Targeting PERK mediated endoplasmic reticulum stress attenuates neuroinflammation and alleviates lipopolysaccharide-induced depressive-like behavior in male mice

Neuroinflammation plays a key role in the development of depression-like behaviors. Endoplasmic reticulum (ER) stress, defined as accumulation of unfolded proteins in the ER, is suggested to collaborate with inflammation process to drive sustained neuroinflammation. Protein kinase R-like endoplasmic reticulum kinase (PERK) is of particularly attractive target because it plays key role in the regulation of ER stress-induced neuroinflammation, however, little is known whether PERK mediated ER stress is implicated in LPS-induced depression-like behaviors. Thus, we aimed to evaluate the induction of PERK pathway in mice with depression-like behaviors induced by LPS, as well as the alterations in depression-like behaviors following the blocking of PERK pathway. We found that LPS challenges resulted in enhanced PERK in the hippocampus, with no alteration in the prefrontal cortex. Importantly, we found that PERK inhibitor ISRIB reduced the proinflammatory responses of microglia in the context of acute LPS-induced brain inflammation, and subsequent the preserved hippocampal neurogenesis, and improvement in depression-like behavior outcomes following LPS challenges. It was also worth mentioning that ISRIB treatment reduced the peripheral pro-inflammatory cytokines including IL-1 beta, IL-6 and IL-18. Thus, targeting PERK mediated Endoplasmic reticulum stress may be a promising antidepressant and anti-inflammatory candidate drug for the alleviation of neuroinflammation mediated depression, and PERK inhibitor ISRIB may have benefits for combating major depressive disorder.