中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2021, Vol. 16 ›› Issue (12): 2438-2445.doi: 10.4103/1673-5374.313047

• 原著:退行性病与再生 • 上一篇    下一篇

地塞米松可使创伤性脑损伤大鼠线粒体功能和突触发生异常的蛋白组学分析

  

  • 出版日期:2021-12-15 发布日期:2021-05-15
  • 基金资助:

    国家自然科学基金项目（81771327）；神经系统损伤基础研究与临床转化平台建设项目；北京神经外科研究所科研培养基金（2020002号）

Protein profiling identified mitochondrial dysfunction and synaptic abnormalities after dexamethasone intervention in rats with traumatic brain injury

Fei Niu1, #, Bin Zhang2, #, Jie Feng3, Xiang Mao4, Xiao-Jian Xu1, Jin-Qian Dong2, Bai-Yun Liu1, 2, 5, 6, *   

  1. 1Department of Neurotrauma, Beijing Key Laboratory of Central Nervous System Injury, Beijing Neurosurgical Institute, Capital Medical University, Beijing, China; 2Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China; 3Key Laboratory of Central Nervous System Injury Research, Center for Brain Tumor, Beijing Institute of Brain Disorders, Beijing Neurosurgical Institute, Capital Medical University, Beijing, China; 4Department of Neurosurgery, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China; 5Center for Nerve Injury and Repair, Beijing Institute of Brain Disorders, Beijing, China; 6China National Clinical Research Center for Neurological Diseases, Beijing, China
  • Online:2021-12-15 Published:2021-05-15
  • Contact: Bai-Yun Liu, MD, liubaiyun@163.com.
  • Supported by:
    This study was supported by the National Natural Science Foundation of China, No. 81771327 (to BYL), the Platform Construction of Basic Research and Clinical Translation of Nervous System Injury, China, No. PXM2020_026280_000002 (to BYL); and the Scientific Research and Cultivation Fund of Beijing Neurosurgical Institute of China, No. 2020002 (to FN).

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摘要：

地塞米松因其抗炎、恢复血管通透性、抑制自由基、减少脑脊液生成等特点，在多种神经外科手术后广泛应用。但是美国颅脑创伤治疗指南显示大剂量糖皮质激素具有神经损伤作用。为了探索大剂量糖皮质激素对脑创伤产生有害作用的原因，实验通过可控性皮质撞击法建立创伤性脑损伤模型，在术后1h以及第2天内腹腔注射地塞米松（10 mg/kg）。(1)发现创伤性脑损伤模型大鼠和地塞米松治疗大鼠31种蛋白表达被显著上调，12种明显下调；(2)功能通路分析，这些差异表达的蛋白可富集在线粒体功能障碍通路和突触形成信号通路中；(3)在这2个信号通路中选择烟酰胺腺嘌呤二核苷酸脱氢酶[泛醌]铁硫蛋白2（Ndufs2）、烟酰胺腺嘌呤二核苷酸脱氢酶[泛醌]黄素蛋白2（Ndufv2）、单胺氧化酶B（Maob）和α-氨基-3-羟基-5-甲基-4-异恶唑丙酸离子能谷氨酸受体3（Gria3）行western blot和免疫组化验证表明，地塞米松治疗组大鼠海马中Ndufs2，Ndufv2，Maob和Gria3的表达水平和阳性细胞数量均明显高于模型组；(4)实验结果表明，地塞米松可能促进复合物I亚单位（Ndufs2和Ndufv2）的补偿性增加，增加线粒体酶Maob的表达，并上调突触传递相关蛋白Gria3，从而引发创伤性脑损伤后的神经损伤。实验于2018年6月6日经北京市神经外科研究所伦理委员会批准（批准号201802001）。

https://orcid.org/0000-0001-8204-2623 (Bai-Yun Liu)

关键词: 创伤性脑损伤, 地塞米松, 蛋白质组学, 质谱, 线粒体功能障碍, 突触异常, 烟酰胺腺嘌呤二核苷酸脱氢酶[泛醌]铁硫蛋白2, 烟酰胺腺嘌呤二核苷酸脱氢酶[泛醌]黄素蛋白2, 单胺氧化酶B, α-氨基-3-羟基-5-甲基-4-异恶唑丙酸离子能谷氨酸受体3

Abstract: Dexamethasone has been widely used after various neurosurgical procedures due to its anti-inflammatory property and the abilities to restore vascular permeability, inhibit free radicals, and reduce cerebrospinal fluid production. According to the latest guidelines for the treatment of traumatic brain injury in the United States, high-dose glucocorticoids cause neurological damage. To investigate the reason why high-dose glucocorticoids after traumatic brain injury exhibit harmful effect, rat controlled cortical impact models of traumatic brain injury were established. At 1 hour and 2 days after surgery, rat models were intraperitoneally administered dexamethasone 10 mg/kg. The results revealed that 31 proteins were significantly upregulated and 12 proteins were significantly downregulated in rat models of traumatic brain injury after dexamethasone treatment. The Ingenuity Pathway Analysis results showed that differentially expressed proteins were enriched in the mitochondrial dysfunction pathway and synaptogenesis signaling pathway. Western blot analysis and immunohistochemistry results showed that Ndufv2, Maob and Gria3 expression and positive cell count in the dexamethasone-treated group were significantly greater than those in the model group. These findings suggest that dexamethasone may promote a compensatory increase in complex I subunits (Ndufs2 and Ndufv2), increase the expression of mitochondrial enzyme Maob, and upregulate synaptic-transmission-related protein Gria3. These changes may be caused by nerve injury after traumatic brain injury treatment by dexamethasone. The study was approved by Institutional Ethics Committee of Beijing Neurosurgical Institute (approval No. 201802001) on June 6, 2018.

Key words: dexamethasone, Gria3, Maob, mass spectrometry, mitochondrial dysfunction, Ndufs2, Ndufv2, proteomics, synaptic abnormalities, traumatic brain injury

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