Chloroquine Promotes the Recovery of Acute Spinal Cord Injury by Inhibiting Autophagy-Associated Inflammation and Endoplasmic Reticulum Stress.
Spinal cord injury (SCI) is a severe nervous system disease that may lead to lifelong disability. Studies have shown that autophagy plays a key role in various diseases; however, the mechanisms regulating cross-talk between autophagy, inflammation, and endoplasmic reticulum (ER) stress during SCI recovery remain unclear. This study was designed to investigate the mechanism by which chloroquine (CQ) inhibits autophagy-associated inflammation and ER stress in rats during their recovery from acute SCI. We evaluated the locomotor function, level of autophagy, and levels of inflammatory cytokines and ER-stress-associated proteins and examined the degradation of the key regulator of inflammation inhibitor of kappa B alpha (I-κBα) through autophagy by analyzing the colocalization of I-κBα, p62, and microtubule-associated protein 1 light chain 3-II. In addition, overexpression of the p62 and activating transcription factor 4 (ATF4) silencing plasmids was used to verify the important roles for autophagic degradation and ER stress. In this study, locomotor function is improved, and autophagy and inflammation are significantly inhibited by, CQ treatment in the model rats. In addition, CQ significantly inhibits the degradation of ubiquitinated I-κBα and blocks the nuclear translocation of nuclear factor kappa B p65 and expression of inflammatory factors. Overexpression of p62 increases I-κBα degradation and improves inflammatory responses. Moreover, CQ treatment also inhibits the activation of ER stress in the rat SCI model, and the ATF4 signaling pathway is required for ER-stress-induced activation of autophagy. These findings reveal a novel mechanism underlying the beneficial effects of CQ on the recovery of SCI, particularly the mechanisms regulating cross-talk between autophagy, inflammation, and ER stress.
['Wu|Fenzan|F|', 'Wei|Xiaojie|X|', 'Wu|Yanqing|Y|', 'Kong|Xiaoxia|X|', 'Hu|Aiping|A|', 'Tong|Songlin|S|', 'Liu|Yanlong|Y|', 'Gong|Fanhua|F|', 'Xie|Ling|L|', 'Zhang|Jinjing|J|', 'Xiao|Jian|J|', 'Zhang|Hongyu|H|']
D000818:Animals D001343:Autophagy D002738:Chloroquine D059865:Endoplasmic Reticulum Stress D005260:Female D007249:Inflammation D018696:Neuroprotective Agents D051381:Rats D017207:Rats, Sprague-Dawley D013119:Spinal Cord Injuries
spinal cord injury inflammation endoplasmic reticulum stress autophagy chloroquine (CQ)