Neuroprotective effect of a Keap1-Nrf2 Protein-Protein Inter-action inhibitor on cerebral Ischemia/Reperfusion injury.

Oxidative stress has been confirmed to be closely related to the occurrence and development of cerebral ischemic/reperfusion (I/R). The Keap1-Nrf2 pathway is widely recognized as a defensive system to maintain cellular redox homeostasis. Targeting Keap1-Nrf2 interaction by small molecules to release Nrf2 should be a promising strategy to treat cerebral I/R injury. The piperazinyl-naphthalenesulfonamide 6 K was reported to be a Keap1-Nrf2 protein-protein interaction inhibitor, showing promising antioxidative effect. Herein, this study is to investigate whether 6 K could prevent brain from I/R injury. The related mechanism of oxidative stress was also elucidated using in vivo mice middle cerebral artery occlusion (MCAO) model and in vitro SH-SY5Y oxygen-glucose deprivation/reperfusion (OGD/R) model. The results indicated that treatment of 6 K markedly decreased infarct volume, apoptotic neurons and oxidative damage and promoted neurologic recovery in vivo. The cell model revealed that the reactive oxygen species (ROS) was decreased, and cell viability was increased. Western blots and immunofluorescence staining demonstrated that compound treatment promoted Nrf2 release and nuclear translocation. The downstream protective enzymes were significantly enhanced at both in vivo and in vitro levels. Collectively, 6 K is a promising protective agent against cerebral I/R injury through activation of Nrf2 to suppress oxidative stress.

Qi Z ，Tong Y ，Luo H ，Chen M ，Zhou N ，Chen L ... -  《-》

Neuroprotective Effect of Swertiamain on Cerebral Ischemia/Reperfusion Injury by Inducing the Nrf2 Protective Pathway.

Wang H ，Wei W ，Lan X ，Liu N ，Li Y ，Ma H ，Sun T ，Peng X ，Zhuang C ，Yu J ... -  《ACS Chemical Neuroscience》

Rhein attenuates cerebral ischemia-reperfusion injury via inhibition of ferroptosis through NRF2/SLC7A11/GPX4 pathway.

Liu H ，Zhang TA ，Zhang WY ，Huang SR ，Hu Y ，Sun J ... -  《-》

Neuroprotective effects of Chrysanthemum morifolium on cerebral ischemia- reperfusion injury contributes to the oxidative stress suppression and related Keap1/Nrf2 pathway.

Zhang Z ，Pang X ，Wei Y ，Chen H ，Jin X ，Lv Q ... -  《-》

Loureirin C inhibits ferroptosis after cerebral ischemia reperfusion through regulation of the Nrf2 pathway in mice.

Ischemic stroke (IS) is considered as a serious cerebral vascular disease. Ferroptosis is a novel type of regulated cell death (RCD), that closely related to the occurrence and progress of IS. Loureirin C, a type of dihydrochalcone compound derived from the Chinese Dragon's blood (CDB). The effective components extracted from CDB have shown neuroprotective effects in ischemia reperfusion models. However, the role of Loureirin C in mice after IS is not well understood. Thus, it is worth to identify the effect and mechanism of Loureirin C on IS. The present research aims to prove the existence of ferroptosis in IS and explore whether Loureirin C can inhibit ferroptosis by regulating nuclear factor E2 related factor 2 (Nrf2) pathway in mice and exert neuroprotective effects on IS models. Middle cerebral artery occlusion and reperfusion (MCAO/R) model was established to evaluate the occurrence of ferroptosis and the potential Loureirin C brain-protective effect in vivo. The analysis of free iron, glutamate content, reactive oxygen species (ROS) and lipid peroxidation levels, along with transmission electron microscope (TEM) was applied to prove the existence of ferroptosis. The function of Loureirin C on Nrf2 nuclear translocation was verified by immunofluorescence staining. In vitro, primary neurons and SH-SY5Y cells were processed with Loureirin C after oxygen and glucose deprivation-reperfusion (OGD/R). ELISA kits, western blotting, co-immunoprecipitation (Co-IP) analysis, immunofluorescence, and quantitative real-time PCR were devoted to proving the neuroprotective effects of Loureirin C on IS via regulating ferroptosis and Nrf2 pathways. The results showed that Loureirin C not only dramatically alleviated brain injury and inhibited neurons ferroptosis in mice after MCAO/R, but also dose-dependently reduce ROS accumulation in ferroptosis after OGD/R. Further, Loureirin C inhibits ferroptosis by activating Nrf2 pathway, and promoting nuclear translocation of Nrf2. Besides, Loureirin C increases heme oxygenase 1 (HO-1), quinone oxidoreductase 1 (NQO1) and glutathione peroxidase 4 (GPX4) content after IS. Intriguingly, the anti-ferroptosis effect of Loureirin C is weakened by Nrf2 knockdown. Our discoveries first revealed that the inhibitory action of Loureirin C on ferroptosis may greatly depend on its adjusting effect on the Nrf2 pathway, suggesting that Loureirin C could act as a novel anti-ferroptosis candidate and play a therapeutic role in IS. These novel discoveries on the role of Loureirin C on IS models reveal an innovative method that may contribute to neuroprotection for the prevention of IS.

Liu Y ，Mi Y ，Wang Y ，Meng Q ，Xu L ，Liu Y ，Zhou D ，Wang Y ，Liang D ，Li W ，Li N ，Hou Y ... -  《-》