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Natural polyphenols ameliorate ischemic stroke by overcoming the double-edged sword effect of AMPK activation

ABSTRACT: Although stimulating microglia to phagocytose abnormally infiltrated cells and tissue debris is crucial for improving the prognosis of ischemic stroke, this energy-intensive physiological process is hindered by the cerebral artery block-induced oxygen/ glucose deprivation. AMP-activated protein kinase (AMPK), as a key molecule regulating energy metabolism, shows promise in resolving this dilemma by elevating intracellular ATP levels in microglia. Here, we uncovered that while activation of AMPK can enhance energy metabolism, it also induces mitochondrial damage via reactive oxygen species (ROS), which demonstrates its double-edged effect. Based on this, from the library of natural polyphenols, gallic acid and ellagic acid were screened for their ability to effectively activate AMPK and scavenge ROS, and exhibit therapeutic effects in a photothrombotic (PT) stroke model. To overcome the poor bioavailability and targeting capability of natural polyphenols, we constructed a class of metal-organic frameworks (MOFs) as neuroprotective agents, which are formed by coordinating gallic acid with metal ions. Microglia benefiting from these MOFs exhibit more efficient phagocytosis, lower ROS levels, and higher cell viability. In a PT stroke model, stereotaxic injection of MOFs significantly increased microglial phagocytosis, provided superior neuronal protection, and improved behavioral outcomes. This strategy highlights the potential of natural polyphenols as neuroprotective agents and emphasizes the complexity and feasibility of regulating microglial phagocytosis via AMPK activation to promote stroke recovery, offering valuable insights into improving prognosis.

ORGANISM(S): Homo Sapiens

SUBMITTER: Zheng Wang

PROVIDER: PXD071975 | iProX | Fri Dec 12 00:00:00 GMT 2025

REPOSITORIES: iProX

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