GPX4 Inhibition Contributes to NLRP3-Mediated Pyroptosis and Cognitive Impairment in Ketamine-Exposed Neonatal Rats.
Molecular neurobiology – May 23, 2025
Source: PubMed
Summary
Early exposure to ketamine, a common anesthetic, can trigger brain cell death through a newly discovered mechanism in developing rats. Scientists found that a protective protein called GPX4 helps shield the hippocampus - a brain region crucial for memory - from damage. When this protection fails, cells undergo pyroptosis, a specific form of cell death. Blocking GPX4 worsened memory problems, while boosting protective mechanisms reduced hippocampal injury.
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.