Key Takeaways & Executive Findings
- •• Prostaglandin E1 pretreatment attenuates spinal cord ischemia-reperfusion injury by inhibiting ferroptosis in endothelial cells. • The protective mechanism involves activation of the Nrf2/HO-1 signaling pathway. • Prostaglandin E1 reduces oxidative stress and lipid peroxidation, preserving blood-spinal cord barrier integrity. • Inhibition of Nrf2 with ML385 reverses the protective effects, confirming pathway specificity.
Abstract
BACKGROUND: Ferroptosis is an important pathological mechanism in spinal cord ischemia-reperfusion injury. Although studies have confirmed that prostaglandin E1 attenuates cerebral microvascular endothelial cell injury in the hippocampus induced by chronic cerebral hypoperfusion, its effect on ferroptosis of endothelial cells after spinal cord ischemia-reperfusion injury remains poorly studied. OBJECTIVE: To investigate whether prostaglandin E1 pretreatment attenuates spinal cord ischemia-reperfusion injury by inhibiting ferroptosis in endothelial cells and to elucidate possible mechanisms. METHODS: (1) Cell experiment: Rat spinal cord microvascular endothelial cells were divided into four groups. Control group was cultured under normoxia (20% O2) with complete medium. Model group was subjected to oxygen-glucose deprivation (OGD) for 3 hours (hypoxia chamber with 95% N2 and 5% CO2, glucose-free serum-free medium) followed by reoxygenation for 12 hours (normoxia, complete medium) to simulate spinal cord ischemia-reperfusion injury. Pretreatment group received prostaglandin E1 for 2 hours after OGD and before reoxygenation. Inhibitor group received ML385 (Nrf2 inhibitor) for 2 hours after OGD, then prostaglandin E1 for 2 hours, followed by reoxygenation for 12 hours. After treatment, intracellular malondialdehyde, glutathione, and Fe2+ levels were measured; cell viability was assessed by CCK-8; immunofluorescence staining and western blot were used to detect ACSL4 and GPX4 expression; flow cytometry measured reactive oxygen species; western blot detected Nrf2 and HO-1 protein expression. (2) Animal experiment: 45 rats were randomly divided into three groups: sham group (n=15) underwent laparotomy without aortic occlusion; model group (n=15) underwent occlusion of abdominal aorta for 30 minutes followed by tail vein injection of saline, then reperfusion; pretreatment group (n=15) underwent occlusion for 30 minutes followed by tail vein injection of prostaglandin E1, then reperfusion. At 24 hours after reperfusion, motor function and neuronal injury were assessed by BBB score, inclined plane test, and Nissl staining; blood-spinal cord barrier integrity and microvascular density were evaluated by spinal cord water content, immunofluorescence staining of ZO-1, and CD34 immunohistochemistry; ferroptosis in spinal cord tissue was assessed by immunofluorescence, Prussian blue staining, western blot, and biochemical assays. RESULTS AND CONCLUSION: (1) Cell experiment: OGD/reoxygenation reduced cell viability, induced ferroptosis, and downregulated Nrf2 and HO-1 protein expression in rat spinal cord microvascular endothelial cells. Prostaglandin E1 pretreatment inhibited these effects; ML385 partially reversed the protective effect of prostaglandin E1. (2) Animal experiment: Prostaglandin E1 pretreatment alleviated motor dysfunction, neuronal injury, and blood-spinal cord barrier damage, improved microvascular density, and inhibited ferroptosis in spinal cord tissue after spinal cord ischemia-reperfusion injury. (3) These results indicate that prostaglandin E1 pretreatment protects against spinal cord ischemia-reperfusion injury by activating the Nrf2/HO-1 signaling pathway to inhibit ferroptosis in endothelial cells.
1. Introduction
Spinal cord ischemia-reperfusion injury is a serious complication following spinal decompression surgery and thoracoabdominal aortic repair, with limited clinical treatment options. Exploring its pathological mechanisms is crucial for developing effective therapeutic strategies. Previous studies have shown that ferroptosis plays a key role in the pathophysiology of spinal cord ischemia-reperfusion injury. Ferroptosis is a regulated form of cell death caused by iron overload and excessive accumulation of lipid peroxides. After spinal cord ischemia-reperfusion injury, Fe2+ accumulation and inhibition of glutathione peroxidase 4 antioxidant function disrupt intracellular redox homeostasis, thereby inducing ferroptosis. Inhibiting ferroptosis can rescue neuronal damage and improve neurological function after spinal cord ischemia-reperfusion injury.
However, besides neurons, whether spinal cord ischemia-reperfusion injury causes ferroptosis in other cell types, particularly endothelial cells, remains unclear. Endothelial cells constitute the blood-spinal cord barrier, and their damage exacerbates barrier disruption and secondary injury. Prostaglandin E1 has been reported to attenuate cerebral microvascular endothelial cell injury in chronic cerebral hypoperfusion, but its effect on endothelial ferroptosis after spinal cord ischemia-reperfusion injury has not been investigated. Therefore, this study aimed to determine whether prostaglandin E1 pretreatment can reduce spinal cord ischemia-reperfusion injury by inhibiting endothelial ferroptosis and to elucidate the underlying molecular mechanisms.
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Huang Yushan, Wang Rongrong, Li Xiangmiao, Bai Jinzhu (2026). Prostaglandin E1 pretreatment inhibits ferroptosis in endothelial cells in a rat model of spinal cord ischemia-reperfusion injury. Chinese Journal of Tissue Engineering Research. https://doi.org/10.12307/2026.21237
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Frequently Asked Questions
What is the role of ferroptosis in spinal cord ischemia-reperfusion injury?
Ferroptosis is a regulated cell death mechanism characterized by iron-dependent lipid peroxidation. In spinal cord ischemia-reperfusion injury, ferroptosis contributes to neuronal and endothelial cell damage, exacerbating neurological deficits.
How does prostaglandin E1 protect against spinal cord ischemia-reperfusion injury?
Prostaglandin E1 pretreatment activates the Nrf2/HO-1 signaling pathway, which upregulates antioxidant defenses and inhibits ferroptosis in endothelial cells, thereby preserving blood-spinal cord barrier integrity and improving neurological outcomes.
What experimental models were used in this study?
The study used both in vitro oxygen-glucose deprivation/reoxygenation in rat spinal cord microvascular endothelial cells and an in vivo rat model of spinal cord ischemia-reperfusion injury induced by transient aortic occlusion.
What are the key findings of this research?
Prostaglandin E1 pretreatment significantly reduced ferroptosis markers, improved cell viability, and attenuated tissue damage. The protective effects were partially reversed by the Nrf2 inhibitor ML385, confirming the involvement of the Nrf2/HO-1 pathway.
What are the clinical implications of this study?
Prostaglandin E1 may serve as a potential therapeutic agent to prevent or mitigate spinal cord ischemia-reperfusion injury in surgical settings, offering a new strategy to improve patient outcomes.
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