Combination of acamprosate and baclofen (PXT864) as a potential new therapy for amyotrophic lateral sclerosis.,Journal of Neuroscience Research

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Combination of acamprosate and baclofen (PXT864) as a potential new therapy for amyotrophic lateral sclerosis.
Journal of Neuroscience Research ( IF 2.9 ) Pub Date : 2020-08-19 , DOI: 10.1002/jnr.24714
Lydie Boussicault ₁ , Julien Laffaire ₁ , Peter Schmitt ₁ , Philippe Rinaudo ₁ , Noëlle Callizot ₂ , Serguei Nabirotchkin ₁ , Rodolphe Hajj ₁ , Daniel Cohen ₁

Affiliation

There is currently no therapy impacting the course of amyotrophic lateral sclerosis (ALS). The only approved treatments are riluzole and edaravone, but their efficacy is modest and short‐lasting, highlighting the need for innovative therapies. We previously demonstrated the ability of PXT864, a combination of low doses of acamprosate and baclofen, to synergistically restore cellular and behavioral activity in Alzheimer's and Parkinson's disease models. The overlapping genetic, molecular, and cellular characteristics of these neurodegenerative diseases supported investigating the effectiveness of PXT864 in ALS. As neuromuscular junction (NMJ) alterations is a key feature of ALS, the effects of PXT864 in primary neuron‐muscle cocultures injured by glutamate were studied. PXT864 significantly and synergistically preserved NMJ and motoneuron integrity following glutamate excitotoxicity. PXT864 added to riluzole significantly improved such protection. PXT864 activity was then assessed in primary cultures of motoneurons derived from SOD1^G93A rat embryos. These motoneurons presented severe maturation defects that were significantly improved by PXT864. In this model, glutamate application induced an accumulation of TDP‐43 protein in the cytoplasm, a hallmark that was completely prevented by PXT864. The anti‐TDP‐43 aggregation effect was also confirmed in a cell line expressing TDP‐43 fused to GFP. These results demonstrate the value of PXT864 as a promising therapeutic strategy for the treatment of ALS.

中文翻译：

阿坎酸和巴氯芬 (PXT864) 的组合作为肌萎缩侧索硬化症的潜在新疗法。

目前没有影响肌萎缩侧索硬化 (ALS) 病程的疗法。唯一获得批准的治疗方法是利鲁唑和依达拉奉，但它们的疗效适中且持续时间短，突出了对创新疗法的需求。我们之前证明了 PXT864（低剂量阿坎酸和巴氯芬的组合）在阿尔茨海默病和帕金森病模型中协同恢复细胞和行为活动的能力。这些神经退行性疾病的重叠遗传、分子和细胞特征支持研究 PXT864 在 ALS 中的有效性。由于神经肌肉接头 (NMJ) 改变是 ALS 的一个关键特征，因此研究了 PXT864 在受谷氨酸损伤的原代神经元肌肉共培养物中的作用。PXT864 在谷氨酸兴奋性毒性后显着且协同地保留了 NMJ 和运动神经元的完整性。添加到利鲁唑中的 PXT864 显着改善了这种保护。然后在源自 SOD1 的运动神经元的原代培养物中评估 PXT864 活性^G93A大鼠胚胎。这些运动神经元表现出严重的成熟缺陷，PXT864 显着改善了这些缺陷。在该模型中，谷氨酸盐应用诱导细胞质中 TDP-43 蛋白的积累，这是 PXT864 完全阻止的标志。在表达与 GFP 融合的 TDP-43 的细胞系中也证实了抗 TDP-43 聚集效应。这些结果证明了 PXT864 作为治疗 ALS 的有前途的治疗策略的价值。

更新日期：2020-10-19

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