Open AccessZinc attenuates ferroptosis and promotes functional recovery in contusion spinal cord injury by activating Nrf2/GPX4 defense pathway
Author(s) -
Ge Minghao,
Tian He,
Mao Liang,
Li Daoyong,
Lin Jiaquan,
Hu Hengshuo,
Huang Shuocheng,
Zhang Chuanjie,
Mei Xifan
Publication year - 2021
Publication title -
cns neuroscience and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 69
eISSN - 1755-5949
pISSN - 1755-5930
DOI - 10.1111/cns.13657
Subject(s) - chemistry , lipid peroxidation , malondialdehyde , spinal cord injury , superoxide dismutase , reactive oxygen species , pharmacology , spinal cord , glutathione peroxidase , neuroprotection , gpx4 , glutathione , oxidative stress , nissl body , biochemistry , pathology , medicine , staining , biology , neuroscience , enzyme
Aim Spinal cord injury (SCI) involves multiple pathological processes. Ferroptosis has been shown to play a critical role in the injury process. We wanted to explore whether zinc can inhibit ferroptosis, reduce inflammation, and then exert a neuroprotective effect. Methods The Alice method was used to establish a spinal cord injury model. The Basso Mouse Scale (BMS), Nissl staining, hematoxylin‐eosin staining, and immunofluorescence analysis were used to investigate the protective effect of zinc on neurons on spinal cord neurons and the recovery of motor function. The regulation of the nuclear factor E2/heme oxygenase‐1 (NRF2/HO‐1) pathway was assessed, the levels of essential ferroptosis proteins were measured, and the changes in mitochondria were confirmed by transmission electron microscopy and 5,5′,6,6′‐tetrachloro‐1,1′,3,3′‐tetraethyl‐imidacarbocyanine iodide (JC‐1) staining. In vitro experiments using VSC4.1 (spinal cord anterior horn motor neuroma cell line), 4‐hydroxynonenal (4HNE), reactive oxygen species (ROS), superoxide dismutase (SOD), malondialdehyde (MDA), glutathione (GSH), lipid peroxides, and finally the levels of inflammatory factors were detected to assess the effect of zinc. Results Zinc reversed behavioral and structural changes after SCI. Zinc increased the expression of NRF2/HO‐1, thereby increasing the content of glutathione peroxidase 4 (GPX4), SOD, and GHS and reducing the levels of lipid peroxides, MDA, and ROS. Zinc also rescued injured mitochondria and effectively reduced spinal cord injury and the levels of inflammatory factors, and the NRF2 inhibitor Brusatol reversed the effects of zinc. Conclusion Zinc promoted the degradation of oxidative stress products and lipid peroxides through the NRF2/HO‐1 and GPX4 signaling pathways to inhibit ferroptosis in neurons.