Ferroptosis inhibition protects vascular endothelial cells and maintains integrity of the blood-spinal cord barrier after spinal cord injury

NEURAL REGENERATION RESEARCH, 2023 · DOI: https://doi.org/10.4103/1673-5374.371377 · Published: March 15, 2023

Simple Explanation

This study investigates the role of ferroptosis, a form of cell death, in the disruption of the blood-spinal cord barrier (BSCB) following spinal cord injury (SCI). The BSCB is crucial for spinal cord recovery. The researchers hypothesized that inhibiting ferroptosis could protect the BSCB and improve recovery after SCI. They used liproxstatin-1 (Lip-1), a ferroptosis inhibitor, in a rat model of SCI. The results showed that Lip-1 treatment reduced BSCB disruption, inhibited ferroptosis in vascular endothelial cells, and improved functional recovery in rats with SCI. This suggests that targeting ferroptosis could be a potential therapeutic strategy for SCI.

Study Duration

8 weeks

Participants

Female Wistar rats (8 weeks old, 220–240 g)

Evidence Level

Not specified

Key Findings

1
Liproxstatin-1 (Lip-1) reduces blood-spinal cord barrier (BSCB) disruption after spinal cord injury (SCI) by upregulating the expression of tight junction protein ZO-1 in endothelial cells.
2
Lip-1 inhibits the ferroptosis pathway after SCI by upregulating GPX4 levels and downregulating ACSL4 levels, reducing lipid peroxidation, and modulating glutathione and iron content.
3
Lip-1 inhibits the infiltration of macrophages and neutrophils after SCI, attenuating the inflammatory response in the spinal cord parenchyma.

Research Summary

This study demonstrates that ferroptosis inhibition by Lip-1 maintains BSCB integrity after SCI and reduces vascular endothelial ferroptosis both in vitro and in vivo. Infiltrated immune cells, both macrophages and neutrophils, were reduced after Lip-1 treatment. Ferroptosis inhibition by Lip-1 led to the functional recovery after SCI. Our study reveals the novel mechanism of ferroptosis in the BSCB disruption after SCI.

Practical Implications

Therapeutic Target

Ferroptosis inhibition could be a novel therapeutic target for spinal cord injury.

Clinical Translation

The clinical translation of Lip-1 in SCI is promising and is generalizable to other neurological diseases that involve ferroptosis.

Drug Development

Further research into ferroptosis inhibitors could lead to new treatments for SCI and other neurological disorders.

Study Limitations

1
The study primarily focuses on the effect of Lip-1 on endothelial cell ferroptosis and does not rule out the contribution of ferroptosis in other cell types.
2
The study focuses on major ferroptosis regulators, but the role of iron metabolism in the BSCB and in endothelial cells after SCI requires further exploration.
3
Whether ferroptosis interferes with astrocyte end-feet, neurovascular remodeling and angiogenesis is not yet clear.

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