The effect of the NLRP1 inflammasome on methamphetamine-induced cognitive impairment in rats

  • Drug Alcohol Depend. 2022 Aug 1:237:109537. doi: 10.1016/j.drugalcdep.2022.109537.
Runyue Fan  1 ,  Yao Shen  1 ,  Xiaofang Li  2 ,  Hu Luo  2 ,  Peng Zhang  1 ,  Yingying Liu  3 ,  Zizhen Si  4 ,  Wenhua Zhou  5 ,  Yu Liu  6
Affiliations
  • 1. School of Public Health, School of Medicine, Ningbo University, 818 Fenghua Road, Ningbo, Zhejiang 315211, PR China.
  • 2. School of Teaching and Education, Ningbo University, 818 Fenghua Road, Ningbo, Zhejiang 315211, PR China.
  • 3. School of Medicine, Ningbo University, 818 Fenghua Road, Ningbo, Zhejiang 315211, PR China.
  • 4. Department of Pharmacy, the Affiliated Hospital of Ningbo University Medical School, Ningbo , Zhejiang 315211, PR China; Department of Physiology and Pharmacology, School of Medicine, Ningbo University, 818 Fenghua Road, Ningbo, Zhejiang 315211, PR China.
  • 5. Kangning Hospital, 1 South Zhuangyu Road, Ningbo, Zhejiang 315201, PR China.
  • 6. Department of Physiology and Pharmacology, School of Medicine, Ningbo University, 818 Fenghua Road, Ningbo, Zhejiang 315211, PR China. Electronic address: [email protected].
PMID: 35752024 DOI: 10.1016/j.drugalcdep.2022.109537
Abstract

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/Caspase-1/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-1β and TNF-α and the presence of GSDMD-mediated Pyroptosis in the hippocampus 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-1β and TNF-α. 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.

Keywords
Cognitive impairments; Methamphetamine; NLRP1 inflammasome; Neurotoxicity; Pyroptosis.
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