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

Abstract

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 tocollaboratewithinflammation process to drive sustained neuroinflammation. Protein kinase R-like endoplasmic reticulum kinase (PERK) is ofparticularly attractive target because it plays key rolein the regulation of ER stress-induced neuroinflammation, however, little isknown whether PERKmediatedER stress is implicated in LPS-induced depression-like behaviors.Thus, we aimed to evaluate the induction of PERK pathwayin mice with depression-like behaviors induced by LPS, as well as the alterations in depression-like behaviorsfollowing 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 PERKinhibitorISRIB reducedthe proinflammatory responsesof microglia in the context of acute LPS-induced brain inflammation, and subsequent the preserved hippocampal neurogenesis, and improvement in depression-like behavioroutcomes following LPS challenges.It was also worth mentioning thatISRIB treatmentreduced the peripheral pro-inflammatory cytokines includingIL-1β, IL-6 and IL-18. Thus, targetingPERK mediated Endoplasmic reticulum stress may be a promising antidepressant and anti-inflammatory candidate drug for the alleviation of neuroinflammationmediated depression, and PERKinhibitorISRIBmay havebenefits for combating major depressive disorder.

Keywords: Depression; Endoplasmic reticulum stress; Microglia; Neuroinflammation; PERK.