Motor neuron degeneration and neuroinflammation are the most striking pathological features of amyotrophic lateral sclerosis (ALS). ALS currently has no cure and approved drugs have only a modest clinically therapeutic effect in patients. Drugs targeting different deleterious inflammatory pathways in ALS appear as promising therapeutic alternatives. Here, we have assessed the potential therapeutic effect of an electrophilic nitroalkene benzoic acid derivative, (E)-4-(2-nitrovinyl) benzoic acid (BANA), to slow down paralysis progression when administered after overt disease onset in SOD1^G93A rats. BANA exerted a significant inhibition of NF-κB activation in NF-κB reporter transgenic mice and microglial cell cultures. Systemic daily oral administration of BANA to SOD1^G93A rats after paralysis onset significantly decreased microgliosis and astrocytosis, and significantly reduced the number of NF-κB-p65-positive microglial nuclei surrounding spinal motor neurons. Numerous microglia bearing nuclear NF-κB-p65 were observed in the surrounding of motor neurons in autopsy spinal cords from ALS patients but not in controls, suggesting ALS-associated microglia could be targeted by BANA. In addition, BANA-treated SOD1^G93A rats after paralysis onset showed significantly ameliorated spinal motor neuron pathology as well as conserved neuromuscular junction innervation in the skeletal muscle, as compared to controls. Notably, BANA prolonged post-paralysis survival by ~30%, compared to vehicle-treated littermates. These data provide a rationale to therapeutically slow paralysis progression in ALS using small electrophilic compounds such as BANA, through a mechanism involving microglial NF-κB inhibition.

运动神经元变性和神经炎症是肌萎缩侧索硬化症（ALS）最显着的病理特征。 ALS 目前尚无治愈方法，批准的药物对患者的临床治疗效果也有限。针对 ALS 中不同有害炎症途径的药物似乎是有前途的治疗替代方案。在这里，我们评估了亲电硝基烯苯甲酸衍生物 ( E )-4-(2-硝基乙烯基)苯甲酸 (BANA) 在 SOD1 ^G93A大鼠明显疾病发作后给药时减缓麻痹进展的潜在治疗效果。 BANA 对 NF-κB 报告基因转基因小鼠和小胶质细胞培养物中的 NF-κB 激活具有显着抑制作用。瘫痪发作后，SOD1 ^G93A大鼠每日全身口服 BANA 可显着减少小胶质细胞增生和星形细胞增多，并显着减少脊髓运动神经元周围 NF-κB-p65 阳性小胶质细胞核的数量。在 ALS 患者尸检脊髓的运动神经元周围观察到许多携带核 NF-κB-p65 的小胶质细胞，但在对照组中没有观察到，这表明 BANA 可以靶向 ALS 相关的小胶质细胞。此外，与对照组相比，BANA 治疗的 SOD1 ^G93A大鼠在瘫痪发作后表现出脊髓运动神经元病理学显着改善以及骨骼肌中保守的神经肌肉接头神经支配。值得注意的是，与媒介物处理的同窝小鼠相比，BANA 将瘫痪后存活率延长了约 30%。这些数据为使用 BANA 等小型亲电子化合物通过抑制小胶质细胞 NF-κB 的机制来减缓 ALS 麻痹进展提供了理论依据。