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Quercetin Alleviates Cerebral Ischemia-Induced Neuroinflammation by Inhibiting Microglia-Mediated
Da Shen1,2, Weiao Kong1,2, Haoke Qiu1,2
1College of Life Science, Zhejiang Chinese Medical University, Hangzhou 310053, China.
Abstract:
In the pathological cascade of cerebral ischemia, the pyroptosis axis mediated by the NLRP3 inflammasome in activated microglia is a core link driving neuroinflammation and secondary brain injury. Quercetin has been proven to possess multi-target neuroprotective activity, and its anti-inflammatory effect has attracted particular attention. However, direct molecular evidence is lacking regarding how quercetin precisely regulates the NLRP3/Caspase-1/GSDMD core pyroptosis axis in microglia in cerebral ischemia models and whether it can directly target NLRP3 to inhibit this axis, thereby alleviating cerebral ischemic injury. This study aimed to investigate the molecular mechanism by which quercetin alleviates cerebral ischemic injury through inhibiting the pyroptosis axis, combining cellular and animal models with molecular docking and molecular dynamics simulations. The oxygen-glucose deprivation (OGD) model of BV2 microglia and the photothrombotic (PT) model of focal cortical ischemia in male C57BL/6 mice were used to detect the ameliorative effect of quercetin on cerebral ischemia-related injury through cellular and animal experiments. AutoDock Vina 1.5.7 and GROMACS 2025.3 software were employed for molecular docking and molecular dynamics simulations, respectively, to analyze the binding mode and complex stability between quercetin and the NLRP3 protein. The results showed that quercetin could significantly ameliorate OGD-induced injury in BV2 cells and downregulate the expression of pyroptosis and inflammation-related proteins and factors. Meanwhile, it relieved motor dysfunction in PT mice, attenuated cortical neuronal injury, and inhibited the activation of the cerebral pyroptosis axis. At the molecular level, molecular simulation predictions indicated that quercetin might specifically bind to the NACHT domain of the NLRP3 protein, forming a complex with a stable conformation, and van der Waals interactions served as the main driving force for binding. This study confirmed that quercetin can directly bind to the NLRP3 protein and alleviate cerebral ischemia-induced inflammatory injury by inhibiting the activation of the NLRP3/Caspase-1/GSDMD pyroptosis axis and the release of downstream inflammatory factors. Combined with the molecular simulation results, a predictive hypothesis is proposed: direct binding of quercetin to the NLRP3 protein is one of its core mechanisms of action. These findings provide direct experimental evidence for the development of NLRP3-based drugs against ischemic brain injury.
Insights
Quercetin directly targets the NLRP3 inflammasome, inhibiting pyroptosis and neuroinflammation to protect against cerebral ischemic injury. This study provides molecular evidence for quercetin
Area of Science:
- Neuroscience
- Pharmacology
- Biochemistry
Background:
- Cerebral ischemia triggers neuroinflammation and secondary brain injury via the NLRP3 inflammasome-mediated pyroptosis axis in microglia.
- Quercetin exhibits neuroprotective and anti-inflammatory properties, but its precise molecular mechanism in cerebral ischemia remains unclear.
- Direct evidence is needed to confirm quercetin's regulation of the NLRP3/Caspase-1/GSDMD pyroptosis axis and its potential as a therapeutic agent.
Purpose of the Study:
- To investigate the molecular mechanism of quercetin in alleviating cerebral ischemic injury by inhibiting the pyroptosis axis.
- To determine if quercetin directly targets NLRP3 to suppress pyroptosis and reduce neuroinflammation.
- To provide direct experimental evidence for quercetin's therapeutic potential in ischemic brain injury.
Main Methods:
- Utilized oxygen-glucose deprivation (OGD) and photothrombotic (PT) models of cerebral ischemia in BV2 microglia and C57BL/6 mice.
- Assessed quercetin's effects on cell viability, pyroptosis, and inflammation markers.
- Employed molecular docking and molecular dynamics simulations to analyze quercetin's interaction with the NLRP3 protein.
Main Results:
- Quercetin significantly ameliorated OGD-induced microglial injury and reduced pyroptosis and inflammation.
- Quercetin improved motor function, attenuated neuronal injury, and inhibited the pyroptosis axis in PT mice.
- Molecular simulations predicted stable binding of quercetin to the NACHT domain of NLRP3, driven by van der Waals interactions.
Conclusions:
- Quercetin directly binds to NLRP3, inhibiting the NLRP3/Caspase-1/GSDMD pyroptosis axis and downstream inflammatory factors.
- Quercetin alleviates cerebral ischemia-induced inflammatory injury through direct inhibition of the NLRP3 inflammasome.
- This study provides direct molecular evidence supporting quercetin as a potential therapeutic agent for ischemic brain injury.
