Enhancer of zeste homolog-2 (EZH2), a
histone methyltransferase, has been recognized to play a pivotal role in regulating the immune response in various diseases. However, its role in the inflammatory response induced by
ischaemic stroke remains to be further investigated. The aim of this study was to determine the role of EZH2 in microglia-associated
inflammation in
ischaemic stroke and to further detect the effects of the EZH2 inhibitor,
3-deazaadenosine A (
DZNep), in ischaemic
brain injury. Here, we found that both in vivo ischemic/reperfusion (I/R) injury and in vitro
oxygen-
glucose deprivation (OGD) treatment induced a marked upregulation of EZH2 in microglia. The administration of the EZH2 inhibitor
DZNep improved behavioural performance and reduced the
infarct volume in mice after experimental
stroke. Furthermore, we showed that
DZNep blocked pro-inflammatory (CD86+) microglial activation and triggered anti-inflammatory (CD206+) microglial polarization in experimental
stroke. Pro-inflammatory
cytokines such as IL-1β,
IL-6, TNF-α and CXCL10 were also significantly downregulated by
DZNep. In addition, it was found that
DZNep blocked the phosphorylation of
signal transducer and activator of transcription 3 (STAT3) in microglia, which was increased by I/R injury and OGD. Collectively, we demonstrated that EZH2 is implicated in regulating microglial activation and exacerbates neurological deficits after
ischaemic stroke, probably via activating STAT3, and that the EZH2 inhibitor
DZNep can exert
neuroprotective effects after
ischaemic stroke.