Clioquinol与Vitamin B12对慢性铅引起的突触可塑性损伤的协同修复作用

发布时间：2018-06-02 12:38

本文选题：Clioquinol(CQ) + 铅　；参考：《中国科学技术大学》2007年博士论文

【摘要】： 铅是最重要的环境神经毒物之一。现已被证实儿童在发育过程中的慢性铅暴露会引起学习和记忆功能和神经行为等认知功能损伤，这在不同的动物模型中也得到了证实。海马是与学习和记忆功能密切相关的一个重要脑区，海马神经元活性依赖的突触可塑性被认为是学习和记忆功能的细胞与分子基础。在发育过程中，铅暴露损伤了大鼠海马的突触可塑性，这可能是慢性铅暴露损伤学习和记忆功能和神经行为等认知功能的机制之一。目前，螯合剂驱铅治疗被普遍采用。但是，常用的那些螯合剂表现出许多无法克服的副作用，而且并不能修复铅已经造成的神经元结构与功能的损伤。寻找有效而副作用小的铅修复药物是当前研究热点。最近，一个对二价金属离子有低亲和性的金属螯合剂或者离子载体Clioquinol(CQ)已经被用于一些与金属离子功能紊乱相关的疾病动物模型和临床实验中，如老年痴呆，帕金森氏和亨廷顿氏疾病等，并取得了一些较好的效果。在二十世纪七十年代，由于在日本暴发thesubacute myelo-optic neuropathy(SMON)病症，并被认为与应用CQ有关，因此，从那时起CQ被禁用。然而近年来的研究表明，CQ相关的副作用可以通过补充Vitamin B12(VB12)加以克服。为了探明CQ处理是否可以修复铅引起的突触可塑性损伤及其作用机理，本论文中，我们通过在位场电位技术在麻醉wistar大鼠的PP—DG通路上研究了不同处理组动物的输入／输出功能，双脉冲响应和长时程增强等参数，同时，我们还应用电感耦合等离子体质谱仪检测了不同处理组动物的海马铅水平。主要结果如下： 1．Clioquinol(CQ)单独处理并没有修复慢性铅暴露引起的突触可塑性损伤在对照组，双脉冲响应的平均峰值易化是225±17.3％，在高频刺激后一个小时，兴奋性突触后电位的长时程增强的平均幅度是136±4％，群体峰电位的长时程增强的平均幅度是266±17.3％；在慢性铅暴露组，双脉冲响应的平均峰值易化是180±12.5％，在高频刺激后一个小时，兴奋性突触后电位的长时程增强的平均幅度是122±2％，群体峰电位的长时程增强的平均幅度是195±10.4％：在对慢性铅暴露的大鼠进行CQ单独处理组，双脉冲响应的平均峰值易化是180±24.3％，在高频刺激后一个小时，兴奋性突触后电位的长时程增强的平均幅度是125±3.4％，群体峰电位的长时程增强的平均幅度是199±14.7％。相应的数据进行比较可以得出慢性铅暴露引起了双脉冲响应的平均峰值易化，兴奋性突触后电位的长时程增强的平均幅度和群体峰电位的长时程增强的平均幅度的损伤；并且Clioquinol(CQ)单独处理并没有修复慢性铅暴露引起的这些损伤。铅能够通过模拟钙离子同机体内的许多大分子结合形成金属蛋白复合物，这可能导致了抗氧化的金属蛋白复合物系统的损伤从而介导了铅引起的损伤。CQ能够作为一个金属—蛋白衰减元素同金属蛋白复合物相互作用，CQ可能会结合到铅一蛋白复合物上而衰减该复合物的内部相互作用而取得有益的效果。然而，已有报道，用CQ处理过的小鼠的血液和大脑内的VB12减少，CQ处理而引起的VB12的缺乏被怀疑与SMON病症有关。CQ单独处理不能修复铅诱导的损伤可能就是由于CQ同时造成了VB12缺乏，这拮抗了CQ的修复效应。 2．Vitamin B12(VB12)单独处理仅部分地修复了慢性铅暴露引起的损伤在对慢性铅暴露的大鼠进行VB12单独处理组，双脉冲响应的平均峰值易化是178±19.4％，在高频刺激后一个小时，兴奋性突触后电位的长时程增强的平均幅度是126±3.6％，群体峰电位的长时程增强的平均幅度是226±15.2％。结合前述的对照组和慢性铅暴露组的数据，表明单独VB12处理仅仅修复了兴奋性突触后电位的长时程增强的平均幅度和群体峰电位的长时程增强的平均幅度，而且修复后的幅度和对照组相比，显著地小于对照组的幅度。VB12单独处理仅部分地修复了慢性铅暴露引起的损伤。慢性铅暴露引起神经元功能的损伤，部分是通过铅的氧化损伤。铅神经毒性的一个可能的分子机制就是铅引起了促氧化／抗氧化平衡系统的紊乱。VB12的补充可能重新平衡了促氧化／抗氧化系统，这可能是VB12补充可以部分地修复铅引起的长时程增强损伤机理。 3．CQ和VB12的协同作用几乎完全修复了铅引起的突触可塑性损伤，并且在对照组这种协同作用并不存在，它对铅暴露组有特异性在对慢性铅暴露的大鼠进行CQ和VB12共处理组，双脉冲响应的平均峰值易化是216±19.3％，在高频刺激后一个小时，兴奋性突触后电位的长时程增强的平均幅度是138±2.8％，群体峰电位的长时程增强的平均幅度是273±18.1％。结合前述的对照组和慢性铅暴露组的数据，表明CQ和VB12共处理几乎完全修复了慢性铅引起的双脉冲响应的平均峰值易化，兴奋性突触后电位的长时程增强的平均幅度和群体峰电位的长时程增强的平均幅度的损伤。提示二者有协同效应，这种协同效应大大增强了对铅引起的损伤的修复作用。在CQ和VB12共同处理的条件下，不仅CQ能纠正由慢性铅暴露产生的金属蛋白系统的紊乱，降低由慢性铅暴露引起的氧化损伤，而且，VB12的补充能够拮抗由于CQ处理带来的VB12的缺乏。因此，CQ和VB12共同处理在修复铅引起的突触可塑性损伤方面显示了协同作用，几乎完全修复了这些损伤。另外在对照组中CQ和VB12共同处理并没有增强其突触可塑性，，提示对慢性铅暴露有特异的协同修复作用。另外，结合不同处理组海马铅水平的检测，提示这种协同修复作用并不是通过驱除组织铅实现的。
[Abstract]:Lead is one of the most important environmental neurotoxicants. It has been confirmed that chronic lead exposure in children can cause cognitive impairment of learning and memory function and neural behavior, which is also confirmed in different animal models. Hippocampus is an important brain area associated with learning and memory function, hippocampal neurons. Activity dependent synaptic plasticity is considered to be the cellular and molecular basis of learning and memory functions. During development, lead exposure damages synaptic plasticity in the hippocampus of rats, which may be one of the mechanisms of cognitive functions such as learning and memory and neurobehavioral impairment in chronic lead exposure.
Currently, chelating agents are widely used for lead treatment. However, the commonly used chelates show many unconquered side effects and can not repair the damage to the structure and function of neurons caused by lead. Finding effective and minor lead repair drugs is the current research focus. Recently, a low parent metal ion has a low affinity for two valence metal ions. The metal chelating agent or Clioquinol (CQ) has been used in animal models and clinical trials related to the dysfunction of metal ions, such as Alzheimer's, Parkinson's and Huntington's diseases, and has achieved some good results in 1970s, due to the outbreak of thesubacute m in Japan. Yelo-optic neuropathy (SMON) is considered to be associated with the application of CQ, so CQ has been banned from that time. However, recent studies have shown that the side effects of CQ can be overcome by supplementing Vitamin B12 (VB12).
In order to find out whether CQ can repair the synaptic plasticity damage caused by lead and its mechanism, in this paper, we have studied the input / output function, double pulse response and long term potentiation of different treatment groups by the incumbent field potential technique in the PP - DG pathway of anesthetized Wistar rats, and we also applied electricity. The lead levels in hippocampus of different treatment groups were detected by ICP-MS. The main results are as follows:
1.Clioquinol (CQ) alone did not repair synaptic plasticity injury caused by chronic lead exposure.
In the control group, the average peak value of the double pulse response is 225 + 17.3%. The average amplitude of the long term potentiation of the excitatory postsynaptic potential is 136 + 4% at one hour after the high frequency stimulation, and the average amplitude of the long period enhancement of the peak potential is 266 + 17.3%, and the average peak value of the double pulse response is 180 + 1 in the chronic lead exposure group. 2.5%, at an hour after high frequency stimulation, the average amplitude of the long term potentiation of the excitatory postsynaptic potential is 122 + 2%, and the average amplitude of the long period enhancement of the peak potential of the group is 195 + 10.4%:
For the rats exposed to chronic lead exposure, the average peak value of the double pulse response was 180 + 24.3%. The average amplitude of the long time potentiation of the excitatory postsynaptic potential was 125 + 3.4% at one hour after the high frequency stimulation. The average amplitude of the long time enhancement of the peak potential of the group was 199 + 14.7%. corresponding data. It can be concluded that chronic lead exposure causes the average peak susceptibility of the double impulse response, the average amplitude of the long time potentiation of the excitatory postsynaptic potential and the average amplitude of the long period enhancement of the peak potential of the group; and Clioquinol (CQ) alone does not repair these injuries caused by chronic lead exposure.
Lead can form a metal protein complex through the combination of calcium ions and many large molecules in the body, which may cause damage to the antioxidant metalloprotein complex system and mediate lead induced damage.CQ can interact with metal egg white complexes as a metal protein attenuating element, and CQ may be combined. However, it has been reported that the blood and VB12 in the brain of mice treated with CQ were reduced, and the VB12 deficiency caused by CQ treatment was suspected to be associated with the SMON disease that.CQ alone could not repair lead induced damage due to CQ. The deficiency of VB12 resulted in the antagonistic effect of CQ.
2.Vitamin B12 (VB12) alone has partially repaired the damage caused by chronic lead exposure.
In the group of rats exposed to chronic lead exposure, the average peak value of the double pulse response was 178 + 19.4%. The average amplitude of the long time potentiation of the excitatory postsynaptic potential was 126 + 3.6% at one hour after the high frequency stimulation. The average amplitude of the long time enhancement of the peak potential of the group was 226 + 15.2%. combined with the previous control group. Data from the chronic lead exposure group showed that a single VB12 treatment only repaired the mean amplitude of long time potentiation of the excitatory postsynaptic potential and the mean range of long time potentiation of the peak potential of the group, and the amplitude after repair was significantly smaller than that of the control group, and the amplitude of.VB12 alone was only partially repaired by the control group. Damage caused by lead exposure.
A possible molecular mechanism of lead neurotoxicity is that lead causes the disorder of the oxidative / antioxidant balance system.VB12 supplementation may rebalance the oxidation / antioxidant system, which may be that VB12 supplements can partially repair lead lead. The long term enhanced mechanism of damage.
The synergistic effects of 3.CQ and VB12 almost completely repair the synaptic plasticity damage caused by lead, and this synergistic effect in the control group does not exist. It is specific to the lead exposure group.
In the CQ and VB12 co processing groups of rats exposed to chronic lead exposure, the average peak value of the double pulse response is 216 + 19.3%. The average amplitude of the long term potentiation of the excitatory postsynaptic potential is 138 + 2.8% at one hour after high frequency stimulation. The average amplitude of the long period enhancement of the peak potential of the group is 273 + 18.1%. combined with the previous control. The data of the group and the chronic lead exposure group showed that the co processing of CQ and VB12 almost completely repaired the average peak susceptibility of the double pulse response induced by chronic lead, the average amplitude of the long time potentiation of the excitatory postsynaptic potential and the average amplitude of the long period enhancement of the peak potential of the group. It suggested that the synergistic effect of the two groups was synergistic. It greatly enhanced the repair effect of lead induced injury.
Under the conditions of CQ and VB12, not only CQ can correct the disorder of the metalloprotein system caused by chronic lead exposure, and reduce the oxidative damage caused by chronic lead exposure. Moreover, the VB12 supplement can antagonize the lack of VB12 caused by CQ treatment. Therefore, CQ and VB12 are co treated with the repair of the synaptic plasticity damage caused by lead. In addition, CQ and VB12 co treated in the control group did not enhance their synaptic plasticity, suggesting a specific synergistic effect on chronic lead exposure. In addition, the synergistic effect of the synergistic repair was not taken by the removal of the group of lead in the hippocampus of different treatment groups. Textile lead is realized.
【学位授予单位】：中国科学技术大学
【学位级别】：博士
【学位授予年份】：2007
【分类号】：R363

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