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.
Ketamine, a common anesthetic for children, can harm the developing brain by triggering two forms of cell death: ferroptosis and pyroptosis. In experiments on newborn rats and cultured nerve cells, giving N-acetylcysteine (NAC) beforehand reduced damage. NAC lowered harmful lipid oxidation and mitochondrial injury, blocked pyroptosis driven by the NLRP3/caspase-1 pathway, and lessened hippocampal tissue damage and later cognitive problems. The results indicate that reactive oxygen species (ROS) are central to ketamine's developmental neurotoxicity, and NAC protects the brain by inhibiting ROS-driven ferroptosis and pyroptosis.