Artemisinin alleviates ischemic stroke injury and promotes neurogenesis through PPARγ-mediated M2 polarization of microglia

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Artemisinin alleviates ischemic stroke injury and promotes neurogenesis through PPARγ-mediated M2 polarization of microglia

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https://doi.org/10.1016/j.phymed.2025.156769

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Abstract

Background

Ischemic stroke (IS) remains a challenge in clinical treatment due to limited therapeutic options. While artemisinin (ART), an antimalarial drug, shields against acute IS via anti-inflammatory, antioxidant, and anti-apoptotic properties, the long-term benefits and specific underlying mechanisms have not been fully elucidated. Here, we investigate whether ART ameliorates IS injury and promotes neurogenesis by activating the peroxisome proliferator-activated receptor γ (PPARγ)-dependent M2 microglial polarization.

Methods

The experimental models included transient middle cerebral artery occlusion/reperfusion (MCAO/R) in rats and oxygen-glucose deprivation/reoxygenation (OGD/R) in primary microglial cultures to simulate IS. The therapeutic effects of ART were evaluated by neurological functions and infarct volume. PPARγ inhibitor T0070907 (T007) intraperitoneally injected 24 h following MCAO/R at a dose of 2 mg/kg in vivo and a concentration of 10 μM for 30 min before OGD in vitro. We utilized real-time quantitative polymerase chain reaction (RT-qPCR) along with Western blot analyses to detect the microglia markers and PPARγ. The proliferation and differentiation of neural stem cells (NSCs) both in vivo and in vitro were assessed via immunofluorescence labeling. Neurogenic potential of ART-treated microglia was investigated by conditioned medium. The levels of brain-derived growth factor (BDNF) and insulin-like growth factor-1 (IGF-1) in microglia were measured by immunofluorescence staining and enzyme-linked immunosorbent assay (ELISA).

Results

ART treatment significantly alleviated short- and long-term neurological deficits and reduced cerebral infarct volume in rats with IS. Experiments conducted both in vivo and in vitro experiments illustrated that ART directed microglia away from the pro-inflammatory M1 state towards the anti-inflammatory M2 state, enhanced neurogenesis, and upregulated the expression of PPARγ, BDNF, and IGF-1. In addition, the conditioned medium from ART-exposed microglia stimulated the proliferation and neuronal differentiation of primary NSCs. However, these positive effects were effectively counteracted by the use of PPARγ inhibitor T0070907 (T007).

Conclusion

Our findings demonstrate that ART ameliorates IS injury and promotes neurogenesis mainly through PPARγ-mediated microglia M2 polarization. Therefore, ART can be considered a potential therapeutic drug for IS.