Abstract
Aberrantly expressed microRNAs (miRNAs) after spinal cord injury (SCI) participate in diverse biological pathways and processes, including apoptosis, inflammation, oxidative stress responses, peroxidation, and ferroptosis. This study was aimed at exploring the mechanisms underlying miRNA-mediated ferroptosis in an SCI rat model. In the present study, a T10 weight-dropping SCI model was established and miRNA profiling was used to detect miRNA expression profiles post-SCI. Basso-Beattie-Bresnahan scores and inclined plane test, hematoxylin and eosin (HE) and Nissl staining, immunohistochemistry and immunofluorescence, western blotting, cell viability, and Annexin V/7-aminoactinomycin D (7-AAD) assays were used to evaluate locomotor activity, histological changes in the injured spinal cords, neuronal ferroptosis, ferroptosis suppressor protein 1 (FSP1) expression, and cell death, respectively. It was observed that many miRNAs were differentially expressed after SCI, and miR-672-3p, which increased significantly, was selected after cross-referencing with predicted target miRNAs. The luciferase reporter assay demonstrated that miR-672-3p downregulated FSP1, a glutathione-independent ferroptosis suppressor, by binding to its 3′ untranslated region. Oxygen and glucose deprivation- (OGD-) treated PC12 and AGE1.HN cells were treated with miR-672-3p mimics or inhibitors in vitro. The effect of miR-672-3p mimics or inhibitor on OGD-PC12/AGE1.HN ferroptosis was evaluated by flow cytometry, immunohistochemistry, immunofluorescence, and western blotting. The miR-672-3p mimics promoted ferroptosis after SCI, whereas the miR-672-3p inhibitor inhibited this process. Rats with SCI treated with miR-672-3p mimics or inhibitor showed similar results in vivo. Furthermore, the ferroptosis-related changes caused by SCI or miR-672-3p were reversed by overexpression of FSP1 lentivirus in vivo and in vitro. These results indicated that sh-miR-672-3p exerted a neural restoration effect in vivo and in vitro by inhibiting ferroptosis via the FSP1 pathway.
Highlights
Spinal cord injury (SCI) is a neurological disease that mainly manifests as irreversible functional loss and repair obstruction caused by trauma [1]
Ferroptosis is an iron-dependent form of necrotic cell death that is marked by oxidative damage to phospholipids and can lead to various diseases such as tissue ischemia, reperfusion injury, acute renal failure, and neurodegeneration [5]
To investigate if ferroptosis plays roles in the process of spinal cord injury, rats were divided into three groups: the sham, SCI, and Fer-1 groups
Summary
Spinal cord injury (SCI) is a neurological disease that mainly manifests as irreversible functional loss and repair obstruction caused by trauma [1]. The annual incidence of SCI is 12.1–195.4 cases per million worldwide [2]. Many therapeutics have been used to treat patients with SCI, but limited therapeutic opportunities have been demonstrated [3]. Ferroptosis has recently been discovered as a type of programmed cell death that is iron-dependent and differs from apoptosis, cell necrosis, and autophagy [4]. Ferroptosis is an iron-dependent form of necrotic cell death that is marked by oxidative damage to phospholipids and can lead to various diseases such as tissue ischemia, reperfusion injury, acute renal failure, and neurodegeneration [5].
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