2. Academic Validation
  3. Blockade of the NLRP3/caspase-1 axis attenuates ketamine-induced hippocampus pyroptosis and cognitive impairment in neonatal rats

Blockade of the NLRP3/caspase-1 axis attenuates ketamine-induced hippocampus pyroptosis and cognitive impairment in neonatal rats

  • J Neuroinflammation. 2021 Oct 19;18(1):239. doi: 10.1186/s12974-021-02295-9.
Zhiheng Zhang  # 1 2,  Hui Bai  # 1 2,  Xiangying Ma 1 2,  Meilun Shen 1 2,  Rouqian Li 1 2,  Di Qiu 1 2,  Siyao Li 1 2,  Li Gao 3 4
Affiliations

Affiliations

  • 1 College of Veterinary Medicine, Northeast Agricultural University, No. 600 Changjiang Rd, Xiangfang District, Harbin, 150030, China.
  • 2 Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, College of Veterinary Medicine, Northeast Agriculture University, Harbin, China.
  • 3 College of Veterinary Medicine, Northeast Agricultural University, No. 600 Changjiang Rd, Xiangfang District, Harbin, 150030, China. [email protected].
  • 4 Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, College of Veterinary Medicine, Northeast Agriculture University, Harbin, China. [email protected].
  • # Contributed equally.
PMID: 34666787 DOI: 10.1186/s12974-021-02295-9
Abstract

Background: Multiple studies have revealed that repeated or long-term exposure to ketamine causes neurodegeneration and cognitive dysfunction. Pyroptosis is an inflammatory form of programmed cell death that has been linked to various neurological diseases. However, the role of NLRP3/Caspase-1 axis-related Pyroptosis in ketamine-induced neurotoxicity and cognitive dysfunction remains uncertain.

Methods: To evaluate whether ketamine caused NLRP3/caspase1-dependent Pyroptosis, flow cytometry analysis, western blotting, ELISA test, histopathological analysis, Morris water maze (MWM) test, cell viability assay, and Lactate Dehydrogenase release (LDH) assay were carried out on PC12 cells, HAPI cells, and 7-day-old rats. In addition, the NLRP3 Inhibitor MCC950 or the Caspase-1 inhibitor VX-765 was used to investigate the role of the NLRP3/Caspase-1 axis in ketamine-induced neurotoxicity and cognitive dysfunction.

Results: Our findings demonstrated that ketamine exposure caused cell damage and increased the levels of Pyroptosis in PC12 cells, HAPI cells, and the hippocampus of neonatal rats. After continuous exposure to ketamine, targeting NLRP3 and Caspase-1 with MCC950 or VX765 improved Pyroptosis, reduced neuropathological damages, and alleviated cognitive dysfunction.

Conclusion: NLRP3/Caspase-1 axis-dependent Pyroptosis is involved in ketamine-induced neuroinflammation and cognitive dysfunction, and it provides a promising strategy to treat ketamine-related neurotoxicity.

Keywords

Caspase-1; Developing rats; Ketamine; NLRP3; Pyroptosis.

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