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

被引：76

作者：

Zhang, Zhiheng ^{[1
,2
]}

Bai, Hui ^{[1
,2
]}

Ma, Xiangying ^{[1
,2
]}

Shen, Meilun ^{[1
,2
]}

Li, Rouqian ^{[1
,2
]}

Qiu, Di ^{[1
,2
]}

Li, Siyao ^{[1
,2
]}

Gao, Li ^{[1
,2
]}

机构：

[1] Northeast Agr Univ, Coll Vet Med, 600 Changjiang Rd, Harbin 150030, Peoples R China

[2] Northeast Agr Univ, Coll Vet Med, Heilongjiang Key Lab Lab Anim & Comparat Med, Harbin, Peoples R China

来源：

JOURNAL OF NEUROINFLAMMATION | 2021年 / 18卷 / 01期

基金：

中国国家自然科学基金; 国家重点研发计划;

关键词：

Pyroptosis; Developing rats; Ketamine; NLRP3; Caspase-1; NLRP3 INFLAMMASOME ACTIVATION; SYNAPTIC PLASTICITY; NEURONAL APOPTOSIS; GENERAL-ANESTHESIA; EARLY EXPOSURE; AMYLOID-BETA; BRAIN; CELLS; NEURODEGENERATION; DIFFERENTIATION;

D O I：

10.1186/s12974-021-02295-9

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

071005 [微生物学]; 100108 [医学免疫学];

摘要：

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.

引用

页数：12

共 58 条

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