3区 · 综合性期刊
ArticleOA
作者: Chumakov, Ilya ; Nabirotchkin, Serguei ; Cholet, Nathalie ; Milet, Aude ; Boucard, Aurelie ; Toulorge, Damien ; Pereira, Yannick ; Graudens, Esther ; Traore, Sory ; Foucquier, Julie ; Guedj, Mickael ; Vial, Emmanuel ; Callizot, Noelle ; Steinschneider, Remy ; Maurice, Tangui ; Bertrand, Viviane ; Scart-Gres, Catherine ; Hajj, Rodolphe ; Cohen, Daniel
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.