BL-918,a small-molecule activator of ULK1,induces cytoprotective autophagy for amyotrophic lateral sclerosis therapy  

作　　者：Wei Liu Shi-ou Zhu Yu-lin Guo Long-fang Tu Yong-qi Zhen Rong-yan Zhao Liang Ou-Yang Hiroshi Kurihara Rong-Rong He Bo Liu 

机构地区：[1]State Key Laboratory of Biotherapy and Cancer Center,West China Hospital,Sichuan University,Chengdu 610041,China [2]Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research,College of Pharmacy,Jinan University,Guangzhou 510632,China [3]Guangdong Engineering Research Center of Chinese Medicine&Disease Susceptibility,Jinan University,Guangzhou 510632,China

出　　处：《Acta Pharmacologica Sinica》2023年第3期524-537,共14页中国药理学报（英文版）

基　　金：National Natural Science Foundation of China(Grant No.81873209,82172649,21314120 and 81922064);Key R&D Program of Sichuan Province(Grant No.2021YFS0046);the Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program(grant number 2017BT01Y036)and GDUPS;Research Foundation for Administration of traditional Chinese medicine of Sichuan Province(Grant No.2020HJZX002);CAMS Innovation Fund for Medical Science(Grant 2019-RC-HL-023);National Clinical Research Center for Geriatrics,West China Hospital,Sichuan University(Grant Z20201004);Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences(grant 2020-JKCS-014).

摘　　要：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(5,10μM)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.

关 键 词：amyotrophic lateral sclerosis cytoprotective autophagy ULK1 BL-918 PHARMACOKINETIC 

分 类 号：R285.5[医药卫生—中药学]