forename: Rodolphe
authors.initials: R
authors.lastname: Hajj
authors.affiliation: Pharnext, 11 rue des Peupliers, 92130 Issy-Les-Moulineaux, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Cohen
mesh_terms: D000077443:Acamprosate; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000633:toxicity; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001418:Baclofen / Q000494:pharmacology / Q000627:therapeutic use*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D058492:Drug Repositioning; D004357:Drug Synergism; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D013654:Taurine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D018696:Neuroprotective Agents; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); C074636:amyloid beta-protein (25-35); D013654:Taurine; D001418:Baclofen; D000077443:Acamprosate