Identification of Novel Oxindole Compounds That Suppress ERStress-Induced Cell Death as Chemical Chaperones

Endoplasmic reticulum (ER) stress and oxidativestress lead to protein misfolding, and the resulting accumulation ofprotein aggregates is often associated with the pathogenesis ofneurodegenerative diseases, including Alzheimer's disease, Parkin-son's disease, amyotrophic lateral sclerosis, and prion disease. Smallmolecules preventing these pathogenic processes may be effectiveinterventions for such neurodegenerative disorders. In this paper,we identify several novel oxindole compounds that can prevent ERstress- and oxidative stress-induced cell death. Among them,derivatives of the lead compound GIF-0726-r in which a hydrogenatom at the oxindole ring 5 position is substituted with a methyl(GIF-0852-r), bromine (GIF-0854-r), or nitro (GIF-0856-r) grouppotently suppressed global ER stress. Furthermore, GIF-0854-r and-0856-r prevented protein aggregate accumulationin vitroand in cultured hippocampal HT22 neuronal cells, indicating that thesetwo compounds function effectively as chemical chaperones. In addition, GIF-0852-r, -0854-r, and -0856-r prevented glutamate-induced oxytosis and erastin-induced ferroptosis. Collectively, these results suggest that the novel oxindole compounds GIF-0854-rand -0856-r may be useful therapeutics against protein-misfolding diseases as well as valuable research tools for studying themolecular mechanisms of ER and oxidative stress

Automated summary

This paper identifies several novel oxindole compounds that can prevent ER stress- and oxidative stress-induced cell death and suppress protein aggregate accumulation. These compounds also prevent glutamate-induced oxytosis and erastin-induced ferroptosis. The results suggest that these compounds may be useful therapeutics against protein-misfolding diseases and valuable research tools for studying the molecular mechanisms of ER and oxidative stress.