1. Academic Validation
  2. Neuroprotective Effect of Hydrogen Sulfide Subchronic Treatment Against TBI-Induced Ferroptosis and Cognitive Deficits Mediated Through Wnt Signaling Pathway

Neuroprotective Effect of Hydrogen Sulfide Subchronic Treatment Against TBI-Induced Ferroptosis and Cognitive Deficits Mediated Through Wnt Signaling Pathway

  • Cell Mol Neurobiol. 2023 Aug 25. doi: 10.1007/s10571-023-01399-5.
Jie Chen # 1 2 Zhennan Chen # 1 Dongyu Yu 1 Yufei Yan 1 Xiuli Hao 1 Mingxia Zhang 2 Tong Zhu 3
Affiliations

Affiliations

  • 1 College of Forensic Medicine, Xi'an Jiaotong University Health Science Center, No.76 Yanta West Road, Xi'an, 710061, Shaanxi, China.
  • 2 Clinical Experimental Center, Xi'an Engineering Technology Research Center for Cardiovascular Active Pep-Tides, The Affiliated Xi'an International Medical Center Hospital, Northwest University, No.777 Xitai Road, Xi'an, 710100, Shaanxi, China.
  • 3 Clinical Experimental Center, Xi'an Engineering Technology Research Center for Cardiovascular Active Pep-Tides, The Affiliated Xi'an International Medical Center Hospital, Northwest University, No.777 Xitai Road, Xi'an, 710100, Shaanxi, China. zt1995@stu.xjtu.edu.cn.
  • # Contributed equally.
Abstract

Emerging evidence shows that targeting Ferroptosis may be a potential therapeutic strategy for treating traumatic brain injury (TBI). Hydrogen sulfide (H2S) has been proven to play a neuroprotective role in TBI, but little is known about the effects of H2S on TBI-induced Ferroptosis. In addition, it is reported that the Wnt signaling pathway can also actively regulate Ferroptosis. However, whether H2S inhibits Ferroptosis via the Wnt signaling pathway after TBI remains unclear. In this study, we first found that in addition to alleviating neuronal damage and cognitive impairments, H2S remarkably attenuated abnormal iron accumulation, decreased lipid peroxidation, and improved the expression of Glutathione Peroxidase 4, demonstrating the potent anti-ferroptosis action of H2S after TBI. Moreover, Wnt3a or liproxstatin-1 treatment obtained similar results, suggesting that activation of the Wnt signaling pathway can render the cells less susceptible to Ferroptosis post-TBI. More importantly, XAV939, an inhibitor of the Wnt signaling pathway, almost inversed Ferroptosis inactivation and reduction of neuronal loss caused by H2S treatment, substantiating the involvement of the Wnt signaling pathway in anti-ferroptosis effects of H2S. In conclusion, the Wnt signaling pathway might be the critical mechanism in realizing the anti-ferroptosis effects of H2S against TBI. TBI induces ferroptosis-related changes characterized by iron overload, impaired antioxidant system, and lipid peroxidation at the chronic phase after TBI. However, NaHS subchronic treatment reduces the susceptibility to TBI-induced Ferroptosis, at least partly by activating the Wnt signaling pathway.

Keywords

Cognitive impairments; Ferroptosis; Hydrogen sulfide; Neuronal damage; Traumatic brain injury; Wnt signaling pathway.

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