Stroke is one of the most threatening diseases worldwide, particularly in countries with larger populations; it is associated with high morbidity, mortality and disability rates. As a result, extensive research efforts are being made to address these issues. Stroke can include either hemorrhagic stroke (blood vessel ruptures) or ischemic stroke (blockage of an artery). Whilst the incidence of stroke is higher in the elderly population (≥65), it is also increasing in the younger population. Ischemic stroke accounts for ~85% of all stroke cases. The pathogenesis of cerebral ischemic injury can include inflammation, excitotoxic injury, mitochondrial dysfunction, oxidative stress, ion imbalance and increased vascular permeability. All of the aforementioned processes have been extensively studied, providing insights into the disease. Other clinical consequences observed include brain edema, nerve injury, inflammation, motor deficits and cognitive impairment, which not only cause disabilities obstructing daily life but also increase the mortality rates. Ferroptosis is a type of cell death that is characterized by iron accumulation and increased lipid peroxidation in cells. In particular, ferroptosis has been previously implicated in ischemia-reperfusion injury in the central nervous system. It has also been identified as a mechanism involved in cerebral ischemic injury. The tumor suppressor p53 has been reported to modulate the ferroptotic signaling pathway, which both positively and negatively affects the prognosis of cerebral ischemia injury. The present review summarizes the recent findings on the molecular mechanisms of ferroptosis under the regulation of p53 underlying cerebral ischemia injury. Understanding of the p53/ferroptosis signaling pathway may provide insights into developing methods for improving the diagnosis, treatment and even prevention of stroke.
Contents1. Introduction 2. Potential pathogenesis and treatment status of cerebral ischemia injury 3. Ferroptosis 4. p53 5. p53-mediated regulation of iron and lipid metabolism involved in ferroptosis 6. p53-mediated ferroptosis 7. p53-mediated ferroptosis in the MCAO model 8. Conclusions and future perspectives
BackgroundStroke is one of the most severe diseases worldwide, resulting in physical and mental problems. Dl-3-n-butylphthalide, a compound derived from celery seed, has been approved for treating ischemic stroke in China. No study has evaluated how Dl-3-n-butylphthalide affects the ferroptosis SLC7A11/GSH/GPX4 signal pathway and blood–brain barrier (BBB) PDGFRβ/PI3K/Akt signal pathways in the rat middle cerebral artery occlusion/reperfusion (MCAO/R) model of ischemic stroke.MethodsSprague–Dawley rats were used to develop the MCAO/R model. Our study used three incremental doses (10, 20, and 30) of Dl-3-n-butylphthalide injected intraperitoneally 24 h after MCAO/R surgery. The neuroprotective effect and success of the model were evaluated using the neurofunction score, brain water content determination, and triphenyl-tetrazolium chloride-determined infarction area changes. Pathological changes in the brain tissue and the degree of apoptosis were examined by hematoxylin and eosin, Nissl, and terminal deoxynucleotidyl transferase dUTP nick end labeling staining. In addition, pathway proteins and RNA expression levels were studied to verify the effects of Dl-3-n-butyphthalide on both pathways. At the same time, commercial kits were used to detect glutathione, reactive oxygen species, and malondialdehyde, to detect oxidative stress in brain tissues.ResultsThe middle dose of Dl-3-n-butylphthalide not only improved MCAO-induced brain dysfunction and alleviated pathological damage, brain inflammatory response, oxidative stress, and apoptosis but also protected against ferroptosis and reduced BBB damage. These changes resulted in improved neurological function in the cerebral cortex.ConclusionWe speculate that Dl-3-n-butylphthalide has a neuroprotective effect on focal cerebral ischemia/reperfusion, which may be mediated through ferroptosis-dependent SLC7A11/GSH/GPX4 signal pathway and PDGFRβ/PI3/Akt signal pathway.
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