2. Academic Validation
  3. N-Acetylcysteine Mitigates Ketamine Neurotoxicity in Young Rats by Modulating ROS-Mediated Pyroptosis and Ferroptosis

N-Acetylcysteine Mitigates Ketamine Neurotoxicity in Young Rats by Modulating ROS-Mediated Pyroptosis and Ferroptosis

  • Mol Neurobiol. 2025 Mar 20. doi: 10.1007/s12035-025-04860-2.
Hui Bai # 1 2 3,  Hui Chen # 1 2,  Shan Du # 1 2,  Di Qiu 3,  Siyao Li 3,  Tianwen Ma 3,  Ruifeng Gao 4 5,  Zhiheng Zhang 6 7 8
Affiliations

Affiliations

  • 1 College of Veterinary Medicine, Inner Mongolia Agricultural University, Hohhot, China.
  • 2 Key Laboratory of Clinical Diagnosis and Treatment Techniques for Animal Disease, Ministry of Agriculture, Inner Mongolia Agricultural University, Hohhot, China.
  • 3 College of Veterinary Medicine, Northeast Agricultural University, Harbin, China.
  • 4 College of Veterinary Medicine, Inner Mongolia Agricultural University, Hohhot, China. grfneinongda@163.com.
  • 5 Key Laboratory of Clinical Diagnosis and Treatment Techniques for Animal Disease, Ministry of Agriculture, Inner Mongolia Agricultural University, Hohhot, China. grfneinongda@163.com.
  • 6 College of Veterinary Medicine, Inner Mongolia Agricultural University, Hohhot, China. zzh449756020@163.com.
  • 7 Key Laboratory of Clinical Diagnosis and Treatment Techniques for Animal Disease, Ministry of Agriculture, Inner Mongolia Agricultural University, Hohhot, China. zzh449756020@163.com.
  • 8 College of Veterinary Medicine, Northeast Agricultural University, Harbin, China. zzh449756020@163.com.
  • # Contributed equally.
PMID: 40111652 DOI: 10.1007/s12035-025-04860-2
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.

Keywords

Cognitive impairment; Ferroptosis; Ketamine; N-acetylcysteine; Pyroptosis; ROS.

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