[Ameliorative effects and mechanisms of an integrated endoplasmic reticulum stress inhibitor on lipopolysaccharide-induced cognitive impairment in mice].

OBJECTIVES

The integrated endoplasmic reticulum stress inhibitor (ISRIB) is a selective inhibitor of the protein kinase R-like endoplasmic reticulum kinase (PERK) signaling pathway within endoplasmic reticulum stress (ERS) and can improve spatial and working memory in aged mice. Although ERS and oxidative stress are tightly interconnected, it remains unclear whether ISRIB alleviates cognitive impairment by restoring the balance between ERS and oxidative stress. This study aims to investigate the effects and mechanisms of ISRIB on lipopolysaccharide (LPS)-induced cognitive impairment in mice.

METHODS

Eight-week-old male ICR mice were randomly divided into 3 groups: Normal saline (NS) group, LPS group, and ISRIB+LPS group. NS and LPS groups received daily intraperitoneal injections of normal saline for 7 days; on day 7, LPS group mice received intraperitoneal LPS (0.83 mg/kg) to establish a cognitive impairment model. ISRIB+LPS group received ISRIB (0.25 mg/kg) intraperitoneally for 7 days, with LPS injected 30 minutes after ISRIB on day 7. Cognitive ability was evaluated by the novel place recognition test (NPRT). Real-time fluorogenic quantitative PCR (RT-qPCR) was used to detect changes in nitric oxide synthase (), superoxide dismutase-1 (), and catalase () gene expression in the hippocampus and prefrontal cortex. Oxidative stress markers malondialdehyde (), glutathione (), and oxidized glutathione (), were measured in hippocampal and prefrontal cortex tissues.

RESULTS

Compared with the NS group, mice in LPS group showed a significant reduction in novel place recognition ratio, upregulation of hippocampal and mRNA, downregulation of and mRNA, increased and , decreased , and reduced ratio (all <0.05). Compared with the LPS group, mice in ISRIB+LPS group exhibited significantly improved novel place recognition, downregulated and mRNA, upregulated and mRNA, decreased and , increased , and an elevated ratio in the hippocampus (all <0.05). No significant changes were observed in the prefrontal cortex.

CONCLUSIONS

ISRIB improves LPS-induced cognitive impairment in mice by restoring the oxidative/antioxidant balance in the hippocampus.