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. 2025 Nov 10;20(1):101.
doi: 10.1007/s11481-025-10251-0.

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

Weilong Hua #  1 , Hongye Xu #  1   2 , Rundong Chen #  1   3 , Hongjian Zhang  1   4   5   3 , Yongxin Zhang  1 , Xiaoxi Zhang  1 , Yongwei Zhang  1 , Jianmin Liu  1   4 , Lei Zhang  6 , Pengfei Yang  7
Affiliations

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

Weilong Hua et al. J Neuroimmune Pharmacol. .

Abstract

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.

Keywords: Cerebral ischemia–reperfusion injury; Gallic acid; Microglial polarization; NLRP3 inflammasome; mTOR signaling pathway.

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Conflict of interest statement

Declarations. Ethics Approval and Consent to Participate: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was approved by Institutional Review Board of Changhai Hospital, Naval Medical University. Consent for Publication: Not applicable. Competing interests: The authors declare no competing interests.

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