JNK-IN-8 treatment improves ARDS-induced cognitive impairment by inhibiting JNK/NF-κB-mediated NLRP3 inflammasome

Abstract

Purpose: Cognitive impairment is a critical complication of acute respiratory distress syndrome (ARDS). However, effective interventions are lacking. Growing evidence demonstrates that c-Jun N-terminal kinase (JNK)-mediated neuroinflammation is involved in the development of ARDS. Therefore, we hypothesized that the JNK pathway is involved in ARDS-induced cognitive impairment.

Methods: An in vivo rat model of ARDS was established by treating it with lipopolysaccharide. The cognitive function was assessed by behavioral tests. The levels of pro-inflammatory cytokines, JNK and NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) were analyzed by enzyme-linked immunosorbent assay, western blot, or immunohistochemical analysis.

Results: We found that JNK inhibitor 8 (JNK-IN-8) alleviated cognitive impairment, neuroinflammation, and NLRP3 inflammasome activation in the ARDS rat model. Additionally, an in vivo study showed that the protective effect of JNK-IN-8 on cognitive impairment was blocked by nigericin, an NLRP3 activator.

Conclusions: Our data suggest that JNK-IN-8 treatment improves ARDS-induced cognitive impairment by inhibiting the JNK/nuclear factor-κB-mediated NLRP3 inflammasome.

Keywords: JNK-IN-8; JNK/NF-κB pathway; NLRP3 inflammasome; acute respiratory distress syndrome; cognitive impairment.