Study reveals microglia form extracellular traps during cerebral ischemic reperfusion, suggesting succinate oxidation is crucial for neuronal injury.
Ischemia reperfusion (I/R) injury associated with recanalization therapy in acute ischemic stroke (AIS) exacerbates the initial brain damage. However, it remains a clinical challenge due to limited understanding of the underlying mechanisms of I/R injury. This study aims to investigate the mechanism of succinate dehydrogenase (SDH)‐mediated succinate oxidation in microglia extracellular traps (MiETs) formation and neuronal injury after cerebra I/R injury. The results show that microglia are the main cell type producing extracellular traps (ETs) at 24 h at cerebral parenchyma after cerebral I/R. Additionally, oxygen glucose deprivation/re‐oxygenation (OGD/R) could induce MiETs formation and increased level of mitochondrial reactive oxygen species (mtROS). Microglia switches toward glycolysis with enhanced SDH activity and upregulated expression of SDH subunit A (SDHA) during MiETosis. Dimethyl malonate (DMM), a competitive SDH inhibitor, could reduce MiETosis by inhibiting succinate oxidation and mtROS production during reperfusion. Furthermore, DMM is found to alleviate neuronal injury after OGD/R exposure and neurological behavior disorders after cerebral I/R, and the effect is similar to MiETosis inhibitor BB‐Cl amidine. These findings reveal a novel functional state of microglia and the role of succinate oxidation in MiETosis after cerebral I/R and provide a novel potential target for the treatment of AIS.
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Zhao et al. (2025) studied this question.
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