您的位置：山东大学 -> 科技期刊社 -> 《山东大学学报（医学版）》

山东大学学报（医学版） ›› 2015, Vol. 53 ›› Issue (6): 39-43.doi: 10.6040/j.issn.1671-7554.0.2014.812

• 基础医学 • 上一篇    下一篇

新型组蛋白脱乙酰酶抑制剂11r对癫痫持续状态大鼠的神经保护作用

乔珊, 韩涛, 李文娜, 王胜军, 赵秀鹤, 杨雪, 刘学伍   

  1. 山东大学齐鲁医院神经内科, 山东 济南 250012
  • 收稿日期:2014-11-11 修回日期:2015-02-23 出版日期:2015-06-10 发布日期:2015-06-10
  • 通讯作者: 刘学伍。E-mail:snlxw1966@163.com E-mail:snlxw1966@163.com
  • 基金资助:
    国家自然科学基金(81171071);山东省自然科学基金(ZR2010HM052)

Neuroprotective effects of histone deacetylases inhibitor 11r on rats following status epilepticus

QIAO Shan, HAN Tao, LI Wenna, WANG Shengjun, ZHAO Xiuhe, YANG Xue, LIU Xuewu   

  1. Department of Neurology, Qilu Hospital of Shandong University, Jinan 250012, Shandong, China
  • Received:2014-11-11 Revised:2015-02-23 Online:2015-06-10 Published:2015-06-10

PDF (PC)

117

摘要： 目的 探讨新型组蛋白脱乙酰酶(HDACs)抑制剂11r对癫痫导致脑损伤的神经保护作用。方法 将40只Sprague-Dawley大鼠随机平均分为5组:对照组、匹鲁卡品组、治疗Ⅰ组(致痫后腹腔注射11r,2.5 mg/kg,1次/d,连续3 d)、治疗Ⅱ组(致痫后腹腔注射11r,25 mg/kg, 1次/d,连续3 d)、11r预处理组。通过氯化锂-匹鲁卡品诱发癫痫持续状态(SE),观察大鼠的行为学表现。致痫24 h,通过HE染色观察各组大鼠脑组织形态学改变情况。致痫72 h,通过尼氏染色和免疫组化方法观察各组大鼠海马CA1、CA3区神经元存活情况及组蛋白乙酰化水平。结果 与匹鲁卡品组相比,11r预处理组SE发作潜伏期延长且致痫大鼠死亡率降低(P<0.05)。与匹鲁卡品组相比,治疗Ⅰ组及治疗Ⅱ组海马CA1及CA3区神经元变性的程度降低。治疗Ⅰ组及治疗Ⅱ组海马CA1及CA3区的组蛋白乙酰化水平比匹鲁卡品组高(P<0.05),治疗Ⅰ组与治疗Ⅱ组间的差异无统计学意义(P >0.05)。结论 11r可改善氯化锂-匹鲁卡品诱发癫痫持续状态后急性期脑组织的病理变化及组蛋白乙酰化水平,对癫痫所致脑损伤有一定的保护作用。

关键词: 组蛋白乙酰化, 癫痫, 神经保护, 海马, 抗惊厥

Abstract: Objective To investigate the neuroprotective effects of histone deacetylases(HDACs) inhibitor 11r on rats after seizures. Methods A total of 40 rats were randomly divided into 5 groups: control group,pilocarpine group, treatment group I(administered with 11r, 2.5 mg/kg, once a day,intraperitoneally in three consecutive days), treatment group Ⅱ(administered with 11r, 25 mg/kg, once a day, intraperitoneally in three consecutive days), and 11r pretreatment group. Lithium chloride and pilocarpine were used to induce status epilepticus. The behaviors of rats in each group were observed. HE staining was performed to detect neuronal degeneration in hippocampus 24 hours after pilocarpine-induced seizure. At 72 hour after seizures, Nissl staining and immunohistochemical staining were used to evaluate the loss of neurons and histone acetylation levels of hippocampal CA1 and CA3 regions in each group. Results Compared with pilocarpine group, 11r pretreatment group showed delayed pilocarpine-induced seizures and reduced mortality (P<0.05). Compared with those in pilocarpine group, the degrees of neuronal loss and degeneration in both treatment group Ⅰ and Ⅱ reduced (P<0.05), and the levels of histone acetylation in hippocampal CA1 and CA3 regions increased (P<0.05),while, the difference was not statistically significant between treatment group Ⅰ and Ⅱ (P>0.05). Conclusion New HDACs inhibitor 11r can improve pathological changes and histone acetylation levels of the brain in rats in the acute phase of pilocarpine-induced status epilepticus, which exerts neuroprotective effects on rats after seizures.

Key words: Hippocampus, Neuroprotection, Anticonvulsant, Seizures, Histone acetylation

中图分类号: 

  • R742.1
[1] Henshall DC, Murphy BM. Modulators of neuronal cell death in epilepsy[J]. Curr Opin Pharmacol, 2008, 8(1):75-81.
[2] Butler KV, Kozikowski AP. Effects of antiepileptic drugs on mood and behavior[J]. Epilepsia, 2006, 47 (Suppl 2)28-33.
[3] Butler KV, Kozikowski AP.Chemical origins of isoform selectivity in histone deacetylase inhibitors[J]. Curr Pharm Des, 2008, 14(6):505-528.
[4] Baltan S, Murphy SP, Danilov CA, et al. Histone deacetylase (HDAC) inhibitors preserve white matter, structure and function during ischemia by conserving ATP and reducing excitotoxicity[J]. J Neurosci, 2011, 31(11): 3990-3999.
[5] Kim HJ, Rowe M, Ren M, et al. Histone deacetylase inhibitors exhibit anti-inflammatory and neuroprotective effects in a rat permanent ischemic model of stroke: multiple mechanisms of action[J]. J Pharmacol Exp Ther, 2007, 321(3):892-901.
[6] Gardian G, Browne SE, Choi DK, et al. Neuroprotective effects of phenylbutyrate in the N171-82Q transgenic mouse model of Huntington's disease[J]. Biol Chem, 2005, 280(1):556-563.
[7] Li X, Inks ES, Li X, et al. Discovery of the first N-hydroxycinnamamide-based histone deacetylase 1/3 dual inhibitors with potent oralantitumor activity[J].Med Chem, 2014, 57(8):3324-3341.
[8] Racine RJ. Modification of seizure activity by electrical stimulation. II. Motor seizure[J]. Electroencephalogr Clin Neurophysiol, 1972, 32(3):281-294.
[9] Xu, WS, Parmigiani RB, Marks PA.Histone deacetylase inhibitors: molecular mechanisms of action[J]. Oncogene, 2007, 26(37):5541-5552.
[10] Thomas EA. Involvement of HDAC1 and HDAC3 in the pathology of polyglutamine disorders: therapeutic implications for selective HDAC1/HDAC3 inhibitors[J].Pharmaceuticals (Basel), 2014, 7(6):634-661.
[11] 陈刚,邓艳春.组蛋白乙酰化与癫痫相关基因转录调控研究进展[J]. 中华神经外科疾病研究杂志, 2008, 7(2):188-190
[12] Kim HJ, Rowe M, Ren M, et al. Histone deacetylase inhibitors exhibit anti—inflammatory and neuroprotective effects in a rat permanent ischemic modeI of stroke:multiple mechanisms of action[J].J PharmacoI Exp Ther, 2007, 321(3):892-901.
[13] Rossetti F, de Araujo Furtado M, Pak T, et al. Combined diazepam and HDAC inhibitor treatment protects against seizures and neuronal damage caused by soman exposure[J]. Neurotoxicology, 2012, 33(3):500-511.
[14] Liu YF, Gao F, Li XW, et al. The anticonvulsant and neuroprotective effects of baicalin on pilocarpine-induced epileptic model in rats[J]. Neurochem Res, 2012, 37(8):1670-1680.
[15] Zhang B, West EJ, Van KC, et al. HDAC inhibitor increases histone H3 acetylation and reduces microglia inflammatory response following traumatic brain injury in rats[J].Brain Res, 2008, 1226:181-191.
[16] Miao F, Gonzalo IG, Lanting L, et al. In vivo chromatin remodeling events leading to inflammatory gene transcription under diabetic conditions[J]. J Biol Chem, 2004, 279(17):18091-18097.
[1] 葛丽娟 金瑞峰 王纪文 许新升 李癊. 多药耐药基因1 C1236T多态性与癫痫患者对药物反应性的相关性[J]. 山东大学学报(医学版), 2209, 47(6): 99-102.
[2] 李岩,郭珺,王荣祺,刘永玲. 难治性癫痫相关Sturge-Weber综合征7例临床及病理分析[J]. 山东大学学报（医学版）, 2017, 55(4): 91-95.
[3] 李国华,池恒,邢慧敏,唐吉友. Orexin-A对缺氧状态下海马神经元的影响及其机制[J]. 山东大学学报（医学版）, 2016, 54(4): 17-24.
[4] 赵秀芹,邓春颖,李世英,张晋霞,贺永贵,余红,刘斌. 丁苯酞注射液对大鼠局灶性脑缺血再灌注损伤的神经保护作用[J]. 山东大学学报（医学版）, 2016, 54(4): 25-31.
[5] 孙永锋,刘会昭,钟建卫,王涛,袁俊,翟卫东. 超声引导电生理监测下手术治疗儿童海绵状血管瘤继发癫痫6例[J]. 山东大学学报（医学版）, 2016, 54(4): 55-59.
[6] 王娜,陈乃耀. 脐带间充质干细胞对小胶质细胞增殖及活化的影响[J]. 山东大学学报（医学版）, 2016, 54(10): 16-20.
[7] 贾俊伟,周雪颖,李秋红,于凯,周国钰,周盛年. Annexin A7在匹罗卡品癫痫小鼠模型脑组织中的表达[J]. 山东大学学报（医学版）, 2016, 54(10): 6-10.
[8] 赵振英, 周雪颖, 刘黎青, 刘峰, 周盛年. 二肽基肽酶6在难治性颞叶癫痫患者中的表达[J]. 山东大学学报（医学版）, 2015, 53(10): 37-41.
[9] Gleniece Irving, 王硕, 王辉, 郭盈, 姜路路, 赵秀兰, 谢克勤. 二硫化碳暴露对大鼠学习能力的影响[J]. 山东大学学报（医学版）, 2015, 53(10): 82-86.
[10] 钱冰，吕春娥，田晓康，高殿帅，刘志安. 钙调蛋白依赖性蛋白激酶Ⅱ在AD样大鼠海马的表达及其与细胞凋亡的关系[J]. 山东大学学报（医学版）, 2014, 52(2): 44-47.
[11] 苗玉连，武传龙，刘金波，张晓黎. 白藜芦醇对高脂饮食去卵巢肥胖大鼠脑组织炎症反应及海马Aβ1-42水平的影响[J]. 山东大学学报(医学版), 2013, 51(8): 17-21.
[12] 丁娟，江虹，潘芳. 癫痫患者婚姻质量与心理应激的相关性[J]. 山东大学学报(医学版), 2013, 51(8): 99-102.
[13] 邱小雪，曹丽丽，杨雪，迟兆富. 癫痫持续状态大鼠海马线粒体分裂、融合的变化[J]. 山东大学学报(医学版), 2013, 51(7): 15-19.
[14] 李旭阳，刘德山，梁尔顺，董玲芬，赵莉，高伟. 脑神康胶囊对糖尿病大鼠记忆能力及海马HIF-1α表达的影响[J]. 山东大学学报(医学版), 2013, 51(7): 20-24.
[15] 李婧，李保敏，雷革非，贾桂娟，童丽丽，王纪文. 儿童良性癫痫伴中央颞区棘波的不典型表现[J]. 山东大学学报(医学版), 2013, 51(7): 42-44.
Viewed
Full text


Abstract

Cited
  Shared   
  Discussed   
No Suggested Reading articles found!
版权所有 © 2018 《山东大学学报(医学版)》编辑部　
地址:山东大学科技期刊社（济南市历城区山大南路27号山东大学中心校区明德楼B座721室） 电话: 0531-88366918 E-mail: xbyxb@sdu.edu.cn
本系统由北京玛格泰克科技发展有限公司设计开发