State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, China.
Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, 510632, China.
Acta Pharmacol Sin. 2023 Mar;44(3):524-537. doi: 10.1038/s41401-022-00972-w. Epub 2022 Aug 30.
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-NSC34 cells, treatment with BL-918 (5, 10 μM) dose-dependently induced ULK1-dependent autophagy, and eliminated toxic SOD1 aggregates. In SOD 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神经退行性疾病之一。ALS 的发病机制与突变 SOD1 产生的有毒 SOD1 聚集体有关。由于自噬负责清除包括 SOD1 聚集体在内的有毒蛋白聚集体，因此诱导自噬已被认为是治疗 ALS 的一种潜在策略。自噬信号由 UNC-51 样自噬激活激酶 1（ULK1）复合物起始。我们之前发现 BL-918 是一种特异性 ULK1 激活剂，它在体外和体内对帕金森病具有细胞保护作用。在这项研究中，我们研究了 BL-918 是否对 ALS 有治疗作用，并对其在大鼠中的药代动力学特征进行了表征。在 hSOD-NSC34 细胞中，BL-918（5、10μM）处理剂量依赖性地诱导 ULK1 依赖性自噬，并消除有毒的 SOD1 聚集体。在 SOD 小鼠中，BL-918（40、80mg/kg，bid，ig）给药剂量依赖性地延长了生存期并改善了运动功能，并通过诱导自噬增强了脊髓和大脑皮层中 SOD1 聚集体的清除。在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；与 M8 和 M10 相比，经口服和静脉给药后，BL-918 达到了最高的血液浓度。总之，ULK1 激活剂 BL-918 通过诱导细胞保护自噬显示出对 ALS 的治疗潜力。这项研究为 ALS 发病机制中的自噬功能障碍提供了进一步的线索。
