Amyotrophic lateral sclerosis (ALS) is one of the most common fatal neurodegenerative diseases in adults. ALS pathogenesis is associated with toxic SOD1 aggregates generated by mutant SOD1. Since autophagy is responsible for the clearance of toxic protein aggregates including SOD1 aggregates, autophagy induction has been considered as a potential strategy for treating ALS. Autophagic signaling is initiated by unc-51 like autophagy activating kinase 1 (ULK1) complex. We previously identified that BL-918 as a specific ULK1 activator, which exerted cytoprotective effect against Parkinson’s disease in vitro and in vivo. In this study we investigated whether BL-918 exerted a therapeutic effect against ALS, and characterized its pharmacokinetic profile in rats. In hSOD^G93A-NSC34 cells, treatment with BL-918 (5, 10 μM) dose-dependently induced ULK1-dependent autophagy, and eliminated toxic SOD1 aggregates. In SOD^G93A mice, administration of BL-918 (40, 80 mg/kg, b.i.d., i.g.) dose-dependently prolonged lifespan and improved the motor function, and enhanced the clearance of SOD1 aggregates in spinal cord and cerebral cortex through inducing autophagy. In the pharmacokinetic study conducted in rats, we found BL-918 and its 2 metabolites (M8 and M10) present in spinal cord and brain; after intragastric and intravenous administration, BL-918 reached the highest blood concentration compared to M8 and M10. Collectively, ULK1 activator BL-918 displays a therapeutic potential on ALS through inducing cytoprotective autophagy. This study provides a further clue for autophagic dysfunction in ALS pathogenesis.

肌萎缩侧索硬化症 (ALS) 是成人中最常见的致命性神经退行性疾病之一。ALS 发病机制与突变体 SOD1 产生的有毒 SOD1 聚集体有关。由于自噬负责清除有毒蛋白质聚集体，包括 SOD1 聚集体，自噬诱导被认为是治疗 ALS 的潜在策略。自噬信号由 unc-51 样自噬激活激酶 1 (ULK1) 复合物启动。我们之前将 BL-918 鉴定为一种特定的 ULK1 激活剂，它在体外和体内对帕金森氏病发挥细胞保护作用。在这项研究中，我们调查了 BL-918 是否对 ALS 发挥治疗作用，并描述了它在大鼠中的药代动力学特征。在 hSOD ^G93A-NSC34 细胞，用 BL-918（5、10 μM）剂量依赖性地诱导 ULK1 依赖性自噬，并消除有毒的 SOD1 聚集体。在SOD ^G93A小鼠，给药 BL-918（40、80 mg/kg，bid，ig）剂量依赖性地延长寿命并改善运动功能，并通过诱导自噬增强脊髓和大脑皮层中 SOD1 聚集体的清除。在对大鼠进行的药代动力学研究中，我们发现 BL-918 及其 2 种代谢物（M8 和 M10）存在于脊髓和大脑中；灌胃和静脉给药后，与M8和M10相比，BL-918的血药浓度最高。总的来说，ULK1 激活剂 BL-918 通过诱导细胞保护性自噬显示出对 ALS 的治疗潜力。该研究为 ALS 发病机制中的自噬功能障碍提供了进一步的线索。