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Abstract Objective Ischaemic stroke is a leading cause of death and disability in individuals worldwide. Cerebral ischaemia reperfusion injury (CIRI) usually leads to severe secondary injury and complications following reperfusion therapy. Microglia play critical roles in the inflammatory reaction of CIRI. However, less attention has been given to microglial death in this process. Our study aimed to explore microglial death in CIRI and the effect and mechanism of minocycline treatment on microglia Methods A middle cerebral artery occlusion (MCAO) model was applied to induce CIRI in rats. At 0 h, 24 h and 48 h postoperation, 45 mg/kg minocycline was intraperitoneally injected into the rats. Neurological deficit scoring, 2,3,5-triphenyltetrazolium chloride (TTC) staining, activated microglia and mitochondrial structure were observed and checked at 72 h after reperfusion. Moreover, an in vitro model of oxygen-glucose deprivation/reperfusion (OGD/R) model was established. BV-2 cells were treated with either various pharmacological inhibitors of cell death or minocycline. Cell viability, lipid peroxidation, mitochondrial structure and functioning, and labile Fe2+ and ferroptosis-associated gene/proteins levels were measured. Hemin was used for further validation after transcriptome analysis. Results In the MCAO and OGD/R models, ferroptosis was identified as a major form of microglial death. Minocycline inhibited microglial ferroptosis by reducing HO-1 expression. In addition, minocycline improved mitochondrial membrane potential, mitochondrial structures and microglial survival in vivo. Minocycline also decreased labile Fe2+ levels, lipid peroxidation, and ferritin heavy chain (FTH) expression and improved mitochondrial structure and functioning in vitro. HO-1 overexpression counteracted the protective effect of minocycline. Conclusion Ferroptosis is a major form of microglial death in CIRI. The mechanism of the protective role of minocycline in CIRI is partly dependent on its ability to effectively ameliorate microglial ferroptosis by reducing HO-1 expression. Therefore, targeting microglial ferroptosis is a promising treatment for CIRI.
Wang et al. (Tue,) studied this question.