Summary Aims Ferroptosis, a new form of iron‐dependent programmed cell death, has been shown to be involved in a range of diseases. However, the role of ferroptosis in traumatic brain injury (TBI) has yet to be elucidated. We aimed to investigate whether ferroptosis is induced after TBI and whether the inhibition of ferroptosis would protect against traumatic brain injury in a controlled cortical impact injury (CCI) mouse model. Methods After establishing the TBI model in mice, we determined the biochemical and morphological changes associated with ferroptosis, including iron accumulation with Perl's staining, neuronal cell death with Fluoro‐Jade B (FJB) staining, iron metabolism dysfunction with Western blotting, reactive oxygen species (ROS) accumulation with malondialdehyde (MDA) assays, and shrunken mitochondria with transmission electron microscopy. Furthermore, a specific inhibitor of ferroptosis, ferrostatin‐1(fer‐1), was administrated by cerebral ventricular injection after CCI. We used cresyl violet (CV) staining to assess lesion volume, along with the Morris water maze and beam walk test to evaluate long‐term outcomes. Results TBI was followed by iron accumulation, dysfunctional iron metabolism, the upregulation of ferroptosis‐related genes, reduced glutathione peroxidase (GPx) activity, and the accumulation of lipid‐reactive oxygen species (ROS). Three days (d) after TBI, transmission electron microscopy (TEM) confirmed that the mitochondria had shrunk a typical characteristic of ferroptosis. Importantly, the administration of Fer‐1 by cerebral ventricular injection significantly reduced iron deposition and neuronal degeneration while attenuating injury lesions and improving long‐term motor and cognitive function. Conclusion This study demonstrated an effective method with which to treat TBI by targeting ferroptosis.
Aim: To systematically profile RNA m6A modification landscape after traumatic brain injury (TBI) in mice. Materials & methods: Expression of m6A-related genes was detected by quantitative real-time PCR (qPCR). Expression and location of METTL3, a key component of m6A methyltransferase complex, were determined by immunostaining. Genome-wide profiling of m6A-tagged transcripts was conducted by m6A-modified RNA immunoprecipitation sequencing (m6A-RIP-seq) and RNA sequencing (RNA-seq). Results: METTL3 was downregulated after TBI. In total, 922 m6A peaks were differentially expressed as determined by m6A-RIP-seq, with 370 upregulated and 552 downregulated. In addition, we identified differentially expressed hypomethylated and hypermethylated mRNA transcripts. Conclusion: Our data provided novel information regarding m6A modification changes in the early period of TBI, which might be promising therapy targets.
Circular RNAs (circRNAs) are involved in a variety of diseases. However, the roles of circRNAs in traumatic brain injury (TBI) remain unknown. In this study, circRNA microarray was used to profile the altered circRNAs in the rat hippocampus following TBI. A total of 192 circRNAs were observed to be differentially expressed (fold change [FC] ≥1.5 and p < 0.05) after TBI, including 98 upregulated and 94 downregulated. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated that many messenger RNAs (mRNAs) transcribed from the host genes of altered circRNAs were implicated in brain damage and neural regeneration. CircRNA/microRNA (miRNA) interaction was predicted using Arraystar's homemade miRNA target prediction software based on TargetScan and miRanda. Thus, our studies have demonstrated altered circRNA expression pattern in the rat hippocampus after TBI, which may play important roles in post-TBI physiological and pathological processes. These findings may provide not only a new direction for studying the molecular mechanisms underlying TBI but also a new possibility for the treatment of TBI by modulating circRNAs.
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