BL-918, a small-molecule activator of ULK1, induces cytoprotective autophagy for amyotrophic lateral sclerosis therapy
Amyotrophic lateral sclerosis (ALS) is among the most typical fatal neurodegenerative illnesses in grown-ups. ALS pathogenesis is connected with toxic SOD1 aggregates generated by mutant SOD1. Since autophagy accounts for the clearance of toxic protein aggregates including SOD1 aggregates, autophagy induction continues to be regarded as a possible technique for treating ALS. Autophagic signaling is initiated by unc-51 like autophagy activating kinase 1 (ULK1) complex. We formerly identified that BL-918 like a specific ULK1 activator, which exerted cytoprotective effect against Parkinson’s disease in vitro as well as in vivo. Within this study we investigated whether BL-918 exerted a therapeutic effect against ALS, and characterised its pharmacokinetic profile in rats. In hSODG93A-NSC34 cells, treatment with BL-918 (5, 10 µM) dose-dependently caused ULK1-dependent autophagy, and eliminated toxic SOD1 aggregates. In SODG93A rodents, administration of BL-918 (40, 80 mg/kg, b.i.d., i.g.) dose-dependently prolonged lifespan and improved the motor function, that has been enhanced the clearance of SOD1 aggregates in spinal-cord and cerebral cortex through inducing autophagy. Within the pharmacokinetic study conducted in rats, we found BL-918 and it is 2 metabolites (M8 and M10) contained in spinal-cord and brain after intragastric and intravenous administration, BL-918 arrived at the greatest bloodstream concentration when compared with M8 and M10. With each other, ULK1 activator BL-918 displays a therapeutic potential on ALS through inducing cytoprotective autophagy. This research supplies a further clue for autophagic disorder in ALS pathogenesis.