本文選題：Clioquinol(CQ) + 鉛　； 參考：《中國科學(xué)技術(shù)大學(xué)》2007年博士論文

【摘要】： 鉛是最重要的環(huán)境神經(jīng)毒物之一。現(xiàn)已被證實兒童在發(fā)育過程中的慢性鉛暴露會引起學(xué)習(xí)和記憶功能和神經(jīng)行為等認知功能損傷，這在不同的動物模型中也得到了證實。海馬是與學(xué)習(xí)和記憶功能密切相關(guān)的一個重要腦區(qū)，海馬神經(jīng)元活性依賴的突觸可塑性被認為是學(xué)習(xí)和記憶功能的細胞與分子基礎(chǔ)。在發(fā)育過程中，鉛暴露損傷了大鼠海馬的突觸可塑性，這可能是慢性鉛暴露損傷學(xué)習(xí)和記憶功能和神經(jīng)行為等認知功能的機制之一。 目前，螯合劑驅(qū)鉛治療被普遍采用。但是，常用的那些螯合劑表現(xiàn)出許多無法克服的副作用，而且并不能修復(fù)鉛已經(jīng)造成的神經(jīng)元結(jié)構(gòu)與功能的損傷。尋找有效而副作用小的鉛修復(fù)藥物是當(dāng)前研究熱點。最近，一個對二價金屬離子有低親和性的金屬螯合劑或者離子載體Clioquinol(CQ)已經(jīng)被用于一些與金屬離子功能紊亂相關(guān)的疾病動物模型和臨床實驗中，如老年癡呆，帕金森氏和亨廷頓氏疾病等，并取得了一些較好的效果。在二十世紀七十年代，由于在日本暴發(fā)thesubacute myelo-optic neuropathy(SMON)病癥，并被認為與應(yīng)用CQ有關(guān)，因此，從那時起CQ被禁用。然而近年來的研究表明，CQ相關(guān)的副作用可以通過補充Vitamin B12(VB12)加以克服。 為了探明CQ處理是否可以修復(fù)鉛引起的突觸可塑性損傷及其作用機理，本論文中，我們通過在位場電位技術(shù)在麻醉wistar大鼠的PP—DG通路上研究了不同處理組動物的輸入／輸出功能，雙脈沖響應(yīng)和長時程增強等參數(shù)，同時，我們還應(yīng)用電感耦合等離子體質(zhì)譜儀檢測了不同處理組動物的海馬鉛水平。主要結(jié)果如下： 1．Clioquinol(CQ)單獨處理并沒有修復(fù)慢性鉛暴露引起的突觸可塑性損傷 在對照組，雙脈沖響應(yīng)的平均峰值易化是225±17.3％，在高頻刺激后一個小時，興奮性突觸后電位的長時程增強的平均幅度是136±4％，群體峰電位的長時程增強的平均幅度是266±17.3％；在慢性鉛暴露組，雙脈沖響應(yīng)的平均峰值易化是180±12.5％，在高頻刺激后一個小時，興奮性突觸后電位的長時程增強的平均幅度是122±2％，群體峰電位的長時程增強的平均幅度是195±10.4％：在 對慢性鉛暴露的大鼠進行CQ單獨處理組，雙脈沖響應(yīng)的平均峰值易化是180±24.3％，在高頻刺激后一個小時，興奮性突觸后電位的長時程增強的平均幅度是125±3.4％，群體峰電位的長時程增強的平均幅度是199±14.7％。相應(yīng)的數(shù)據(jù)進行比較可以得出慢性鉛暴露引起了雙脈沖響應(yīng)的平均峰值易化，興奮性突觸后電位的長時程增強的平均幅度和群體峰電位的長時程增強的平均幅度的損傷；并且Clioquinol(CQ)單獨處理并沒有修復(fù)慢性鉛暴露引起的這些損傷。 鉛能夠通過模擬鈣離子同機體內(nèi)的許多大分子結(jié)合形成金屬蛋白復(fù)合物，這可能導(dǎo)致了抗氧化的金屬蛋白復(fù)合物系統(tǒng)的損傷從而介導(dǎo)了鉛引起的損傷。CQ能夠作為一個金屬—蛋白衰減元素同金屬蛋白復(fù)合物相互作用，CQ可能會結(jié)合到鉛一蛋白復(fù)合物上而衰減該復(fù)合物的內(nèi)部相互作用而取得有益的效果。然而，已有報道，用CQ處理過的小鼠的血液和大腦內(nèi)的VB12減少，CQ處理而引起的VB12的缺乏被懷疑與SMON病癥有關(guān)。CQ單獨處理不能修復(fù)鉛誘導(dǎo)的損傷可能就是由于CQ同時造成了VB12缺乏，這拮抗了CQ的修復(fù)效應(yīng)。 2．Vitamin B12(VB12)單獨處理僅部分地修復(fù)了慢性鉛暴露引起的損傷 在對慢性鉛暴露的大鼠進行VB12單獨處理組，雙脈沖響應(yīng)的平均峰值易化是178±19.4％，在高頻刺激后一個小時，興奮性突觸后電位的長時程增強的平均幅度是126±3.6％，群體峰電位的長時程增強的平均幅度是226±15.2％。結(jié)合前述的對照組和慢性鉛暴露組的數(shù)據(jù)，表明單獨VB12處理僅僅修復(fù)了興奮性突觸后電位的長時程增強的平均幅度和群體峰電位的長時程增強的平均幅度，而且修復(fù)后的幅度和對照組相比，顯著地小于對照組的幅度。VB12單獨處理僅部分地修復(fù)了慢性鉛暴露引起的損傷。 慢性鉛暴露引起神經(jīng)元功能的損傷，部分是通過鉛的氧化損傷。鉛神經(jīng)毒性的一個可能的分子機制就是鉛引起了促氧化／抗氧化平衡系統(tǒng)的紊亂。VB12的補充可能重新平衡了促氧化／抗氧化系統(tǒng)，這可能是VB12補充可以部分地修復(fù)鉛引起的長時程增強損傷機理。 3．CQ和VB12的協(xié)同作用幾乎完全修復(fù)了鉛引起的突觸可塑性損傷，并且在對照組這種協(xié)同作用并不存在，它對鉛暴露組有特異性 在對慢性鉛暴露的大鼠進行CQ和VB12共處理組，雙脈沖響應(yīng)的平均峰值易化是216±19.3％，在高頻刺激后一個小時，興奮性突觸后電位的長時程增強的平均幅度是138±2.8％，群體峰電位的長時程增強的平均幅度是273±18.1％。結(jié)合前述的對照組和慢性鉛暴露組的數(shù)據(jù)，表明CQ和VB12共處理幾乎完全修復(fù)了慢性鉛引起的雙脈沖響應(yīng)的平均峰值易化，興奮性突觸后電位的長時程增強的平均幅度和群體峰電位的長時程增強的平均幅度的損傷。提示二者有協(xié)同效應(yīng)，這種協(xié)同效應(yīng)大大增強了對鉛引起的損傷的修復(fù)作用。 在CQ和VB12共同處理的條件下，不僅CQ能糾正由慢性鉛暴露產(chǎn)生的金屬蛋白系統(tǒng)的紊亂，降低由慢性鉛暴露引起的氧化損傷，而且，VB12的補充能夠拮抗由于CQ處理帶來的VB12的缺乏。因此，CQ和VB12共同處理在修復(fù)鉛引起的突觸可塑性損傷方面顯示了協(xié)同作用，幾乎完全修復(fù)了這些損傷。另外在對照組中CQ和VB12共同處理并沒有增強其突觸可塑性，，提示對慢性鉛暴露有特異的協(xié)同修復(fù)作用。另外，結(jié)合不同處理組海馬鉛水平的檢測，提示這種協(xié)同修復(fù)作用并不是通過驅(qū)除組織鉛實現(xiàn)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.
【學(xué)位授予單位】：中國科學(xué)技術(shù)大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2007
【分類號】：R363

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