Neural Regeneration Research ›› 2023, Vol. 18 ›› Issue (7): 1512-1520.doi: 10.4103/1673-5374.355766

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Upregulation of CDGSH iron sulfur domain 2 attenuates cerebral ischemia/reperfusion injury

Miao Hu1, #, Jie Huang1, #, Lei Chen1, Xiao-Rong Sun1, Zi-Meng Yao1, Xu-Hui Tong1, Wen-Jing Jin1, Yu-Xin Zhang1, Shu-Ying Dong1, 2, 3, *   

  1. 1Department of Pharmacology, School of Pharmacy, Bengbu Medical College, Bengbu, Anhui Province, China; 2Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Bengbu Medical College, Bengbu, Anhui Province, China; 3Anhui Engineering Technology Research Center of Biochemical Pharmaceutical, Bengbu, Anhui Province, China
  • Online:2023-07-15 Published:2023-01-12
  • Contact: Shu-Ying Dong, MD, bbmcdsy@126.com.
  • Supported by:
    This work was supported by the National Natural Science Foundation of China, No. 81402930; Natural Science Foundation of Universities in Anhui Province, No. KJ2021A0688; National College Students Innovation and Entrepreneurship Program, No. 202110367071; Key projects of science and technology projects of Bengbu Medical College, No. 2020byzd017; 512 Talents Training Program of Bengbu Medical College, No. BY51201104 (all to SYD).

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Abstract: CDGSH iron sulfur domain 2 can inhibit ferroptosis, which has been associated with cerebral ischemia/reperfusion, in individuals with head and neck cancer. Therefore, CDGSH iron sulfur domain 2 may be implicated in cerebral ischemia/reperfusion injury. To validate this hypothesis in the present study, we established mouse models of occlusion of the middle cerebral artery and HT22 cell models of oxygen-glucose deprivation and reoxygenation to mimic cerebral ischemia/reperfusion injury in vivo and in vitro, respectively. We found remarkably decreased CDGSH iron sulfur domain 2 expression in the mouse brain tissue and HT22 cells. When we used adeno-associated virus and plasmid to up-regulate CDGSH iron sulfur domain 2 expression in the brain tissue and HT22 cell models separately, mouse neurological dysfunction was greatly improved; the cerebral infarct volume was reduced; the survival rate of HT22 cells was increased; HT22 cell injury was alleviated; the expression of ferroptosis-related glutathione peroxidase 4, cystine-glutamate antiporter, and glutathione was increased; the levels of malondialdehyde, iron ions, and the expression of transferrin receptor 1 were decreased; and the expression of nuclear-factor E2-related factor 2/heme oxygenase 1 was increased. Inhibition of CDGSH iron sulfur domain 2 upregulation via the nuclear-factor E2-related factor 2 inhibitor ML385 in oxygen-glucose deprived and reoxygenated HT22 cells blocked the neuroprotective effects of CDGSH iron sulfur domain 2 up-regulation and the activation of the nuclear-factor E2-related factor 2/heme oxygenase 1 pathway. Our data indicate that the up-regulation of CDGSH iron sulfur domain 2 can attenuate cerebral ischemia/reperfusion injury, thus providing theoretical support from the perspectives of cytology and experimental zoology for the use of this protein as a therapeutic target in patients with cerebral ischemia/reperfusion injury.

Key words: cerebral ischemia/reperfusion injury, CDGSH iron sulfur domain 2, ferroptosis, glutathione peroxidase 4, heme oxygenase 1, HT22, nuclear-factor E2-related factor 2, oxygen-glucose deprivation/reoxygenation injury, stroke, transferrin receptor 1