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Aims: Excessive neuroinflammation mediated mainly by microglia plays a crucial role in ischemic stroke. AZD1390, an ataxia telangiectasia mutated (ATM) specific inhibitor, has been shown to promote radio‐sensitization and survival in central nervous system malignancies, while the role of AZD1390 in ischemic stroke remains unknown. Methods: Real‐time PCR, western blot, immunofluorescence staining, flow cytometry and enzyme‐linked immunosorbent assays were used to assess the activation of microglia and the release of inflammatory cytokines. Behavioral tests were performed to measure neurological deficits. 2,3,5‐Triphenyltetrazolium chloride staining was conducted to assess the infarct volume. The activation of NF‐κB signaling pathway was explored through immunofluorescence staining, western blot, co‐immunoprecipitation and proximity ligation assay. Results: The level of pro‐inflammation cytokines and activation of NF‐κB signaling pathway was suppressed by AZD1390 in vitro and in vivo. The behavior deficits and infarct size were partially restored with AZD1390 treatment in experimental stroke. AZD1390 restrict ubiquitylation and sumoylation of the essential regulatory subunit of NF‐κB (NEMO) in an ATM‐dependent and ATM‐independent way respectively, which reduced the activation of the NF‐κB pathway. Conclusion: AZD1390 suppressed NF‐κB signaling pathway to alleviate ischemic brain injury in experimental stroke, and attenuated microglia activation and neuroinflammation, which indicated that AZD1390 might be an attractive agent for the treatment of ischemic stroke. [ABSTRACT FROM AUTHOR]

Aims: Microglia‐mediated neuroinflammation plays an important role in the pathological process of ischemic stroke, and the effect of imperatorin on post‐stroke neuroinflammation is not fully understood. Methods: Primary microglia were treated with imperatorin for 2 h followed by LPS (100 ng/ml) for 24 h. The expression of inflammatory cytokines was detected by RT‐PCR, ELISA, and Western blot. The activation of MAPK and NF‐κB signaling pathways were analyzed by Western blot. The ischemic insult was determined using a transient middle cerebral artery occlusion (tMCAO) model in C57BL/6J mice. Behavior tests were used to assess the neurological deficits of MCAO mice. TTC staining was applied to measure infract volume. Results: Imperatorin suppressed LPS‐induced activation of microglia and pro‐inflammatory cytokines release and attenuated ischemic injury in MCAO mice. The results of transcriptome sequencing and Western blot revealed that downregulation of MAPK and NF‐κB pathways might contribute to the protective effects of imperatorin. Conclusions: Imperatorin downregulated MAPK and NF‐κB signaling pathways and exerted anti‐inflammatory effects in ischemic stroke, which indicated that imperatorin might be a potential compound for the treatment of stroke. [ABSTRACT FROM AUTHOR]