Gallic Acid Alleviates Cerebral Ischemia–reperfusion Injury in Mice by Mediating Microglial Polarization Through the NLRP3/mTOR Axis

Nov 9, 2025Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology

Gallic Acid May Reduce Brain Injury After Stroke in Mice by Changing Immune Cell Responses Through the NLRP3/mTOR Pathway

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Abstract

Gallic acid (GA) treatment significantly improved neurological outcomes in middle cerebral artery occlusion (MCAO) mice by reducing infarct size and brain edema.

GA is associated with promoting M2 polarization of microglia while inhibiting M1 polarization.
Enhanced autophagy and suppressed NLRP3 inflammasome activation via the mTOR pathway were observed with GA treatment.
Inhibition of autophagy reversed the protective effects of GA, leading to increased M1 polarization and exacerbated neuroinflammation.
Activation of the NLRP3 inflammasome counteracted the neuroprotective effects of GA, highlighting its role in microglial modulation.
GA may serve as a potential therapeutic agent for reducing neuroinflammation in cerebral ischemia-reperfusion injury.

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Cerebral ischemia-reperfusion (I/R) injury is a critical condition leading to severe neurological deficits. Inflammation, driven by microglial polarization, plays a significant role in the progression of I/R injury. Gallic acid (GA), a natural polyphenol, has been recognized for its anti-inflammatory and neuroprotective properties. Male mice subjected to middle cerebral artery occlusion (MCAO) were treated with GA. Neurological deficits, infarct size, and brain edema were assessed to evaluate the neuroprotective effects of GA. In vitro, oxygen-glucose deprivation/reoxygenation (OGD/R) models were used to simulate I/R injury in microglial cells. The polarization of microglia was analyzed by flow cytometry, qPCR, and Western blot, focusing on M1 and M2 markers. Autophagy and inflammasome activation were investigated using Western blot, immunofluorescence, and flow cytometry, with the effects of GA modulated by autophagy and inflammasome inhibitors. GA treatment significantly improved neurological outcomes in MCAO mice by reducing infarct size, brain edema, and promoting the M2 polarization of microglia while inhibiting M1 polarization. GA enhanced autophagy and suppressed NLRP3 inflammasome activation via the mTOR pathway, reducing pro-inflammatory cytokine expression. Inhibition of autophagy reversed the protective effects of GA, leading to increased M1 polarization and exacerbated neuroinflammation. Additionally, activation of the NLRP3 inflammasome counteracted GA's effects, emphasizing the role of this pathway in microglial modulation. GA exerts neuroprotective effects in cerebral I/R injury by modulating microglial polarization through the NLRP3/mTOR axis. Its ability to promote autophagy and suppress inflammasome activation positions GA as a potential therapeutic agent for reducing neuroinflammation and improving outcomes in I/R injury.

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Gallic Acid Alleviates Cerebral Ischemia–reperfusion Injury in Mice by Mediating Microglial Polarization Through the NLRP3/mTOR Axis

Abstract

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