ferrostatin-1 and Ischemic-Stroke

Cerebrovascular diseases, such as ischemic stroke, pose serious medical challenges worldwide due to their high morbidity and mortality and limitations in clinical treatment strategies. Studies have shown that reactive oxygen species (ROS)-mediated inflammation, excitotoxicity, and programmed cell death of each neurovascular unit during post-stroke hypoxia and reperfusion play an important role in the pathological cascade. Ferroptosis, a programmed cell death characterized by iron-regulated accumulation of lipid peroxidation, is caused by abnormal metabolism of lipids, glutathione (GSH), and iron, and can accelerate acute central nervous system injury. Recent studies have gradually uncovered the pathological process of ferroptosis in the neurovascular unit of acute stroke. Some drugs such as iron chelators, ferrostatin-1 (Fer-1) and liproxstatin-1 (Lip-1) can protect nerves after neurovascular unit injury in acute stroke by inhibiting ferroptosis. In addition, combined with our previous studies on ferroptosis mediated by natural compounds in ischemic stroke, this review summarized the progress in the regulation mechanism of natural chemical components and herbal chemical components on ferroptosis in recent years, in order to provide reference information for future research on ferroptosis and lead compounds for the development of ferroptosis inhibitors.

Topics: Cyclohexylamines; Ferroptosis; Glutathione; Humans; Iron; Ischemic Stroke; Lipid Peroxidation; Oxidative Stress; Phenylenediamines; Quinoxalines; Reactive Oxygen Species; Spiro Compounds

Ischemic stroke is the major cause of disability and death worldwide, but post-stroke neuronal death and related mechanisms remain unclear. Ferroptosis, a newly identified type of regulated cell death, has been shown to be associated with neurological disorders, yet the exact relationship between ferroptosis and ischemic stroke has not been elucidated. The purpose of this study is to investigate the effects of ferroptosis-specific inhibitor ferrostatin-1 (Fer-1) on neuronal injury after cerebral ischemia/reperfusion (I/R) and the underlying mechanism. In this study, we demonstrated that ferroptosis does occur in the stroke model. We found that Fer-1 reduced the levels of iron and malondialdehyde, and increased the content of glutathione and the expression of solute carrier family 7 member 11 and glutathione peroxidase 4 in cerebral I/R models. Additionally, Fer-1 significantly reduced the infarct volume and improved neurobehavioral outcomes. Moreover, we found that Fer-1 increased the levels of phosphorylated AKT and GSK3β following cerebral I/R. To further investigate the functional role of the AKT in the neuroprotective effects of Fer-1, MCAO models and oxygen-glucose deprivation-induced HT22 cells were pretreated with the AKT inhibitor MK-2206 before treatment with Fer-1 and the protective effects of Fer-1 were reversed. In conclusion, Fer-1 has protective effects on cerebral I/R injury by activating the AKT/GSK3β pathway, indicating that ferroptosis may become a novel target in the treatment of ischemic stroke.

Topics: Brain Ischemia; Glycogen Synthase Kinase 3 beta; Humans; Ischemic Stroke; Proto-Oncogene Proteins c-akt; Reperfusion Injury; Signal Transduction; Stroke

Ferroptosis is a new type of programmed cell death discovered recently and has been demonstrated to be involved in a number of human diseases such as ischemic stroke. Ferroptosis inhibitors are expected to have potential to treat these diseases. Herein, we report the identification of promethazine derivatives as a new type of ferroptosis inhibitors. Structure-activity relationship (SAR) analyses led to the discovery of the most potent compound 2-(1-(4-(4-methylpiperazin-1-yl)phenyl)ethyl)-10H-phenothiazine (51), which showed an EC

Topics: Animals; Cell Line; Ferroptosis; Humans; Ischemic Stroke; Male; Phenothiazines; Rats, Sprague-Dawley