Journal
DRUG AND ALCOHOL DEPENDENCE
Volume 237, Issue -, Pages -Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.drugalcdep.2022.109537
Keywords
Methamphetamine; Neurotoxicity; Cognitive impairments; NLRP1 inflammasome; Pyroptosis
Categories
Funding
- National Natural Science Foundation of China [81971247, 81671323]
- Zhejiang Provincial Key Research and Development Plan [2020C03064, 20181ZDYF020172]
- Ningbo Research and Development Plan [18ZDA215]
- National Social Science Foundation Key Programs [IF2021103]
- Graduate Research and Inno-vation Fund of Ningbo University [81971247]
- National Natural Science Foundation of China [81971247, 81671323]
- Zhejiang Provincial Key Research and Development Plan 2019 [2020C03064]
- Ningbo Research and Development Plan [20181ZDYF020172]
- National Social Science Foundation Key Programs [18ZDA215]
- Graduate Research and Innovation Fund of Ningbo University [IF2021103]
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The study reveals the significant role of NLRP1 and its downstream signaling pathways in METH-induced cognitive deficits, while ATL and NLRP1 siRNA show potential as therapeutic targets for mitigating METH-induced cognitive impairment.
Methamphetamine (METH) use disorder has been shown to be in high comorbidity with cognitive deficits. METH-induced cognitive deficits are accompanied by neurotoxicity which could result from neuroinflammation. The potential role of NLRP1 inflammasome (NLRP1) and the downstream signalling pathway in METH-induced cognitive impairment was explored in the current study. Cognitive functions and the changes of NLRP1/Caspase1/GSDMD signalling pathway were firstly determined in rats receiving daily injections of METH. Subsequently, the effects of aspirin-triggered-lipoxin A4 (ATL), a potent anti-inflammatory mediator, and NLRP1 siRNA was investigated were investigated in both METH-treated rats and HT22 cells. METH induces significant cognitive deficits in rats, using the NOR test. METH-induced cognitive impairment was in line with increased activities of NLRP1, cleaved-Caspase-11, IL-1 beta and TNF-alpha and the presence of GSDMD-mediated pyroptosis in the hippo campus of rats. NLRP1 inhibition by ATL significantly attenuated METH-induced cognitive impairment, in conjunction with the decreased activities of NLRP1 and cleaved-Caspase-1, IL-1 beta and TNF-alpha. ATL and NLRP1 siRNA also prevented the presence of apoptosis in the hippocampus of METH-treated rats and the cell death in METH-treated HT22 cells. These results reveal a novel role of NLRP1 and the downstream signaling pathways in the complex actions of METH-induced cognitive deficits.
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