The isoflavones and extracts from Maclura tricuspidata fruit protect against neuronal cell death in ischemic injury via induction of Nox4-targeting miRNA-25, miRNA-92a, and miRNA-146a

This study evaluated the neuroprotective effects 50% EtOH extract of Maclura tricuspidata fruits (FME50) and isolated compounds, cudraisoflavone I (CFI), and cudraisoflavone H (CFH), on ischemic damage in in vitro model and in vivo model of cerebral ischemia. FME50, CFI, and CFH inhibited OGD/R + glucose-induced neuronal cell death, ROS generation, and Nox4 expression via induction of Nox4-targeting miRNA-25, miRNA-92a, and miRNA-146a in SH-SY5Y cells. Also, FME50 suppressed OGD/R + glucose-induced activation of ASK1-JNK1/p38 MAPK signal cascade. Furthermore, FME50 significantly reduced the MCAO/R-induced brain infarct, Nox4 expression via induction of Nox4-targeting three miRNAs. Additionally, FME50 suppressed MCAO/R-induced MAPK signal pathway. These results demonstrate that FME50, CFI, and CFH exert neuroprotective effects via Nox4 inhibition by the induction of Nox4-targeting miRNAs and inhibition of MAPK signal cascade, suggesting that they might be possible candidates for the treatment of cerebral ischemia.