@article{APS10781,
author = {Wei Liu and Shi-ou Zhu and Yu-lin Guo and Long-fang Tu and Yong-qi Zhen and Rong-yan Zhao and Liang Ou-Yang and Hiroshi Kurihara and Rong-Rong He and Bo Liu},
title = {BL-918, a small-molecule activator of ULK1, induces cytoprotective autophagy for amyotrophic lateral sclerosis therapy},
journal = {Acta Pharmacologica Sinica},
volume = {44},
number = {3},
year = {2023},
keywords = {},
abstract = {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 hSODG93A-NSC34 cells, treatment with BL-918 (5, 10 μM) dose-dependently induced ULK1-dependent autophagy, and eliminated toxic SOD1 aggregates. In SODG93A 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.},
issn = {1745-7254}, url = {http://www.chinaphar.com/article/view/10781}
}