干扰锌代谢对癫痫小鼠易感性、学习记忆和海马神经元损伤的影响研究

doi:10.13418/j.issn.1001-165x.2019.01.010

中国临床解剖学杂志 ›› 2019, Vol. 37 ›› Issue (1): 45-50.doi: 10.13418/j.issn.1001-165x.2019.01.010

干扰锌代谢对癫痫小鼠易感性、学习记忆和海马神经元损伤的影响研究

李霞¹，刘明晨²，　贾雨山²，　吕明普²，　张莉^2,3

锦州医科大学　1.附属第一医院口腔科，　2.组织胚胎学教研室，　3.生物人类学研究所，辽宁锦州 121001

收稿日期:2018-09-01 出版日期:2019-01-25 发布日期:2019-02-20
通讯作者: 张莉，教授，硕士生导师，E-mail: ln_zhangli@hotmail.com
作者简介:李霞(1980-)，辽宁锦州人，硕士，主管护师，研究方向为锌与神经系统疾病，E-mail: 444680770@qq.com
基金资助:
辽宁省自然科学基金（2015020696, 20180530093）；辽宁特聘教授项目（LNTP20183501）锦州医科大学横向基金（LYHX2013024）；锦州医科大学生物人类学创新团队项目（JYLJ201702）

The effect on seizure susceptibility, learning, memory and injury of mice hippocampal neurons by disturbing zinc metabolism

LI Xia¹, LIU Ming-chen², JIA Yu-shan², LV Ming-pu², ZHANG Li^2,3

1.Department of Stomatology, The First Affiliated Hospital, Jinzhou 121001, Liaoning Province, China; 2.Department of Histology and Embryology; 3.Institute of Anthropology, Jinzhou Medical College, Jinzhou 121001, Liaoning Province, China

Received:2018-09-01 Online:2019-01-25 Published:2019-02-20

摘要/Abstract

摘要：

目的　研究氯碘羟喹预处理干扰锌代谢对癫痫小鼠的癫痫易感性、学习记忆和海马神经元损伤的影响。方法　72只CD-1小鼠随机分为对照组、癫痫组和氯碘羟喹组。氯碘羟喹组腹腔注射氯碘羟喹10 mg·kg-1·d-1，对照组和癫痫组给予等量生理盐水。连续注射1周后，癫痫组和氯碘羟喹组腹腔注射匹罗卡品300 mg/kg建立癫痫模型，对照组予以等量生理盐水。在给予匹罗卡品后90 min内观察动物的癫痫发作率、潜伏期和发作级别；第7 天取材，利用金属自显影技术结合图像分析观察锌在海马的分布变化，尼氏染色观察海马神经元形态变化，酶联免疫吸附法检测血清和脑脊液中S-100β和神经元特异性烯醇化酶（neuronspecific enolase, NSE）蛋白的表达；1个月后利用Mirror水迷宫实验检测逃避潜伏期和目标象限停滞时间。结果　与癫痫组相比，氯碘羟喹组的癫痫发作率和发作级别明显增高，潜伏期明显缩短；海马锌含量明显降低；神经元数量显著增多，损伤减轻；血清和脑脊液中的S-100β和NSE蛋白水平明显降低；逃避潜伏期缩短，目标象限停滞时间延长，P<0.01。结论　氯碘羟喹能减轻锌在癫痫小鼠海马的聚集，提高癫痫易感性，抑制神经元的损伤，提高小鼠学习记忆功能。

关键词: 氯碘羟喹, 　癫痫, 　海马, 　锌, 　损伤

Abstract:

Objective　To study the effects of disturbed zinc metabolism on the epilepsy susceptibility, learning, memory ability and hippocampal neuron injury of the epilepsy mice by clioquinol pre-treatment.　Methods　Seventy-two CD-1 mice were randomly divided into a control group, an epilepsy group and a clioquinol group. Mice in clioquinol group were injected intraperitoneally with clioquinol 10 mg·kg-1·d-1. Mice in the control and epilepsy group were given saline instead. One week later, mice in the epilepsy and clioquinol group were treated intraperitoneally with pilocarpine 300 mg/kg to establish the epilepsy model. Mice in he control group were given saline instead. Afterwards, the period of incidence, incubation and seizure level were observed in 90 min after pilocarpine injection. Tissues were obtained on the 7th day. Autometallography was used to detect the distribution of zinc in hippocampus. Nissl staining was used to check the morphological changes of hippocampal neurons. ELISA detection was used to check the level of S-100β and neuronspecific enolase (NSE) protein in serum and cerebrospinal fluid. One month later, Mirror maze experiment was used to detect the escape latency and time in correct quadrant.　Results　Compared with the epilepsy group, the incidence and seizure level was increased and incubation period shortened in clioquinol group (P<0.01). The zinc level was lower in the clioquinol group than the epilepsy group (P<0.01). There were much more hippocampal neurons in the clioquinol group. The injury of neurons was remedied in the clioquinol group. The expression of S-100β and NSE protein in serum and cerebrospinal fluid decreased significantly in the clioquinol group (P<0.01). Mirror experiment showed that the escape latency was shorter and time in correct quadrant were longer than in epilepsy group (P<0.01).　Conclusion　Clioquinol can lower the zinc accumulation in the epilepsy mice hippocampus, increase the epilepsy susceptibility, inhibit the injury of neurons and improve the learning and memory capability.

Key words: Clioquinol; , Epilepsy; , Hippocampus; , Zinc; , Injury

李霞,刘明晨,贾雨山,吕明普,张莉. 干扰锌代谢对癫痫小鼠易感性、学习记忆和海马神经元损伤的影响研究[J]. 中国临床解剖学杂志, 2019, 37(1): 45-50.

LI Xia, LIU Ming-chen, JIA Yu-shan, LV Ming-pu, ZHANG Li. The effect on seizure susceptibility, learning, memory and injury of mice hippocampal neurons by disturbing zinc metabolism[J]. Chinese Journal Of Clinical Anatomy, 2019, 37(1): 45-50.

参考文献

[1] 郭鸿华, 黄文华, 黄理金, 等. 利用脑局部一致性方法对儿童全身强直发作性癫痫的研究[J]. 中国临床解剖学杂志, 2016, 34(3): 278-284.
[2] Zhu L, Tang Y, Wang HD, et al. Immersion autometallographic demonstration of pathological zinc accumulation in human acute neural diseases[J]. Neurol Sci, 2012, 33(4): 855-861.
[3] Priel T, Aricha-Tamir B, Sekler I. Clioquinol attenuates zinc-dependent beta-cell death and the onset of insulitis and hyperglycemia associated with experimental type I diabetes in mice[J]. Eur J Pharmacol, 2007, 565(1-3): 232-239.
[4] 张亮, 李霞, 刘晓露, 等. 氯碘羟喹抑制癫痫小鼠海马神经元凋亡的实验研究[J]．解剖科学进展, 2015, 21(6): 295-302.
[5] Racine R, Okujava V, Chipashvili S. Modification of seizure activity by electrical stimulation. 3. Mechanisms[J]. Electroencephalogr Clin Neurophysiol, 1972, 32(3): 295-299.
[6] Li-li Li, Mei-fang Jin, Hong Ni. Zinc/CaMK II associated-mitophagy signaling contributed to hippocampal mossy fiber sprouting and cognitive deficits following neonatal seizures and its regulation by chronic leptin treatment[J]. Front Neurol, 2018, 9: 802.
[7] Coulter DA. Mossy fiber zinc and temporal lobe epilepsy: pathological association with altered "epileptic" gamma-aminobutyric acid A receptors in dentate granule cells[J]. Epilepsia, 2000, 41(6): S96-99.
[8] 杨柳, 周月琴, 张敏. Zn2+结合相关基因在耐药性癫痫患者颞叶组织中的表达[J]. 重庆医学, 2012, 41(8): 775-778.
[9] Kim EY, Koh JY, Kim YH, et al. Zn2+ entry produces oxidative neuronal necrosis in cortical cell cultures[J]. Eur J Neurosci, 1999, 11(1): 327-334.
[10]Yokoyama M, Koh J, Choi DW. Brief exposure to zinc is toxic to cortical neurons[J]. Neurosci Lett, 1986, 71(3): 351-355.
[11] Manzerra P, Behrens MM, Canzoniero LM, et al. Zinc induces a Src family kinase-mediated up-regulation of NMDA receptor activity and excitotoxicity[J]. Proc Natl Acad Sci USA, 2001, 98(20): 11055-11061.
[12] 王涛, 周佳敏, 马廷贤, 等. 氯碘羟喹对脑缺血沙土鼠海马神经元的保护作用[J]. 解剖科学进展, 2010, 24(5): 438-441.
[13] 张德辉, 杨锦青, 鞠培新, 等. 锌离子螯合剂DEDTC对小鼠脑缺血再灌注损伤保护作用[J]. 解剖科学进展, 2012, 18(4): 366-369.
[14]Frazzini V, Granzotto A, Bomba M, et al. The pharmacological perturbation of brain zinc impairs BDNF-related signaling and the cognitive performances of young mice[J]. Sci Rep, 2018, 8(1): 9768.
[15] Ismail T, Mauerhofer E, Slomianka L. The hippocampal region of rats and mice after a single i.p. dose of clioquinol: loss of synaptic zinc, cell death and c-Fos induction[J]. Neuroscience, 2008, 157(3): 697-707.
[16]TM Ferrier, AC Schwieger, MJ Eadie. Delayed onset of partial epilepsy of temporal lobe origin following acute clioquinol encephalopathy[J]. J Neurol Neurosurg Psychiatry, 1987, 50(1): 93-95.
[17]Takeda A, Iida M, Ando M, et al. Enhanced susceptibility to spontaneous seizures of noda epileptic rats by loss of synaptic zn(2+)[J]. PloS One, 2013, 8(8): e71372.

干扰锌代谢对癫痫小鼠易感性、学习记忆和海马神经元损伤的影响研究

The effect on seizure susceptibility, learning, memory and injury of mice hippocampal neurons by disturbing zinc metabolism

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