切换至 "中华医学电子期刊资源库"

中华危重症医学杂志(电子版) ›› 2017, Vol. 10 ›› Issue (01) : 18 -22. doi: 10.3877/cma.j.issn.1674-6880.2017.01.004

所属专题: 文献

论著

芬戈莫德改善蛛网膜下腔出血大鼠认知功能及其机制研究
董晓巧1,(), 俞文华1, 杜权1, 王昊1, 杨定博1, 沈永锋1, 江力1, 胡强1, 杜垣峰1, 朱强1, 车志豪1, 孙承龙1, 刘群杰1, 王鼎1   
  1. 1. 310006 杭州,杭州市第一人民医院神经外科
  • 收稿日期:2016-12-24 出版日期:2017-02-01
  • 通信作者: 董晓巧
  • 基金资助:
    浙江省实验动物科技计划项目(2015C37082)

Protective effects of fingolimod on cognitive function in rats with subarachnoid hemorrhage and its mechanism

Xiaoqiao Dong1,(), Wenhua Yu1, Quan Du1, Hao Wang1, Dingbo Yang1, Yongfeng Shen1, Li Jiang1, Qiang Hu1, Yuanfeng Du1, Qiang Zhu1, Zhihao Che1, Chenglong Sun1, Qunjie Liu1, Ding Wang1   

  1. 1. Department of Neurosurgery, Hangzhou First People's Hospital, Hangzhou 310006, China
  • Received:2016-12-24 Published:2017-02-01
  • Corresponding author: Xiaoqiao Dong
  • About author:
    Corresponding author: Dong Xiaoqiao, Email:
引用本文:

董晓巧, 俞文华, 杜权, 王昊, 杨定博, 沈永锋, 江力, 胡强, 杜垣峰, 朱强, 车志豪, 孙承龙, 刘群杰, 王鼎. 芬戈莫德改善蛛网膜下腔出血大鼠认知功能及其机制研究[J/OL]. 中华危重症医学杂志(电子版), 2017, 10(01): 18-22.

Xiaoqiao Dong, Wenhua Yu, Quan Du, Hao Wang, Dingbo Yang, Yongfeng Shen, Li Jiang, Qiang Hu, Yuanfeng Du, Qiang Zhu, Zhihao Che, Chenglong Sun, Qunjie Liu, Ding Wang. Protective effects of fingolimod on cognitive function in rats with subarachnoid hemorrhage and its mechanism[J/OL]. Chinese Journal of Critical Care Medicine(Electronic Edition), 2017, 10(01): 18-22.

目的

探讨芬戈莫德对蛛网膜下腔出血大鼠认知功能的影响及相关机制。

方法

96只大鼠分成对照组、假手术组、模型组和治疗组,每组24只。对照组仅予0.9%氯化钠注射液1 mL腹腔注射。模型组与治疗组大鼠采用枕大池二次注血建立蛛网膜下腔出血大鼠模型,假手术组大鼠两次均注入等量生理盐水。此外,治疗组大鼠模型形成前0.5 h按1 mg/kg剂量予芬戈莫德腹腔注射,假手术组与模型大鼠均予以腹腔注射0.9%氯化钠溶液1 mL。同时,每组取12只大鼠采用Morris水迷宫实验分别于建模成功后8 d及22 d记录大鼠逃避潜伏期,每次历时5 d。另每组取12只大鼠建模24 h后处死,取大鼠海马组织观察炎性细胞浸润,并采用酶联免疫吸附测定法检测海马组织白细胞介素1β(IL-1β)、肿瘤坏死因子α(TNF-α)和IL-6浓度。

结果

四组大鼠在建模后8、9、10、11、12、22、23、24、25、26 d逃避潜伏期比较差异均有统计学意义(F = 171.147、59.363、104.145、91.132、67.732、25.580、21.809、26.693、22.254、24.319,P均< 0.001),模型组与治疗组逃避潜伏期均显著长于对照组和假手术组,且治疗组逃避潜伏期均较模型组显著缩短(P均< 0.001)。模型组与治疗组大鼠海马组织炎性细胞浸润明显增加,四组大鼠海马组织IL-1β、TNF-α和IL-6浓度比较,差异均有统计学意义(F = 231.650、165.281、158.320,P均< 0.001),模型组与治疗组大鼠较对照组和假手术组均显著升高,且治疗组较模型组均显著下降(均P < 0.001)。

结论

芬戈莫德可显著改善蛛网膜下腔出血大鼠认知功能,其作用机制可能与芬戈莫德的中枢炎症抑制作用有关。

Objective

To investigate the effect of fingolimod on cognitive function in rats with subarachnoid hemorrhage and its mechanism.

Methods

A total of 96 rats were randomly assigned to the control group, sham-operation group, model group and treatment group, 24 rats in each group. Rats in the control group only received 1 mL 0.9% sodium chloride injection by intraperitoneal injection. The rats in the model group and treatment group were established subarachnoid hemorrhage model via double autologous blood injection into cisterna magna, and rats in the sham-operation group were injected amount of saline twice. Moreover, rats in the treatment group were administrated intraperitoneally with 1 mg/kg fingolimod at 0.5 h before model establishment, and rats in the sham-operation group and model group were given 1 mL 0.9% sodium chloride injection by intraperitoneal injection at the same time. On 8 and 22 d after model establishment, 12 rats from each group were continuously recorded escape latency 5 d by using Morris water maze. The rest rats were sacrificed at 24 h after model establishment. The hippocampus tissues were used to observe the inflammatory cell infiltration and determine the levels of interleukin-1beta (IL-1β), tumor necrosis factor-alpha (TNF-α) and IL-6 by enzyme linked immunosorbent assay.

Results

The escape latency among the four groups on 8, 9, 10, 11, 12, 22, 23, 24, 25, and 26 d after model establishment were all showed significant differences (F = 171.147, 59.363, 104.145, 91.132, 67.732, 25.580, 21.809, 26.693, 22.254, 24.319; all P < 0.001). The escape latency in the model group and treatment group were longer than those in the control group and sham-operation group, and were longest in the model group (all P < 0.001). Meanwhile, inflammatory cellular infiltration of hippocampus tissues in the model group and treatment group increased. The levels of IL-1β, TNF-α and IL-6 among the four groups also showed significant differences (F = 231.650, 165.281, 158.320; all P < 0.001), and these levels in the model group and treatment group were higher than those in the control group and sham-operation group, and were highest in the model group (all P < 0.001).

Conclusion

Fingolimod can markedly improve the cognitive function of rats with subarachnoid hemorrhage and its mechanism might be related to the inhibition of fingolimod on central nervous system inflammation.

图1 四组大鼠治疗后8~12 d和22~26 d逃避潜伏期的变化(n = 12)。注:a图为治疗后8~12 d逃避潜伏期的变化;b图为治疗后22~26 d逃避潜伏期的变化;与对照组与假手术组比较,*P < 0.05;与模型组比较,#P < 0.05
图2 四组大鼠海马组织病理图。注:a图为对照组;b图为假手术组;c图为模型组;d图为治疗组(苏木素-伊红染色× 400)
图3 四组大鼠海马组织白细胞介素1β、肿瘤坏死因子α和白细胞介素6水平的比较(n = 12)。注:a图为四组大鼠海马组织白细胞介素1β水平的比较;b图为四组大鼠海马组织肿瘤坏死因子α水平的比较;c图为四组大鼠海马组织白细胞介素6水平的比较;与对照组与假手术组比较,*P < 0.05;与模型组比较,#P < 0.05
1
Lee CI, Chou AK, Lin CC, et al. Immune and inflammatory gene signature in rat cerebrum in subarachnoid hemorrhage with microarray analysis[J]. Mol Med Rep, 2012, 5 (1): 118-125.
2
Ayer RE, Ostrowski RP, Sugawara T, et al. Statin-induced T-lymphocyte modulation and neuroprotection following experimental subarachnoid hemorrhage[J]. Acta Neurochir Suppl, 2013 (115): 259-266.
3
李肖亮,单爱军,杜波,等. 急危重症患者继发性脑损伤救治中脑保护的研究进展[J/CD]. 中华危重症医学杂志(电子版),2011,4(1):47-52.
4
Pitman MR, Woodcock JM, Lopez AF, et al. Molecular targets of FTY720 (fingolimod)[J]. Curr Mol Med, 2012, 12 (10): 1207-1219.
5
White C, Alshaker H, Cooper C, et al. The emerging role of FTY720 (Fingolimod) in cancer treatment[J]. Oncotarget, 2016, 7 (17): 23106-23127.
6
Natarajan V, Dudek SM, Jacobson JR, et al. Sphingosine-1-phosphate, FTY720, and sphingosine-1-phosphate receptors in the pathobiology of acute lung injury [J]. Am J Respir Cell Mol Biol, 2013, 49 (1): 6-17.
7
Patmanathan SN, Yap LF, Murray PG, et al. The antineoplastic properties of FTY720: evidence for the repurposing of fingolimod[J]. J Cell Mol Med, 2015, 19 (10): 2329-2340.
8
Zhang L, Wang HD, Ji XJ, et al. FTY720 for cancer therapy (Review)[J]. Oncol Rep, 2013, 30 (6): 2571-2578.
9
Estella-Hermoso de Mendoza A, Castello-Cros R, Imbuluzqueta E, et al. Lipid nanosystems enhance the bioavailability and the therapeutic efficacy of FTY720 in acute myeloid leukemia[J]. J Biomed Nanotechnol, 2015, 11 (4): 691-701.
10
Yoshida Y, Tsuji T, Watanabe S, et al. Efficacy of combination treatment with fingolimod (FTY720) plus pathogenic autoantigen in a glucose-6-phosphate isomerase peptide (GPI325-339)-induced arthritis mouse model [J]. Biol Pharm Bull, 2013, 36 (11): 1739-1746.
11
Vorhees CV, Williams MT. Morris water maze: procedures for assessing spatial and related forms of learning and memory[J]. Nat Protoc, 2006, 1 (2): 848-858.
12
Fujii M, Yan J, Rolland WB, et al. Early brain injury, an evolving frontier in subarachnoid hemorrhage research [J]. Transl Stroke Res, 2013, 4 (4): 432-446.
13
Yuksel S, Tosun YB, Cahill J, et al. Early brain injury following aneurysmal subarachnoid hemorrhage: emphasis on cellular apoptosis[J]. Turk Neurosurg, 2012, 22 (5): 529-533.
14
Rolland WB 2nd, Manaenko A, Lekic T, et al. FTY720 is neuroprotective and improves functional outcomes after intracerebral hemorrhage in mice[J]. Acta Neurochir Suppl, 2011 (111): 213-217.
15
Hasegawa Y, Suzuki H, Sozen T, et al. Activation of sphingosine 1-phosphate receptor-1 by FTY720 is neuroprotective after ischemic stroke in rats[J]. Stroke, 2010, 41 (2): 368-374.
16
Serrone JC, Maekawa H, Tjahjadi M, et al. Aneurysmal subarachnoid hemorrhage: pathobiology, current treatment and future directions[J]. Expert Rev Neurother, 2015, 15 (4): 367-380.
17
Tso MK, Macdonald RL. Subarachnoid hemorrhage: a review of experimental studies on the microcirculation and the neurovascular unit[J]. Transl Stroke Res, 2014, 5 (2): 174-189.
18
Wan H, AlHarbi BM, Macdonald RL. Mechanisms, treatment and prevention of cellular injury and death from delayed events after aneurysmal subarachnoid hemorrhage[J]. Expert Opin Pharmacother, 2014, 15 (2): 231-243.
19
Janssen S, Schlegel C, Gudi V, et al. Effect of FTY720-phosphate on the expression of inflammation-associated molecules in astrocytes in vitro[J]. Mol Med Rep, 2015, 12 (4): 6171-6177.
20
Zhang Z, Zhang Z, Fauser U, et al. FTY720 attenuates accumulation of EMAP-II+ and MHC-II+ monocytes in early lesions of rat traumatic brain injury [J]. J Cell Mol Med, 2007, 11 (2): 307-314.
21
Rolland WB, Lekic T, Krafft PR, et al. Fingolimod reduces cerebral lymphocyte infiltration in experimental models of rodent intracerebral hemorrhage[J]. Exp Neurol, 2013 (241): 45-55.
[1] 刘思锐, 赵辰阳, 张睿, 张一休, 杨萌. 多普勒超声对孕鼠子宫动脉不同节段血流动力学参数的评估[J/OL]. 中华医学超声杂志(电子版), 2024, 21(09): 877-883.
[2] 刘锦程, 王斌, 张雯, 张明周, 刘禹, 叶东樊, 黄赞胜, 邱凌霄, 卿斌, 王创业, 王南博, 王苹, 郭宇航, 周培花, 程秋霞, 徐智. 肺泡灌洗液RASSF1A及SHOX2甲基化联合径向超声特征对肺结节性质鉴别诊断的意义[J/OL]. 中华肺部疾病杂志(电子版), 2024, 17(04): 505-511.
[3] 唐必英, 李钢. 治疗时机对动脉瘤性蛛网膜下腔出血患者预后的影响[J/OL]. 中华神经创伤外科电子杂志, 2024, 10(04): 213-219.
[4] 冯铭, 孙洪涛. 动脉瘤性蛛网膜下腔出血的颅内压监测与管理[J/OL]. 中华神经创伤外科电子杂志, 2024, 10(04): 248-253.
[5] 李晓东, 李昂, 马龙, 刘亮, 魏云, 王汉宇. 基底动脉顶端动脉瘤显微手术治疗[J/OL]. 中华神经创伤外科电子杂志, 2024, 10(04): 254-256.
[6] 张骞, 唐伟, 刘丽丽. 右美托咪定复合羟考酮对老年经皮椎间孔镜腰椎间盘切除术患者术后认知功能、镇痛效果的影响[J/OL]. 中华老年骨科与康复电子杂志, 2024, 10(04): 209-214.
[7] 李晓东, 王汉宇, 马龙, 刘亮, 魏云, 李昂. 小脑后下动脉瘤的显微手术治疗[J/OL]. 中华脑科疾病与康复杂志(电子版), 2024, 14(05): 318-320.
[8] 吉莉, 苏云楠, 王斌, 沈滔, 刘团结, 毛蕾, 徐玉萍, 张婷, 王博. 急性缺血性脑卒中患者脑白质微结构改变对长期认知功能损伤的预测价值研究[J/OL]. 中华脑科疾病与康复杂志(电子版), 2024, 14(04): 193-200.
[9] 孙琴, 梁钿苑, 张源, 任亦星. 代谢异常型肥胖患者对肥胖和减重手术的认知调查研究[J/OL]. 中华肥胖与代谢病电子杂志, 2024, 10(04): 295-299.
[10] 高昊雯, 王桂琦, 庞利云, 张新昕, 谷敬锋. 减重手术治疗肥胖症相关认知障碍的研究进展[J/OL]. 中华肥胖与代谢病电子杂志, 2024, 10(03): 206-212.
[11] 欧春影, 李晓宾, 郭靖, 朱亮, 许可, 王梦, 安晓雷. 丁苯酞对血管性认知障碍大鼠炎症因子的影响及对认知障碍的改善作用[J/OL]. 中华脑血管病杂志(电子版), 2024, 18(05): 483-487.
[12] 王丽娜, 吕书霞, 李亚男. 脑卒中偏瘫患者健康焦虑元认知与疾病接受度、恐惧疾病进展的相关性[J/OL]. 中华脑血管病杂志(电子版), 2024, 18(05): 434-440.
[13] 克地尔牙·马合木提, 胡波, 杨琼, 闫素, 胡岚卿, 高沛沛, 姚恩生. 依达拉奉右莰醇对急性脑梗死后认知功能障碍的疗效观察[J/OL]. 中华脑血管病杂志(电子版), 2024, 18(05): 459-466.
[14] 董立羚, 王添艺, 毛晨晖, 姜宇涵, 尚丽, 包嘉璐, 仇宇悦, 褚珊珊, 金蔚, 倪俊, 高晶. 非出血型脑淀粉样血管病的认知特征——来自北京协和医院痴呆队列的数据[J/OL]. 中华脑血管病杂志(电子版), 2024, 18(04): 295-300.
[15] 董坤, 陈海恋, 王景. 血清CircRNA_0003694与老年急性缺血性卒中患者卒中后认知损害的关系[J/OL]. 中华脑血管病杂志(电子版), 2024, 18(03): 230-235.
阅读次数
全文


摘要