Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, The Intensive Care Unit, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China.
Department of Neurology, Luoding People's Hospital, Affiliated Hospital of Guangdong Medical University, Luoding, China.
Radiat Res. 2021 Apr 1;195(4):355-365. doi: 10.1667/RADE-20-00070.1.
Radiation-induced brain injury (RBI) is a serious complication in patients who have received radiotherapy for head and neck tumors. Currently, there is a scarcity of information on early diagnostic and preventive methods of RBI. Accumulating evidence suggests that microRNAs are involved in the regulation of radiation injury, but the molecular biological mechanism of miRNAs in RBI is largely unknown. Therefore, in our study, microRNA sequencing was used to discover differential miRNAs in the hippocampus of RBI-modeled mice, which suggested that miR-741-3p was most significantly upregulated. To clarify the underlying mechanism of miR-741-3p in RBI-modeled mice, an inhibitor of miR-741-3p (antagomiR-741) was delivered into the brain via the nasal passage before irradiation. The delivery of antagomiR-741 significantly reduced miR-741-3p levels in the hippocampus of RBI-modeled mice, and the cognitive dysfunction and neuronal apoptosis induced by radiation were also alleviated at 6 weeks postirradiation. Downregulation of miR-741-3p was found to improve the protrusion and branching status of microglia after irradiation and reduced the number of GFAP-positive astrocytes. Additionally, antagomiR-741 suppressed the radiation-induced production of pro-inflammatory cytokines IL-6 and TNF-α in the hippocampus and S100B in the serum. Furthermore, Ddr2, PKCα and St8sia1 were revealed as target genes of miR-741-3p and as potential regulatory targets for RBI. Overall, our study provides identification and functional evaluation of miRNA in RBI and lays the foundation for improving the prevention strategy for RBI based on the delivery of miRNA via the nose-brain pathway.
放射性脑损伤（RBI）是头颈部肿瘤患者接受放疗后的一种严重并发症。目前，关于 RBI 的早期诊断和预防方法的信息很少。越来越多的证据表明，miRNAs 参与了辐射损伤的调节，但 miRNA 在 RBI 中的分子生物学机制在很大程度上尚不清楚。因此，在我们的研究中，使用 microRNA 测序发现了 RBI 模型小鼠海马中差异表达的 miRNAs，其中 miR-741-3p 表达上调最显著。为了阐明 miR-741-3p 在 RBI 模型小鼠中的潜在机制，在照射前通过鼻腔途径将 miR-741-3p 的抑制剂（antagomiR-741）递送至大脑。antagomiR-741 的递送显著降低了 RBI 模型小鼠海马中 miR-741-3p 的水平，并且在照射后 6 周也减轻了由辐射引起的认知功能障碍和神经元凋亡。下调 miR-741-3p 被发现可以改善照射后小胶质细胞的突起和分支状态，并减少 GFAP 阳性星形胶质细胞的数量。此外，antagomiR-741 抑制了海马中辐射诱导的促炎细胞因子 IL-6 和 TNF-α以及血清中 S100B 的产生。此外，Ddr2、PKCα 和 St8sia1 被揭示为 miR-741-3p 的靶基因，也是 RBI 的潜在调节靶点。总的来说，我们的研究提供了 RBI 中 miRNA 的鉴定和功能评估，并为基于鼻脑途径递送 miRNA 改善 RBI 的预防策略奠定了基础。
