Combining two repurposed drugs as a promising approach for Alzheimer's disease therapy

Ilya Chumakov; Serguei Nabirotchkin; Nathalie Cholet; Aude Milet; Aurélie Boucard; Damien Toulorge; Yannick Pereira; Esther Graudens; Sory Traoré; Julie Foucquier; Mickael Guedj; Emmanuel Vial; Noëlle Callizot; Rémy Steinschneider; Tangui Maurice; Viviane Bertrand; Catherine Scart-Grès; Rodolphe Hajj; Daniel Cohen

doi:10.1038/srep07608

Combining two repurposed drugs as a promising approach for Alzheimer's disease therapy

Sci Rep. 2015 Jan 8:5:7608. doi: 10.1038/srep07608.

Authors

Ilya Chumakov¹, Serguei Nabirotchkin¹, Nathalie Cholet¹, Aude Milet¹, Aurélie Boucard¹, Damien Toulorge¹, Yannick Pereira¹, Esther Graudens¹, Sory Traoré¹, Julie Foucquier¹, Mickael Guedj¹, Emmanuel Vial¹, Noëlle Callizot², Rémy Steinschneider³, Tangui Maurice⁴, Viviane Bertrand¹, Catherine Scart-Grès¹, Rodolphe Hajj¹, Daniel Cohen¹

Affiliations

¹ Pharnext, 11 rue des Peupliers, 92130 Issy-Les-Moulineaux, France.
² Neuro/Sys, 410 CD 60, 13120 Gardanne, France.
³ Neuronexperts, 51 bd Pierre Dramard, 13916 Marseille, France.
⁴ 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.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acamprosate
Alzheimer Disease / drug therapy*
Alzheimer Disease / pathology
Amyloid beta-Peptides / antagonists & inhibitors
Amyloid beta-Peptides / metabolism
Amyloid beta-Peptides / toxicity
Amyloid beta-Protein Precursor / genetics
Amyloid beta-Protein Precursor / metabolism
Animals
Apoptosis / drug effects
Baclofen / pharmacology
Baclofen / therapeutic use*
Cells, Cultured
Disease Models, Animal
Drug Repositioning*
Drug Synergism
Female
Humans
Male
Mice
Mice, Transgenic
Neurons / cytology
Neurons / drug effects
Neurons / metabolism
Neuroprotective Agents / pharmacology
Neuroprotective Agents / therapeutic use
Peptide Fragments / antagonists & inhibitors
Peptide Fragments / metabolism
Peptide Fragments / toxicity
Rats
Rats, Wistar
Signal Transduction / drug effects
Taurine / analogs & derivatives*
Taurine / pharmacology
Taurine / therapeutic use

Substances

Amyloid beta-Peptides
Amyloid beta-Protein Precursor
Neuroprotective Agents
Peptide Fragments
amyloid beta-protein (1-42)
amyloid beta-protein (25-35)
Taurine
Baclofen
Acamprosate