GPX4 Inhibition Contributes to NLRP3-Mediated Pyroptosis and Cognitive Impairment in Ketamine-Exposed Neonatal Rats.

Repeated or prolonged ketamine exposure can damage the developing hippocampus and impair cognitive function. This study in rats and cell lines shows that the enzyme GPX4 protects against this damage. Inhibiting GPX4 with RSL3 worsened lipid peroxidation, mitochondrial damage, and cell death via the NLRP3/caspase-1 pathway, leading to greater hippocampal injury and cognitive deficits. The antioxidant N-acetylcysteine (NAC) reversed these effects. The findings suggest that GPX4 normally suppresses pyroptosis, and boosting its expression may be a strategy to prevent ketamine-induced neurotoxicity in the developing brain.

Study at a glance

Abstract

Increasing evidence reveals that multiple or prolonged exposure to ketamine causes hippocampal damage and cognitive dysfunction. However, the critical mechanisms underlying ketamine-induced neurotoxicity in the developing brain remain elusive. The present study was designed to investigate the role of GPX4 in ketamine-induced pyroptosis and cognitive dysfunction in the developing rat hippocampus. To achieve this goal, we conducted Western blotting, ELISA tests, histopathological analysis, Morris water maze tests, cell viability assays, and biochemical analyses on PC12 cells, HAPI cells, and 7-day-old rats. Additionally, N-acetylcysteine (NAC) and RSL3 were administered prior to continuous ketamine exposure. Our findings indicate that GPX4 inhibition by RSL3 enhances lipid peroxidation and mitochondrial damage, activates NLRP3/caspase-1 axis-dependent pyroptosis, and exacerbates hippocampal damage and cognitive dysfunction following ketamine exposure, while NAC effectively mitigates the effects of RSL3. Collectively, our in vivo and in vitro results support the notion that GPX4 may serve as a negative regulator of pyroptosis in ketamine-induced hippocampal damage and cognitive dysfunction. Our study proposes a novel strategy for treating ketamine-induced neurotoxicity through upregulating GPX4 expression.