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 Maurice4,5, Viviane Bertrand1, Catherine Scart-Grès1, Rodolphe Hajj1 & Daniel Cohen1

1Pharnext, 11 rue des Peupliers, 92130 Issy-Les-Moulineaux, France, 2Neuro/Sys, 410 CD 60, 13120 Gardanne, France, 3Neuronexperts, 51 bd Pierre Dramard, 13916 Marseille, France, 4Université de Montpellier 2, 34095 Montpellier, France; Inserm, U710, 34095 Montpellier, France; EPHE, 75017 Paris, France, 5Amylgen, 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 (Ab) 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 Ab25–35 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.

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