丹参酮IIA对慢性肾功能衰竭大鼠认知障碍的神经保护作用及其机制

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摘要目的：研究丹参酮IIA（Tan IIA）对慢性肾功能衰竭（CRF）大鼠认知障碍的神经保护作用及潜在机制。方法：雄性SD大鼠60只，采用随机数字表法分为5组，每组12只，分别为：对照组、模型组、内质网应激（ERS）激动剂衣霉素（TM）组、TM+Tan IIA组和Tan IIA组。采用5/6肾切除法模拟CRF模型，造模第4周开始至第12周，TM组和TM+Tan IIA组腹腔注射TM，剂量为4.5 mg/kg，2次/周；TM+Tan IIA组和Tan IIA组腹腔注射Tan IIA 15 mg/kg，1次/d，对照组注射等量0.9%氯化钠溶液。造模完成后采用Morris水迷宫检测大鼠学习记忆能力，HE染色观察海马神经元形态学，Tunel法检测海马神经元细胞凋亡指数，采用试剂盒检测血清和海马组织中的MDA含量和SOD活力，Western blot检测GRP78、CHOP、Caspase-12蛋白的表达。结果：模型组大鼠在Morris水迷宫中表现出的学习记忆能力较对照组明显下降，使用TM干预后下降更为明显，造模12周以后模型组大鼠GRP78、CHOP、Caspase-12蛋白表达水平和凋亡细胞百分比增加，MDA含量增加，SOD水平降低，神经元细胞结构遭到破坏，使用TM干预后ERS相关凋亡水平、氧化应激水平进一步升高，细胞结构破坏较模型组更明显，而Tan IIA干预后ERS相关凋亡蛋白GRP78、CHOP、Caspase-12表达显著下降，抗氧化应激能力显著提高，细胞结构得到明显改善，大鼠在Morris水迷宫中的学习记忆能力得到明显改善。结论：过度ERS诱导的凋亡可能参与了CRF大鼠认知障碍，Tan IIA可能通过抑制ERS相关凋亡、抗氧化应激来发挥神经保护、改善认知作用。

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	朱鸣
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关键词 ：丹参酮IIA；肾功能衰竭, 慢性；认知障碍；内质网应激；氧化性应激；大鼠

Abstract：Objective: To investigate the neuroprotective effect and the potential mechanism of Tan IIA on the cognitive impairment in chronic renal failure (CRF) rats. Methods: Sixty male SD rats were randomly divided into 5 groups with 12 rats in each group. They were grouped as follows: the control group, the model group, the TM group, the TM+Tan IIA group, and the Tan IIA group. The 5/6 renal excision method were adopted to simulate the CRF model. From the 4th weeks to 12th weeks, the TM group and the TM+Tan IIA group were injected TM intra-peritoneal twice per week with the dosage of 4.5 mg/kg, meanwhile the TM+Tan IIA group and the Tan IIA group were injected Tan IIA intraperitoneally once daily with the dosage of 15 mg/kg. The control group was injected intra-peritoneat with an equal volume of saline. Morris water maze test was applied to test the learning and memory abilities of the rats after modeling. HE staining was used to observe the morphology of hippocampal neurons. Tunel staining was used to detect the apoptosis index of hippocampal neurons. MDA content and SOD activity in Serum and hippocampal tissues were detected by the kit. Western blot was used to detect the expression of GRP78, CHOP and Caspase-12 proteins. Results: Compared with the control group, the learning and memory abilities of the model rats in the Morris water maze were significantly decreased, and the decline was more obvious after the TM intervention. Meanwhile, the level of GRP78, CHOP, Caspase-12 protein expressions and the percentage of apoptotic cells increased, accompanied with the increased MDA content reduced SOD levels and disrupted cell structure. In the ERS agonist TM intervention group, increased ERS-associated apoptosis, increased oxidative stress levels, and more pronounced cell structure destruction were observed compared with the model group. The Tan IIA intervention significantly decreased the expression of ERS-associated apoptosis, increased the ability of anti-oxidative stress, and significantly ameliorated the cell structure. Moreover the learning and memory ability of the rats in the Morris water maze was significantly improved. Conclusion: The ERS related excessive apoptosis may be involved in CRF-induced cognitive impairment in rats. Tan IIA probably plays a role in neuroprotection and improves the cognitive function by inhibiting the ERS-related apoptosis and antioxidative stress.

Key words： tanshinone IIA kidney failure, chronic cognitive disorders endoplasmic reticulum stress oxidative stress rats

收稿日期: 2018-01-01

基金资助:浙江省科技厅项目（2017C37106）；浙江省医药卫生科技计划项目（2015DTA017）。

通讯作者: 王霄一，主任医师，Email：hzdysnk@163.com

作者简介: 朱鸣（1963-），男，浙江湖州人，主任医师。

链接本文:

https://xb.wmu.edu.cn/CN/ 或 https://xb.wmu.edu.cn/CN/Y2018/V48/I7/517

[1] ZHANG L, WANG F, WANG L, et al. Prevalence of chronic kidney disease in China: a cross-sectional survey[J]. Lancet, 2012, 379(9818): 815-822.
[2] WANG J, LI X B, HUANG P, et al. Change of peripheral blood Treg/Thl7 in cognitive impairment with chronic renal failure patients[J]. Cell Physiol Biochem, 2018, 45(1): 281-290.
[3] MURRAY A M, TUPPER D E, KNOPMAN D S, et al. Cognitive impairment in hemodialysis patients is common[J]. Neurology, 2006, 67(2): 216-223.
[4] KIM I, XU W, REED J C. Cell death and endoplasmic reticulum stress: disease relevance and therapeutic opportunities [J]. Nat Rev Drug Discov, 2008, 7(12): 1013-1030.
[5] 项冰倩, 高慧, 陈锡文, 等. 内质网过度应激介导低氧高二氧化碳肺动脉高压大鼠的脑损伤[J]. 生理学报, 2017, 69(4): 413-421.
[6] Kovalčíková A, Gyurászová M, Vavrincová-Yaghi D, et al. Oxidative stress in the brain caused by acute kidney injury[J]. Metab Brain Dis, 2018, 33(3): 961-967
[7] FENG J, LI S, CHEN H. Tanshinone IIA inhibits myocardial remodeling induced by pressure overload via suppressing oxidative stress and inflammation:Possible role of silent information regulator 1[J]. Eur J Pharmacol, 2016, 791: 632- 639.
[8] ZHANG Z, LI Y, SHENG C, et al. Tanshinone IIA inhibits apoptosis in the myocardium by inducing microRNA-152-3p expression and thereby downregulating PTEN[J]. Am J Transl Res, 2016, 8(7): 3124-3132.
[9] WENG Y S, WANG H F, PAI P Y, et al. Tanshinone IIA prevents Leu27 IGF-II-induced cardiomyocyte hypertrophy mediated by estrogen receptor and subsequent akt activation[J].Am J Chin Med, 2015, 43(8): 1567-1591
[10] FENG J, LI S, CHEN H. Tanshinone IIA ameliorates apoptosis of cardiomyocytes induced by endoplasmic reticulum stress[J]. Exp Biol Med (Maywood), 2016, 241(18): 2042-2048.
[11] 何治, 潘志红, 鲁文红. 丹参酮IIA对血管性痴呆大鼠的神经保护作用机制[J]. 中国中药杂志, 2010, 35(14): 1883-1886.
[12] XIANG C, WANG Y, ZHANG H, et al. The role of endoplasmic reticulum stress in neurodegenerative disease[J]. Apoptosis, 2017, 22(1): 1-26.
[13] HOTAMISLIGIL G S. Endoplasmic reticulum stress and atherosclerosis[J]. Nat Med, 2010, 16(4): 396-399.
[14] BÁNHEGYI G, BAUMEISTER P, BENEDETTI A, et al. Endoplasmic reticulum stress[J]. Ann N Y Acad Sci, 2010, 1113: 58-71.
[15] HARDY J, SELKOE D J. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics[J]. Science, 2002, 297(5580): 353-356.
[16] 吴彬彬, 董张雷, 连庆泉. 线粒体功能障碍与阿尔茨海默病[J]. 温州医科大学学报, 2014, 44(7): 543-546.
[17] SIMAN R, FLOOD D G, THINAKARAN G, et al. Endoplasmic reticulum stress-induced cysteine protease activation in cortical neurons: effect of an Alzheimer’s disease-linked presenilin-1 knock-in mutation[J]. J Biol Chem, 2001, 276(48): 44736-44743.
[18] LING Z Q, TIAN Q, WANG L, et al. Constant illumination induces Alzheimer-like damages with endoplasmic reticulum involvement and the protection of melatonin[J]. J Alzheimers Dis, 2009, 16(2): 287-300.
[19] RYU E J, HARDING H P, ANGELASTRO J M, et al. Endoplasmic reticulum stress and the unfolded protein response in cellular models of Parkinson’s disease[J]. J Neurosci, 2002, 22(24): 10690-10698.
[20] GÓMEZ-SANTOS C, BARRACHINA M, GIMÉNEZ-XAVIER P, et al. Induction of C/EBPβ and GADD153 expression by dopamine in human neuroblastoma cells: Relationship with α-synuclein increase and cell damage[J]. Brain Res Bull, 2005, 65(1): 87-95.
[21] 魏敏, 闫志强, 董明清, 等. 丹参酮IIA预防慢性缺氧大鼠认知功能障碍的电生理机制[J]. 现代生物医学进展, 2012, 12(11): 2057-2060.
[22] 姜珊, 陆西萍, 高华, 等. 丹参酮IIA对癫痫大鼠认知功能障碍的治疗作用[J]. 神经解剖学杂志, 2014, 30(4): 452-456.
[23] FU J, HUANG H, LIU J, et al. Tanshinone IIA protects cardiac myocytes against oxidative stress-triggered damage and apoptosis[J]. Eur J Pharmacol, 2007, 568(1-3): 213-221.
[24] DONG H, MAO S, WEI J, et al. Tanshinone IIA protects PC12 cells from β-amyloid (25-35)-induced apoptosis via PI3K/Akt signaling pathway[J]. Mol Biol Rep, 2012, 39(6): 6495-6503.
[25] JIN H J, XIE X L, YE J M, et al. Tanshinone IIA and cryptotanshinone protect against hypoxia-induced mitochondrial apoptosis in H9c2 cells[J]. PLoS One, 2013, 8(1): e51720.