Rhein Alleviates Cerebral Ischemia/Reperfusion Injury by Inhibiting the Microglial NLRP3 Inflammasome/Pyroptosis Axis...

Area of Science:

• Neuroscience
• Immunology
• Pharmacology

Background:

• NLRP3 inflammasome activation drives microglial activation and pyroptosis in cerebral ischemia/reperfusion (I/R) injury.
• Modulating neurotoxic microglia is a key strategy for treating cerebral I/R.
• Rhein, a natural compound, exhibits anti-inflammatory properties.

Purpose of the Study:

• To investigate the effects of rhein on NLRP3 inflammasome activation, microglial pyroptosis, and polarization in cerebral I/R and oxygen-glucose deprivation/reoxygenation (OGD/R) models.
• To determine if rhein exerts neuroprotective effects by modulating these pathways.

Main Methods:

• Cerebral I/R models were induced in rats using transient middle cerebral artery occlusion (tMCAO).
• Oxygen-glucose deprivation and reoxygenation (OGD/R) models were established in BV-2 microglial cells.
• Rhein treatment effects on brain injury, cell viability, NLRP3 inflammasome components, and microglial polarization (M1/M2 phenotypes) were assessed.
• Co-administration with NLRP3 inhibitor MCC950 was used to confirm the mechanism of action.

Main Results:

• Rhein crossed the blood-brain barrier and reduced brain injury in tMCAO rats.
• Rhein inhibited NLRP3 inflammasome activation and pyroptosis in both tMCAO and OGD/R models.
• Rhein suppressed M1 microglial polarization and promoted M2 polarization.
• Combined rhein and MCC950 treatment showed synergistic inhibition of NLRP3 inflammasome activation and pyroptosis, and enhanced microglial polarization regulation.

Conclusions:

• Rhein demonstrates significant neuroprotective effects against cerebral I/R injury.
• Rhein ameliorates brain damage by inhibiting NLRP3 inflammasome-mediated microglial pyroptosis and M1 polarization.
• Rhein shifts microglial polarization towards a neuroprotective M2 phenotype, offering a potential therapeutic strategy for stroke.