中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2019, Vol. 14 ›› Issue (9): 1573-1582.doi: 10.4103/1673-5374.255972

• 原著:脑损伤修复保护与再生 • 上一篇    下一篇

虎杖苷可预防创伤性脑损伤后的继发性脑损伤

  

  • 出版日期:2019-09-15 发布日期:2019-09-15
  • 基金资助:

    国家自然科学基金(81501690)和南方医科大学人才引进科学研究基金

Polydatin prevents the induction of secondary brain injury after traumatic brain injury by protecting neuronal mitochondria

Li Li 1, 2, 6 , Hong-Ping Tan 3 , Cheng-Yong Liu 1 , Lin-Tao Yu 4 , Da-Nian Wei 1 , Zi-Chen Zhang 1 , Kui Lu 4 , Ke-Sen Zhao 2 , Marc Maegele 1, 5 , Dao-Zhang Cai 6 , Zheng-Tao Gu 1, 2
   

  1. 1 Department of Treatment Center for Traumatic Injuries, the Third Affiliated Hospital of Southern Medical University, Academy of Orthopedics · Guangdong Province, Guangzhou, Guangdong Province, China
    2 Department of Pathophysiology, Southern Medical University, Guangdong Provincial Key Laboratory of Shock and Microcirculation Research, Guangzhou, Guangdong Province, China
    3 Department of Epilepsy Surgery, Guangdong Sanjiu Brain Hospital, Guangzhou, Guangdong Province, China
    4 Department of Emergency, the Third Affiliated Hospital of Southern Medical University, Academy of Orthopedics · Guangdong Province, Guangzhou, Guangdong Province, China
    5 Department of Traumatology and Orthopedic Surgery, Cologne-Merheim Medical Center (CMMC), University Witten/Herdecke (UW/H), Campus Cologne-Merheim, Cologne, Germany
    6 Department of Orthopedics, the Third Affiliated Hospital of Southern Medical University, Academy of Orthopedics · Guangdong Province, Guangzhou, Guangdong Province, China
  • Online:2019-09-15 Published:2019-09-15
  • Contact: Zheng-Tao Gu, PhD, guzhengtao@126.com; Dao-Zhang Cai, PhD, cdz@smu.edu.cn.
  • Supported by:

    This study was supported by the National Natural Science Foundation of China, No. 81501690 (to ZTG); the Scientific Research Staring Foundation for Talent Introduction for Southern Medical University (to MM).

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摘要：

创伤性脑损伤(TBI)后可出现继发性脑损伤，线粒体功能障碍在此过程中可发挥重要作用。虎杖苷已经被证实具有线粒体保护作用。为了观察虎杖苷在TBI后继发性脑损伤过程中是否具有脑保护效应，实验建立了大鼠液压冲击的颅脑损伤模型后，立即予以虎杖苷(30 mg/kg)或SIRT1激动剂SRT1720(20 mg/kg，作为虎杖苷的阳性对照)腹腔注射，TBI后6 h，Western Blot检测大鼠损伤侧的脑皮质SIRT1、内质网应激相关蛋白以及p38的磷酸化表达情况，流式细胞术检测神经元线粒体中活性氧的释放、线粒体膜电位改变和线粒体通透性转换空的开放情况，电镜观察神经元线粒体的损伤情况。结果发现，使用虎杖苷治疗后，(1) TBI大鼠损伤侧的脑皮质神经元线粒体中活性氧的释放明显减少，神经元线粒体的肿胀减轻、线粒体膜电位得以恢复、线粒体通透性转换孔开放以及内质网相关蛋白p-PERK，spliced XBP-1，cleaved ATF6的激活被抑制；(2) TBI大鼠SIRT1的表达和活性明显提高，p38磷酸化和cleaved-caspase-9/3的激活被抑制。(3) TBI后大鼠的神经功能行为评分明显提高，TBI的死亡率降低。(4)上述数据说明，虎杖苷对神经元线粒体有保护作用，其机制可能与TBI后虎杖苷提高SIRT1表达和活性，抑制p38磷酸化介导的线粒体凋亡通路有关。此项研究于2016年1月1日被中国广州南方医科大学动物伦理委员会批准(批准号：L2016113)。

orcid: 0000-0001-8566-6634 (Zheng-Tao Gu)
           0000-0003-2294-5411 (Dao-Zhang Cai)

关键词: 创伤性颅脑损伤, 虎杖苷, 线粒体, 内质网应激, SIRT1, 活性氧, p38, 线粒体膜电位, 线粒体通透性转换孔, 液压冲击, 神经再生

Abstract:

Polydatin is thought to protect mitochondria in different cell types in various diseases. Mitochondrial dysfunction is a major contributing factor in secondary brain injury resulting from traumatic brain injury. To investigate the protective effect of polydatin after traumatic brain injury, a rat brain injury model of lateral fluid percussion was established to mimic traumatic brain injury insults. Rat models were intra¬peritoneally injected with polydatin (30 mg/kg) or the SIRT1 activator SRT1720 (20 mg/kg, as a positive control to polydatin). At 6 hours post-traumatic brain injury insults, western blot assay was used to detect the expression of SIRT1, endoplasmic reticulum stress related proteins and p38 phosphorylation in cerebral cortex on the injured side. Flow cytometry was used to analyze neuronal mitochondrial su¬peroxide, mitochondrial membrane potential and mitochondrial permeability transition pore opened. Ultrastructural damage in neuronal mitochondria was measured by transmission electron microscopy. Our results showed that after treatment with polydatin, release of reactive oxygen species in neuronal mitochondria was markedly reduced; swelling of mitochondria was alleviated; mitochondrial membrane poten¬tial was maintained; mitochondrial permeability transition pore opened. Also endoplasmic reticulum stress related proteins were inhibited, including the activation of p-PERK, spliced XBP-1 and cleaved ATF6. SIRT1 expression and activity were increased; p38 phosphorylation and cleaved caspase-9/3 activation were inhibited. Neurological scores of treated rats were increased and the mortality was reduced com¬pared with the rats only subjected to traumatic brain injury. These results indicated that polydatin protectrd rats from the consequences of traumatic brain injury and exerted a protective effect on neuronal mitochondria. The mechanisms may be linked to increased SIRT1 ex¬pression and activity, which inhibits the p38 phosphorylation-mediated mitochondrial apoptotic pathway. This study was approved by the Animal Care and Use Committee of the Southern Medical University, China (approval number: L2016113) on January 1, 2016.

Key words: nerve regeneration, traumatic brain injury, polydatin, mitochondria, endoplasmic reticulum stress, SIRT1, reactive oxygen species, p38, mitochondrial membrane potential, mitochondrial permeability transition pore, lateral fluid percussion, neural regeneration