Selective Ferroptosis Inhibitor Liproxstatin-1 Attenuates Neurological Deficits and Neuroinflammation After Subarachnoid Hemorrhage

Ferroptosis is a form of iron-dependent regulated cell death. Evidence of its existence and the effects of its inhibitors on subarachnoid hemorrhage (SAH) is still lacking. In the present study, we found that liproxstatin-1 protected HT22 cells against hemin-induced injury by protecting mitochondrial functions and ameliorating lipid peroxidation. In in vivo experiments, we demonstrated the presence of characteristic shrunken mitochondria in ipsilateral cortical neurons after SAH. Moreover, liproxstatin-1 attenuated the neurological deficits and brain edema, reduced neuronal cell death, and restored the redox equilibrium after SAH. The inhibition of ferroptosis by liproxstatin-1 was associated with the preservation of glutathione peroxidase 4 and the downregulation of acyl-CoA synthetase long-chain family member 4 as well as cyclooxygenase 2. In addition, liproxstatin-1 decreased the activation of microglia and the release of IL-6, IL-1 beta, and TNF-alpha. These data enhance our understanding of cell death after SAH and shed light on future preclinical studies.

Automated summary

Ferroptosis has been shown to contribute to neuronal damage after SAH, while liproxstatin-1 protects neurons from injury by preserving mitochondrial functions and ameliorating lipid peroxidation. Additionally, liproxstatin-1 alleviates neurological deficits and brain edema, reduces neuronal cell death, and restores redox equilibrium after SAH.