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

Abstract

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-1β, and TNF-α. These data enhance our understanding of cell death after SAH and shed light on future preclinical studies.

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Acknowledgements

This work was supported by grants from the National Key R&D Program of China (2018YFC1312600 and 2018YFC1312603), the National Science Foundation of China (81870910 and 81870908), the Natural Science Foundation of Zhejiang Province, China (LY18H090007), and the Scientific Research Fund of Zhejiang Provincial Education Department, China (Y201941838).

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Correspondence to Lin Wang.

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Cao, Y., Li, Y., He, C. et al. Selective Ferroptosis Inhibitor Liproxstatin-1 Attenuates Neurological Deficits and Neuroinflammation After Subarachnoid Hemorrhage. Neurosci. Bull. (2021). https://doi.org/10.1007/s12264-020-00620-5

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Keywords

  • Subarachnoid hemorrhage
  • Ferroptosis
  • Inflammation
  • Liproxstatin-1