N-Acetylcysteine Mitigates Ketamine Neurotoxicity in Young Rats by Modulating ROS-Mediated Pyroptosis and Ferroptosis.
Hui Bai, Hui Chen, Shan Du, Di Qiu, Siyao Li, Tianwen Ma, Ruifeng Gao, Zhiheng Zhang
Molecular Neurobiology March 20, 2025 DOI: 10.1007/s12035-025-04860-2 (opens in new tab)
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Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Postnatal day 7 Sprague-Dawley rats, PC12 cells, and HAPI cells |
| Intervention | N-acetylcysteine |
| Topics | Ketamine Esketamine |
| Keywords | Pediatric anesthesia Oxidative stress Brain development Anesthetic neurotoxicity Cognitive impairment Ferroptosis N-acetylcysteine Pyroptosis Ros Neuroprotection |
| Citations | 4 |
| Key findings | N-acetylcysteine mitigates ketamine-induced hippocampal damage and cognitive deficits by inhibiting ROS-mediated ferroptosis and pyroptosis. |
Abstract
Ketamine, an N-methyl-D-aspartate receptor antagonist with anesthetic and analgesic properties, is extensively utilized for the induction and maintenance of pediatric perioperative anesthesia. Increasing evidence suggests that prolonged exposure to ketamine may induce neurotoxicity in developing animals, adversely affecting their long-term cognitive function. N-acetylcysteine (NAC) is an organic sulfur compound in the Allium genus; however, the mechanisms through which it alleviates ketamine-induced neurotoxicity during developmental stages remain inadequately understood. Refine the investigation of the mechanisms by which Nac mitigates ketamine-induced neurotoxicity during development via ferroptosis and pyroptosis pathways. Postnatal day 7 in SD rats PC12 cells and HAPI cells were used in this study. The neuroprotective mechanism of Nac was elucidated through pathological, histological, and molecular biological methodologies to assess pyroptosis, ferroptosis, hippocampal tissue damage, and behavioral modifications in adulthood. The results suggest that prior administration of Nac reduced lipid peroxidation and mitochondrial injury, along with pyroptosis activated by the NLRP3/caspase-1 pathway, hippocampal damage, and cognitive deficits after exposure to ketamine. In summary, our findings from both in vivo and in vitro studies indicate that ROS plays a significant regulatory role in the neurotoxic effects of ketamine during development. Furthermore, Nac mitigates hippocampal damage and cognitive deficits associated with ketamine exposure by inhibiting ROS-mediated ferroptosis and pyroptosis.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |