Chumakov Ilya, Nabirotchkin Serguei, Cholet Nathalie, Milet Aude, Boucard Aurélie, Toulorge Damien, Pereira Yannick, Graudens Esther, Traoré Sory, Foucquier Julie, Guedj Mickael, Vial Emmanuel, Callizot Noëlle, Steinschneider Rémy, Maurice Tangui, Bertrand Viviane, Scart-Grès Catherine, Hajj Rodolphe, Cohen Daniel
Pharnext, 11 rue des Peupliers, 92130 Issy-Les-Moulineaux, France.
Neuro/Sys, 410 CD 60, 13120 Gardanne, France.
Sci Rep. 2015 Jan 8;5:7608. doi: 10.1038/srep07608.
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.
阿尔茨海默病（AD）是一个重大的医学问题，迄今为止，单一治疗干预措施的疗效有限。我们探索了开发一种联合疗法的可能性，这种联合疗法可能预防该疾病中神经元和内皮结构的退化。我们认为，兴奋性（谷氨酸）和抑制性（γ-氨基丁酸/甘氨酸）系统之间失衡构成了此类干预的治疗靶点。我们发现，两种已获批药物——阿坎酸和巴氯芬——联合使用可在体外协同保护神经元和内皮结构免受β-淀粉样蛋白（Aβ）寡聚体的损伤。这些药物的神经保护作用是通过调节γ-氨基丁酸/甘氨酸能和谷氨酸能途径中的靶点介导的。在体内，该联合用药减轻了急性注射Aβ25-35肽模型和小鼠突变体APP转基因模型中的认知缺陷。AD中改变的几种模式也得到了协同正常化。我们的结果为通过联合使用重新利用的药物来治疗AD开辟了一条有前景的治疗途径。
