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Morin alleviates sepsis-associated encephalopathy through inhibiting ferroptosis via SIRT1
Zhen Wu1, Hui Li1, Xiaoyuan Zhang2
1Department of Anesthesiology, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550004, China.
Purpose:
Sepsis-associated encephalopathy (SAE) is a diffuse central nervous system dysfunction that occurs during sepsis. Morin has anti-inflammatory and antioxidative effects. The role of morin in SAE is unclear.
Methods:
For in vivo experiments, a SAE mouse model was constructed by cecal ligation and perforation (CLP). The mice were treated using morin and erastin (ferroptosis agonist). The Morris water maze was chosen to examine cognitive function. The mouse hippocampus was collected for HE staining, ELISA, RT-qPCR, western blot, and transmission electron microscopy. For in vitro experiments, HT22 cells received LPS to construct a SAE cell model. The cells were treated with morin, erastin and EX527 (SIRT1 inhibitor) and collected for CCK8 assay, ELISA, western blot and immunofluorescence analysis.
Results:
In vivo experiments showed that morin ameliorated cognitive dysfunction, hippocampal pathological damage, peripheral inflammation and neuroinflammation in SAE mice. Morin raised the level of SLC7A11, GPX4, FTH1 and GSH, while decreased the level of ACSL4, MDA and iron in SAE mice. Morin also alleviated CLP-induced mitochondrial damage. Erastin diminished the protective effects of morin on SAE mice. In vitro experiments demonstrated that morin alleviated LPS-induced HT22 cell damage and inflammation. Erastin and EX527 reversed the effects of morin on HT22 cells. EX527 additionally reversed inhibitory effect of morin on ferroptosis in HT22 cells.
Conclusion:
Morin alleviates SAE by inhibiting ferroptosis via SIRT1.
Insights
Morin, a natural compound, protects against sepsis-associated encephalopathy (SAE) by reducing brain inflammation and cell death. It achieves this by inhibiting ferroptosis, a type of cell death, through the SIRT1 pathway.
Area of Science:
- Neuroscience
- Biochemistry
- Pharmacology
Background:
- Sepsis-associated encephalopathy (SAE) is a critical neurological complication of sepsis.
- Morin exhibits anti-inflammatory and antioxidative properties, but its role in SAE is not well-defined.
Purpose of the Study:
- To investigate the therapeutic potential of morin in sepsis-associated encephalopathy.
- To elucidate the underlying mechanisms of morin's action in SAE, focusing on ferroptosis and SIRT1 signaling.
Main Methods:
- Established in vivo (cecal ligation and perforation model) and in vitro (LPS-induced HT22 cells) models of SAE.
- Administered morin, erastin (ferroptosis agonist), and EX527 (SIRT1 inhibitor) to assess treatment effects.
- Evaluated cognitive function, neuroinflammation, oxidative stress markers, ferroptosis indicators, and mitochondrial integrity using various assays and microscopy.
Main Results:
- Morin treatment improved cognitive function and reduced hippocampal damage and neuroinflammation in SAE mice.
- Morin upregulated ferroptosis suppressors (SLC7A11, GPX4, FTH1, GSH) and downregulated ferroptosis inducers (ACSL4, MDA, iron), mitigating mitochondrial damage.
- In vitro, morin protected HT22 cells from LPS-induced damage, an effect reversed by erastin and EX527, confirming ferroptosis inhibition via SIRT1.
Conclusions:
- Morin demonstrates significant neuroprotective effects in sepsis-associated encephalopathy.
- Morin alleviates SAE by inhibiting ferroptosis through activation of the SIRT1 pathway.
- These findings suggest morin as a potential therapeutic agent for SAE.
