Blockade of the NLRP3/caspase-1 axis attenuates ketamine-induced hippocampus pyroptosis and cognitive impairment in neonatal rats
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...
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| Format: | Article |
| Language: | English |
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BMC
2021-10-01
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| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12974-021-02295-9 |
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| author | Zhiheng Zhang Hui Bai Xiangying Ma Meilun Shen Rouqian Li Di Qiu Siyao Li Li Gao |
| author_facet | Zhiheng Zhang Hui Bai Xiangying Ma Meilun Shen Rouqian Li Di Qiu Siyao Li Li Gao |
| author_sort | Zhiheng Zhang |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-20T01:08:51Z |
| format | Article |
| id | doaj.art-e00990795f104c9f88e526615ed72f34 |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-12-20T01:08:51Z |
| publishDate | 2021-10-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-e00990795f104c9f88e526615ed72f342022-12-21T19:58:45ZengBMCJournal of Neuroinflammation1742-20942021-10-0118111210.1186/s12974-021-02295-9Blockade of the NLRP3/caspase-1 axis attenuates ketamine-induced hippocampus pyroptosis and cognitive impairment in neonatal ratsZhiheng Zhang0Hui Bai1Xiangying Ma2Meilun Shen3Rouqian Li4Di Qiu5Siyao Li6Li Gao7College of Veterinary Medicine, Northeast Agricultural UniversityCollege of Veterinary Medicine, Northeast Agricultural UniversityCollege of Veterinary Medicine, Northeast Agricultural UniversityCollege of Veterinary Medicine, Northeast Agricultural UniversityCollege of Veterinary Medicine, Northeast Agricultural UniversityCollege of Veterinary Medicine, Northeast Agricultural UniversityCollege of Veterinary Medicine, Northeast Agricultural UniversityCollege of Veterinary Medicine, Northeast Agricultural UniversityAbstract 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.https://doi.org/10.1186/s12974-021-02295-9PyroptosisDeveloping ratsKetamineNLRP3Caspase-1 |
| spellingShingle | Zhiheng Zhang Hui Bai Xiangying Ma Meilun Shen Rouqian Li Di Qiu Siyao Li Li Gao Blockade of the NLRP3/caspase-1 axis attenuates ketamine-induced hippocampus pyroptosis and cognitive impairment in neonatal rats Journal of Neuroinflammation Pyroptosis Developing rats Ketamine NLRP3 Caspase-1 |
| title | Blockade of the NLRP3/caspase-1 axis attenuates ketamine-induced hippocampus pyroptosis and cognitive impairment in neonatal rats |
| title_full | Blockade of the NLRP3/caspase-1 axis attenuates ketamine-induced hippocampus pyroptosis and cognitive impairment in neonatal rats |
| title_fullStr | Blockade of the NLRP3/caspase-1 axis attenuates ketamine-induced hippocampus pyroptosis and cognitive impairment in neonatal rats |
| title_full_unstemmed | Blockade of the NLRP3/caspase-1 axis attenuates ketamine-induced hippocampus pyroptosis and cognitive impairment in neonatal rats |
| title_short | Blockade of the NLRP3/caspase-1 axis attenuates ketamine-induced hippocampus pyroptosis and cognitive impairment in neonatal rats |
| title_sort | blockade of the nlrp3 caspase 1 axis attenuates ketamine induced hippocampus pyroptosis and cognitive impairment in neonatal rats |
| topic | Pyroptosis Developing rats Ketamine NLRP3 Caspase-1 |
| url | https://doi.org/10.1186/s12974-021-02295-9 |
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