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Updated: May 5, 2026
Two-vessel Occlusion Mouse Model of Cerebral Ischemia-reperfusion
Published on: March 1, 2019
TXNIP/NLRP3 aggravates global cerebral ischemia-reperfusion injury-induced cognitive decline in mice
Chengjie Yang1,2, Jing Mo1,2, Qingmei Liu1,2
1Department of Anesthesiology, The Affiliated Hospital, Southwest Medical University, Luzhou, China.
Abstract:
Global cerebral ischemia/reperfusion (GCI/R) injury poses a risk for cognitive decline, with neuroinflammation considered pivotal in this process. This study aimed to unravel the molecular mechanisms underlying GCI/R injury and propose a potential therapeutic strategy for associated cognitive deficits. Utilizing bioinformatics analysis of a public microarray profile (GSE30655 and GSE80681) in cerebral ischemic mice, it was observed that neuroinflammation emerged as a significant gene ontology item, with an increase in the expression of thioredoxin-interacting protein (TXNIP) and NLRP3 genes. Experimental models involving bilateral occlusion of the common carotid arteries in mice revealed that GCI/R induced cognitive impairment, along with a time-dependent increase in TXNIP and NLRP3 levels. Notably, TXNIP knockdown alleviated cognitive dysfunction in mice. Furthermore, the introduction of adeno-associated virus injection with TXNIP knockdown reduced the number of activated microglia, apoptosis neurons, and levels of oxidative stress and inflammatory cytokines in the hippocampus. Collectively, these findings underscore the significance of TXNIP/NLRP3 in the hippocampus in exacerbating cognitive decline due to GCI/R injury, suggesting that TXNIP knockdown holds promise as a therapeutic strategy.
Insights
Global cerebral ischemia/reperfusion injury causes cognitive decline. Targeting thioredoxin-interacting protein (TXNIP) reduces neuroinflammation and alleviates cognitive deficits, offering a potential therapeutic strategy.
Area of Science:
- Neuroscience
- Molecular Biology
- Pathology
Background:
- Global cerebral ischemia/reperfusion (GCI/R) injury is a significant cause of cognitive decline.
- Neuroinflammation plays a critical role in the pathogenesis of GCI/R-induced brain damage.
- Identifying molecular mechanisms and therapeutic targets is crucial for mitigating GCI/R consequences.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying GCI/R injury and cognitive deficits.
- To investigate the role of thioredoxin-interacting protein (TXNIP) and NLRP3 inflammasome in GCI/R.
- To evaluate TXNIP knockdown as a potential therapeutic strategy for GCI/R-induced cognitive impairment.
Main Methods:
- Bioinformatics analysis of microarray datasets (GSE30655, GSE80681) to identify key genes and pathways.
- Establishment of a mouse model of bilateral common carotid artery occlusion for GCI/R induction.
- Assessment of cognitive function, histological analysis (microglia activation, neuronal apoptosis), and molecular markers (TXNIP, NLRP3, oxidative stress, inflammatory cytokines).
- Gene knockdown of TXNIP using adeno-associated virus (AAV) vectors.
Main Results:
- Bioinformatics analysis highlighted neuroinflammation and identified increased TXNIP and NLRP3 expression in GCI/R.
- GCI/R mice exhibited cognitive impairment, with elevated hippocampal TXNIP and NLRP3 levels in a time-dependent manner.
- TXNIP knockdown significantly ameliorated cognitive dysfunction in GCI/R mice.
- AAV-mediated TXNIP knockdown reduced microglial activation, neuronal apoptosis, oxidative stress, and inflammatory cytokine levels in the hippocampus.
Conclusions:
- TXNIP and NLRP3 are key contributors to hippocampal injury and cognitive decline following GCI/R.
- TXNIP plays a pivotal role in mediating neuroinflammation and neuronal damage in GCI/R.
- Targeting TXNIP, specifically through knockdown, represents a promising therapeutic approach for managing GCI/R-induced cognitive deficits.
