14,15-EET Maintains Mitochondrial Homeostasis to Inhibit Neuronal Pyroptosis After Ischemic Stroke

Area of Science:

• Neuroscience
• Molecular Biology
• Biochemistry

Background:

• Neuronal pyroptosis contributes to cell death and neurological deficits following cerebral ischemia-reperfusion.
• 14,15-Epoxyeicosatrienoic acid (14,15-EET) shows potential in reducing neuronal loss but its precise mechanisms remain unclear.

Purpose of the Study:

• To elucidate how 14,15-EET regulates mitochondrial homeostasis, inhibits neuronal pyroptosis, and promotes neurological functional recovery after cerebral ischemia-reperfusion.
• To investigate the role of the WNT signaling pathway in 14,15-EET-mediated neuroprotection.

Main Methods:

• Utilized a mouse model of middle cerebral artery occlusion and reperfusion to assess neurological function, neuronal morphology, mitophagy, and pyroptosis.
• Employed transmission electron microscopy, Nissl staining, Western blot, and transcriptome analysis to examine molecular pathways.
• Conducted in vitro studies using HT22 cells subjected to oxygen-glucose deprivation/reoxygenation to explore underlying mechanisms.

Main Results:

• 14,15-EET treatment reduced infarct volume and improved neurological function, preserving neuronal structure and dendritic spine density.
• Inhibition of NLRP1, IL-1β, caspase-1, and GSDMD was observed, alongside increased mitophagy proteins (Parkin, LC3B).
• Transcriptome analysis revealed that 14,15-EET activates the WNT signaling pathway, upregulating key proteins like WNT1, WNT3A, β-catenin, and p-GSK-3β.

Conclusions:

• 14,15-EET promotes neurological recovery by regulating mitochondrial homeostasis and inhibiting neuronal pyroptosis.
• Activation of the WNT signaling pathway is a key mechanism by which 14,15-EET exerts its neuroprotective effects.
• These findings offer novel therapeutic targets for managing cerebral ischemia-reperfusion injury.