Blocking P2RX7 Attenuates Ferroptosis in Endothelium and Reduces HG-induced Hemorrhagic Transformation After MCAO by Inhibiting ERK1/2 and P53 Signaling Pathways

Abstract

BackgroundHyperglycemia is a risk factor for poor prognosis after acute ischemic stroke and promote the occurrence of hemorrhagic transformation (HT). The activation of P2RX7 play an important role in endotheliocyte damage and BBB disruption. Ferroptosis is a novel pattern of programmed cell death caused by the accumulation of intracellular iron and lipid peroxidation, resulting in ROS production and cell death. This study is to explore the mechanism of P2RX7 could reduce HT pathogenesis after acute ischemic stroke through regulating endotheliocyte ferroptosis. MethodsMale SD rats were performed to establish middle cerebral artery occlusion (MCAO) model injected with 50% high glucose (HG) and HUVECs were subjected to OGD/R treated with high glucose (30mM) for establishing HT model in vivo and in vitro. P2RX7 inhibitor (BBG) and P2RX7 small interfering RNAs (siRNA) were used to investigate the role of P2RX7 in BBB after MCAO in vivo and OGD/R in vitro, respectively. The neurological de cits, infarct volume, degree of intracranial hemorrhage, integrity of the BBB, immunoblotting and immuno uorescence were evaluated both 24 h after MCAO. ResultsOur study found that the level of P2RX7 was gradually increased after MCAO and/or treated with HG. Our results showed that treatment with HG after MCAO can aggravate neurological de cits, infarct volume, oxidative stress, iron accumulation and integrity of the BBB in HT model, and HG-induced HUVECs damage. The inhibition of P2RX7 reversed the damage effect of HG, signi cantly downregulated the expression level of P53, HO-1 and p-ERK1/2 and upregulated the level of SLC7A11 and GPX4, which implicated that P2RX7 inhibition attenuated oxidative stress and ferroptosis of endothelium in vivo and in vitro. ConclusionOur data provide evidence that the P2RX7 play an important role in HG-associated oxidative stress, endothelial damage and BBB disruption, which regulates HG-induced HT by ERK1/2 and P53 signaling pathways after MCAO.

Role of ferroptosis in the occurrence and progression of acute ischemic stroke

“…A recent study showed that HG intervention after MCAO aggravated neurological deficits, infarct size, oxidative stress, iron accumulation, and BBB damage in a hemorrhagic transformation model. Inhibition of P53 signaling attenuated ferroptosis in the endothelium and reduced HG-induced hemorrhagic transformation after MCAO 116 . In conclusion, p53 may mediate ferroptosis and play an important role in the progression of diabetes and its complications, and inhibition of the p53 signaling pathway may be a new therapeutic target for diabetes and its complications.…”

Ultrasound-Based Micro-/Nanosystems for Biomedical Applications

“…1009,1010 Over the past few decades, numerous research strategies have been developed to deliver drugs to the brain parenchyma, including intracranial injection 1011 and nasal administration. 1012 However, transcranial administration carries the risk of intraoperative injury and damage to the brain parenchyma, 1013 while nasal administration also suffers from limitations in its ability to efficiently deliver drugs.…”

“…The conventional approaches to structurally modifying drugs have limited effectiveness in penetrating the blood-brain barrier and continue to encounter various challenges, including poor efficacy and significant side effects. , Over the past few decades, numerous research strategies have been developed to deliver drugs to the brain parenchyma, including intracranial injection and nasal administration . However, transcranial administration carries the risk of intraoperative injury and damage to the brain parenchyma, while nasal administration also suffers from limitations in its ability to efficiently deliver drugs.…”

The research trends of ferroptosis in diabetes: a bibliometric analysis

“…Wuhan University emerges as a prominent institution with an extensive publication record in this field. Numerous studies originating from Wuhan University elucidate the potential amelioration of symptoms associated with diabetic complications by modulating ferroptosis through diverse pathways (12,(28)(29)(30)(31)(32)(33)(34). Among these, the two most cited studies from this institution delve into the implication of ferroptosis in cardiac injury induced by sepsis and diabetic myocardial ischemia/reperfusion injury (I/RI).…”