Ischemic Preconditioning Provides Neuroprotection by Inhibiting NLRP3 Inflammasome Activation and Cell Pyroptosis

Area of Science:

• Neuroscience
• Immunology
• Cell Biology

Background:

• Ischemic preconditioning (IPC) enhances cerebral tolerance to ischemia.
• The precise mechanisms of IPC neuroprotection remain incompletely understood.
• NLRP3 inflammasome and pyroptosis are implicated in ischemic stroke pathogenesis.

Purpose of the Study:

• To investigate the role of NLRP3 inflammasome and pyroptosis in IPC-mediated neuroprotection after ischemic stroke.
• To elucidate the molecular mechanisms underlying IPC's protective effects.

Main Methods:

• In vitro: BV-2 cells subjected to oxygen-glucose deprivation (OGD) with or without IPC.
• In vivo: Mice underwent transient middle cerebral artery occlusion (MCAO) with or without IPC.
• Assessed NLRP3 inflammasome activation (NLRP3, ASC, caspase-1, GSDMD-N), pyroptosis markers (IL-1β, IL-18), cell viability, infarct size, and neurological deficits.

Main Results:

• IPC increased cell viability under OGD conditions and reduced infarct size and neurological deficits in MCAO mice.
• IPC attenuated NLRP3 inflammasome activation and pyroptosis post-stroke.
• IPC decreased the expression of NLRP3, ASC, cleaved caspase-1, and GSDMD-N, and reduced IL-1β and IL-18 production.
• IPC inhibited Annexin V and SYTOX green staining, indicating reduced cell death.

Conclusions:

• IPC confers neuroprotection against ischemic stroke by suppressing NLRP3 inflammasome activation and pyroptosis.
• The findings highlight a significant link between IPC and the regulation of inflammatory cell death pathways.
• Targeting the NLRP3 inflammasome presents a promising therapeutic strategy for preventing and treating ischemic stroke.