锰中毒致小鼠运动功能障碍及相关分子机制
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摘要
锰是人体必需的一种微量元素,但摄入过量则会对机体产生不良作用。近年来,随着无铅汽油和农药代森锰等的广泛使用,造成环境中锰的含量逐渐升高,增加了普通人群的接触机会。在职业环境中,某些接触锰的作业还可能导致急性中毒,因此锰对人体的影响正日益受到重视。神经系统是锰的主要毒作用器官,锰神经毒性的主要病变部位在苍白球、丘脑下核、尾状核、壳核以及黑质,在临床上表现为全身性的运动徐缓及普遍的肌肉强直,采用左旋多巴等治疗效果也不明显。因此在阐明锰神经毒性机制的基础上提出有效的医学防护措施具有重要的现实意义。
近年来,一些研究证明,锰导致脑代谢异常和DA能神经元的损害,是导致震颤性麻痹症状的主要原因。尽管目前国内外已进行了一系列关于锰神经毒性机制的研究,但是其确切机制仍然不明确。
通过建立实验性锰中毒小鼠的动物模型,观察锰中毒后动物运动行为的变化,旨在探讨锰中毒所致运动功能障碍的相关机制,以期为锰中毒的防治提供理论依据。具体研究内容包括:1.锰中毒对小鼠运动行为的影响;2.锰中毒对黑质中GABA能神经元和DA能神经元的形态学及其活性的影响;3.锰中毒对黑质中KCC2和NKCC1蛋白表达的影响;4.锰中毒对黑质中DA能神经元和微管的形态学影响;锰中毒对黑质中tau以及磷酸化tau的影响。
方法:
1.根据小鼠脑立体定位图谱选定注射点坐标,采用脑立体定位法将浓度为1mol/L的MnCl2.4H2O注射进入动物左侧尾壳核。
2.用滚轴实验、旷场实验和爬杆实验观察锰中毒对小鼠运动行为的影响。
3.免疫荧光双标法观察锰中毒后黑质中GFP和TH分别和Fos的共表达;免疫印迹法检测黑质中Fos、GFP、TH、KCC2和NKCC1蛋白表达水平的影响。
4.免疫组化观察锰中毒对黑质中DA能神经元的影响和免疫荧光双标法观察黑质中微管蛋白β-tubulin3和TH的共表达;Western blot检测黑质中β-tubulin3、tau蛋白磷酸化表达水平的影响。
结果:
1.锰中毒对小鼠运动行为的影响:Rotarod实验结果显示锰作用后24h,动物从滚轴上停留时间与对照组和假手术组相比明显减少(P < 0.05),具有统计学意义;旷场实验结果表明锰作用后,小鼠总水平运动距离(总运动距离)分别与正常组和假手术相比明显缩短(P< 0.01),水平运动能力(动物运动次数)分别与正常组和假手术组无显著变化(P > 0.05);爬杆实验结果显示锰作用后24h,小鼠运动速度明显减慢,动物从开始运动到完全转为头向下的时间和头向下的时间到下到杆底的时间分别与正常组和假手术相比明显延长(P < 0.001),且具有统计学意义。
2.免疫荧光双标法观察锰中毒后黑质中DA能和GABA能神经元形态学及其活性的变化:染锰组黑质中Fos阳性神经元与对照组相比明显增多,而DA能神经元数量无明显变化,且Fos和DA能神经元并未发现共存;染锰后黑质中Fos阳性神经元与对照组相比明显增多,而GABA能神经元数量无明显变化,但Fos和GABA能神经元大量共存;免疫印迹法检测结果显示染锰组黑质中Fos蛋白表达水平与对照组相比明显明显升高,但GFP和TH蛋白表达水平无明显改变。
3. KCC2抑制剂对小鼠运动行为的影响:锰染毒后黑质中KCC2蛋白表达明显升高,NKCC1未见明显变化,使用KCC2抑制剂后KCC2蛋白表达与手术组相比有所降低,可部分逆转锰中毒诱导的小鼠在滚轴上的停留时间;用KCC2抑制剂后也可部分回转锰中毒后小鼠总水平运动距离的减少。
4.锰中毒对黑质中DA能神经元和微管形态的影响:免疫组织化学结果显示锰中毒后黑质中DA能神经元数量与对照组相比明显减少,且β-tubulin3阳性神经元和DA能神经元共存有一定程度的减少;Western blot结果显示锰中毒后β-tubulin3和tau1蛋白表达水平明显降低,tauSer199、tauSer202明显减少、p-tauSer396和p-tauSer404磷酸化程度明显增加。
结论:
1.锰中毒可引起小鼠运动行为的明显变化,如运动减少、迟缓、肌肉僵直等症状。
2.锰中毒使GABA能和DA能神经元的数量未发生变化,且黑质致密部的DA能神经元并未被激活,而黑质网状部大量GABA能神经元被激活,提示GABA能神经元可能是锰中毒引起神经损害的主要靶细胞之一。此外,还有一部分的Fos既不表达在DA能神经元也不表达在GABA能神经元,提示锰中毒引起的毒性效应可能是多种递质综合效应的结果。
3.使用KCC2抑制剂对锰中毒引起的运动行为障碍有一定的改善作用,可能是由于黑质部特有KCC2通过调节黑质网状部GABA能神经元而间接影响黑质致密部DA能神经元的功能,最终影响动物的整体运动行为。
4.锰中毒后DA能神经元出现明显减少,其微管结构也发生了一定程度的变化,微管结构变化可能是通过tau的高度磷酸化实现的;提示微管这种结构的变化可能是引起DA能神经元数量上变化的因素之一。
Manganese is one of essential trace elements. However, the excessive intake of Mn may produce adverse effects on human health. In the recent years, the widespread use of lead-free gasoline and pesticides, such as manganese ethylenebisdithiocarbamate, has increased the content of Mn in the environment and the exposure to Mn in the common population. In the occupational surroundings, some Mn-exposed operations may even cause the acute manganism. Therefore, more attention has been paid to the effects of over-exposure to Mn on the huaman health.
Nervous system is one of the main target organs of manganism. Its main diseased regions include pallidum, subthalamic nucleus, putamen and ubstantia nigra. In clinic, neurotoxicity of Mn features general bradykinesia and muscle rigidity, on which the treatment of L-dopa has no significant effect. So it is of great significance to provide effective medical prevention based on illuminated mechanism of Mn neurotoxicity.
In recent years, some researches showed that abnormal cerebral metabolism and lesion of DAergic neuron caused by Mn are the main factors of shaking palsy. Although a number of studies on the mechanism of Mn neurotoxicity have been conducted, the exact mechanism is still unknown. In this study, with the animal model of manganism, the change in motor ethology was observed to investigate mechanisms of motor dysfunction caused by manganism for the theoretical beses for its prevention. The study mainly includes: 1) the effect of manganism on motor behavior of mice; 2) the effect of manganism on morphology of GABAergic neuron and Dopaminergic neuron and their activity in substantia nigra (SN); 3) the effect of manganism on protein expression of KCC2 and NKCC1; 4) effects of Mn exposure on morphology of Dopaminergic neuron and microtubule; and protein expression of tau and phosphorylated tau.
Methods:
1. One mol/L MnCl2·4H2O was injected into left caudate putamen at the coordinate of striatum following the stereotaxic atlas of mouse brain.
2. The behavioral changes of mice were observed in the behavioral experiments 24 h after Mn exposure, including rotarod test, open field test and pole test.
3. Double immunofluorescences were conducted for GFP and Fos, TH and Fos in SN respectively; Western blot was used for the expression of Fos, GFP, TH, KCC2 and NKCC1 in SN.
4. Immunohistochemistry was used to investigate the effects of manganism on Dopaminergic neuron in SN; double immunofluorescence was conducted to observe coexpression ofβ-tubulin3 and TH; Western blot was employed to determine the expression ofβ-tubulin3, tau and phosphorylated tau in SN.
Results:
1. Results of mice exposed to Mn Behavioral in behavioral tests:
The results of rotarod test showed 24 h after Mn treatment, the time spent on the rotarod was significantly reduced compared with naive and sham (P <0.05); The results of open field test showed that the total horizontal distance was significantly decreased in Mn group compared with na?ve and sham (P <0.01), and the horizontal activity (motion times) showed no significant difference compared with na?ve and sham (P >0.05); the results of pole test showed mice the time from top to headdown and time from headdown to bottom were both increased significantly in Mn group compared with na?ve and sham (P <0.001).
2. Morphological changes of DAergic neuron and GABAergic neuron and their activity 24 h after Mn injection by using double immunofluorescence: Fos-positive neurons were significantly increased in Mn group compared with controls, while DAergic neurons showed no significant change and there was no coexistence of Fos and DAergic neuron in SN; Fos-positive neurons were significantly increased in Mn group, while GABAergic neurons showed no significant change and there were significant coexistence of Fos and GABAergic neurons in SN; The Western blot showed expression of Fos was significantly increased in Mn group compared with controls, while the expression of GFP and TH was not significantly changed.
3. Effect of KCC2 inhibitor on the motor behavior of mice:
The protein expression of KCC2 in SN was significantly increased in Mn group, and that of NKCC1 showed no significant change. The treatment of KCC2 inhibitor reduced the protein expression of KCC2 and partially reversed the time spent on the rotarod of mice exposed to Mn; the treatment of KCC2 inhibitor could in part reverse the reduced total horizontal distance.
4. Effects of manganism on morphology of Dopaminergic neuron and microtubule in SN:
Immunohistochemistry showed the significant decrease in DAergic neurons in SN in Mn group compared with controls, and the decreased coexistence ofβ-tubulin3-positive neurons and Dopaminergic neurons; Western blot showed the significant decrease in the protein expression ofβ-tubulin3 and tau1 in Mn group, and the significant decrease in phosphorylated Ser199, phosphorylated Ser202 and significant decrease phosphorylated Ser396 and phosphorylated Ser404.
Conclusions:
1. Manganism can cause the significant motor behavioral changes in mice, such as hypokinesia, bradykinesia and rigid muscle.
2. Manganism can not cause the alternation in the numbers of Dopaminergic neurons and GABAergic neurons, and GABAergic neuron is activated in SN reticular part, while Dopaminergic neuron is not activated in SN compact part. These results suggest that GABAergic neuron may be one of the target cells in the nervous lesion in the manganism. Besides, some expressions of Fos don’t colocate with either GABAergic neuron or Dopaminergic neuron, suggesting neurotoxicity of manganism may be caused by other neurons falling into neither Dopaminergic neuron nor GABAergic neuron category.
3. The treatment of KCC2 inhibitor can improve the motor behavior to some extent after manganism. The possible mechanism is that KCC2, existing in SN reticular part, specifically affects Dopaminergic neuron in SN compact part through the regulation of GABAergic neuron in SN reticular part, which in time influences the motor behavior of mice.
4. The significantly decreased number of Dopaminergic neurons in SN after manganism, coupled with the slight change of microtubular structure in Dopaminergic neuron suggests that the structure change of microtubule may be one of the factors causing the decrease in the number of Dopaminergic neurons. In addition, the significantly increased expression of phosphorylated tau suggests that hyperphosphorylation of tau may contribute to the structure change of microtubule.
近年来,一些研究证明,锰导致脑代谢异常和DA能神经元的损害,是导致震颤性麻痹症状的主要原因。尽管目前国内外已进行了一系列关于锰神经毒性机制的研究,但是其确切机制仍然不明确。
通过建立实验性锰中毒小鼠的动物模型,观察锰中毒后动物运动行为的变化,旨在探讨锰中毒所致运动功能障碍的相关机制,以期为锰中毒的防治提供理论依据。具体研究内容包括:1.锰中毒对小鼠运动行为的影响;2.锰中毒对黑质中GABA能神经元和DA能神经元的形态学及其活性的影响;3.锰中毒对黑质中KCC2和NKCC1蛋白表达的影响;4.锰中毒对黑质中DA能神经元和微管的形态学影响;锰中毒对黑质中tau以及磷酸化tau的影响。
方法:
1.根据小鼠脑立体定位图谱选定注射点坐标,采用脑立体定位法将浓度为1mol/L的MnCl2.4H2O注射进入动物左侧尾壳核。
2.用滚轴实验、旷场实验和爬杆实验观察锰中毒对小鼠运动行为的影响。
3.免疫荧光双标法观察锰中毒后黑质中GFP和TH分别和Fos的共表达;免疫印迹法检测黑质中Fos、GFP、TH、KCC2和NKCC1蛋白表达水平的影响。
4.免疫组化观察锰中毒对黑质中DA能神经元的影响和免疫荧光双标法观察黑质中微管蛋白β-tubulin3和TH的共表达;Western blot检测黑质中β-tubulin3、tau蛋白磷酸化表达水平的影响。
结果:
1.锰中毒对小鼠运动行为的影响:Rotarod实验结果显示锰作用后24h,动物从滚轴上停留时间与对照组和假手术组相比明显减少(P < 0.05),具有统计学意义;旷场实验结果表明锰作用后,小鼠总水平运动距离(总运动距离)分别与正常组和假手术相比明显缩短(P< 0.01),水平运动能力(动物运动次数)分别与正常组和假手术组无显著变化(P > 0.05);爬杆实验结果显示锰作用后24h,小鼠运动速度明显减慢,动物从开始运动到完全转为头向下的时间和头向下的时间到下到杆底的时间分别与正常组和假手术相比明显延长(P < 0.001),且具有统计学意义。
2.免疫荧光双标法观察锰中毒后黑质中DA能和GABA能神经元形态学及其活性的变化:染锰组黑质中Fos阳性神经元与对照组相比明显增多,而DA能神经元数量无明显变化,且Fos和DA能神经元并未发现共存;染锰后黑质中Fos阳性神经元与对照组相比明显增多,而GABA能神经元数量无明显变化,但Fos和GABA能神经元大量共存;免疫印迹法检测结果显示染锰组黑质中Fos蛋白表达水平与对照组相比明显明显升高,但GFP和TH蛋白表达水平无明显改变。
3. KCC2抑制剂对小鼠运动行为的影响:锰染毒后黑质中KCC2蛋白表达明显升高,NKCC1未见明显变化,使用KCC2抑制剂后KCC2蛋白表达与手术组相比有所降低,可部分逆转锰中毒诱导的小鼠在滚轴上的停留时间;用KCC2抑制剂后也可部分回转锰中毒后小鼠总水平运动距离的减少。
4.锰中毒对黑质中DA能神经元和微管形态的影响:免疫组织化学结果显示锰中毒后黑质中DA能神经元数量与对照组相比明显减少,且β-tubulin3阳性神经元和DA能神经元共存有一定程度的减少;Western blot结果显示锰中毒后β-tubulin3和tau1蛋白表达水平明显降低,tauSer199、tauSer202明显减少、p-tauSer396和p-tauSer404磷酸化程度明显增加。
结论:
1.锰中毒可引起小鼠运动行为的明显变化,如运动减少、迟缓、肌肉僵直等症状。
2.锰中毒使GABA能和DA能神经元的数量未发生变化,且黑质致密部的DA能神经元并未被激活,而黑质网状部大量GABA能神经元被激活,提示GABA能神经元可能是锰中毒引起神经损害的主要靶细胞之一。此外,还有一部分的Fos既不表达在DA能神经元也不表达在GABA能神经元,提示锰中毒引起的毒性效应可能是多种递质综合效应的结果。
3.使用KCC2抑制剂对锰中毒引起的运动行为障碍有一定的改善作用,可能是由于黑质部特有KCC2通过调节黑质网状部GABA能神经元而间接影响黑质致密部DA能神经元的功能,最终影响动物的整体运动行为。
4.锰中毒后DA能神经元出现明显减少,其微管结构也发生了一定程度的变化,微管结构变化可能是通过tau的高度磷酸化实现的;提示微管这种结构的变化可能是引起DA能神经元数量上变化的因素之一。
Manganese is one of essential trace elements. However, the excessive intake of Mn may produce adverse effects on human health. In the recent years, the widespread use of lead-free gasoline and pesticides, such as manganese ethylenebisdithiocarbamate, has increased the content of Mn in the environment and the exposure to Mn in the common population. In the occupational surroundings, some Mn-exposed operations may even cause the acute manganism. Therefore, more attention has been paid to the effects of over-exposure to Mn on the huaman health.
Nervous system is one of the main target organs of manganism. Its main diseased regions include pallidum, subthalamic nucleus, putamen and ubstantia nigra. In clinic, neurotoxicity of Mn features general bradykinesia and muscle rigidity, on which the treatment of L-dopa has no significant effect. So it is of great significance to provide effective medical prevention based on illuminated mechanism of Mn neurotoxicity.
In recent years, some researches showed that abnormal cerebral metabolism and lesion of DAergic neuron caused by Mn are the main factors of shaking palsy. Although a number of studies on the mechanism of Mn neurotoxicity have been conducted, the exact mechanism is still unknown. In this study, with the animal model of manganism, the change in motor ethology was observed to investigate mechanisms of motor dysfunction caused by manganism for the theoretical beses for its prevention. The study mainly includes: 1) the effect of manganism on motor behavior of mice; 2) the effect of manganism on morphology of GABAergic neuron and Dopaminergic neuron and their activity in substantia nigra (SN); 3) the effect of manganism on protein expression of KCC2 and NKCC1; 4) effects of Mn exposure on morphology of Dopaminergic neuron and microtubule; and protein expression of tau and phosphorylated tau.
Methods:
1. One mol/L MnCl2·4H2O was injected into left caudate putamen at the coordinate of striatum following the stereotaxic atlas of mouse brain.
2. The behavioral changes of mice were observed in the behavioral experiments 24 h after Mn exposure, including rotarod test, open field test and pole test.
3. Double immunofluorescences were conducted for GFP and Fos, TH and Fos in SN respectively; Western blot was used for the expression of Fos, GFP, TH, KCC2 and NKCC1 in SN.
4. Immunohistochemistry was used to investigate the effects of manganism on Dopaminergic neuron in SN; double immunofluorescence was conducted to observe coexpression ofβ-tubulin3 and TH; Western blot was employed to determine the expression ofβ-tubulin3, tau and phosphorylated tau in SN.
Results:
1. Results of mice exposed to Mn Behavioral in behavioral tests:
The results of rotarod test showed 24 h after Mn treatment, the time spent on the rotarod was significantly reduced compared with naive and sham (P <0.05); The results of open field test showed that the total horizontal distance was significantly decreased in Mn group compared with na?ve and sham (P <0.01), and the horizontal activity (motion times) showed no significant difference compared with na?ve and sham (P >0.05); the results of pole test showed mice the time from top to headdown and time from headdown to bottom were both increased significantly in Mn group compared with na?ve and sham (P <0.001).
2. Morphological changes of DAergic neuron and GABAergic neuron and their activity 24 h after Mn injection by using double immunofluorescence: Fos-positive neurons were significantly increased in Mn group compared with controls, while DAergic neurons showed no significant change and there was no coexistence of Fos and DAergic neuron in SN; Fos-positive neurons were significantly increased in Mn group, while GABAergic neurons showed no significant change and there were significant coexistence of Fos and GABAergic neurons in SN; The Western blot showed expression of Fos was significantly increased in Mn group compared with controls, while the expression of GFP and TH was not significantly changed.
3. Effect of KCC2 inhibitor on the motor behavior of mice:
The protein expression of KCC2 in SN was significantly increased in Mn group, and that of NKCC1 showed no significant change. The treatment of KCC2 inhibitor reduced the protein expression of KCC2 and partially reversed the time spent on the rotarod of mice exposed to Mn; the treatment of KCC2 inhibitor could in part reverse the reduced total horizontal distance.
4. Effects of manganism on morphology of Dopaminergic neuron and microtubule in SN:
Immunohistochemistry showed the significant decrease in DAergic neurons in SN in Mn group compared with controls, and the decreased coexistence ofβ-tubulin3-positive neurons and Dopaminergic neurons; Western blot showed the significant decrease in the protein expression ofβ-tubulin3 and tau1 in Mn group, and the significant decrease in phosphorylated Ser199, phosphorylated Ser202 and significant decrease phosphorylated Ser396 and phosphorylated Ser404.
Conclusions:
1. Manganism can cause the significant motor behavioral changes in mice, such as hypokinesia, bradykinesia and rigid muscle.
2. Manganism can not cause the alternation in the numbers of Dopaminergic neurons and GABAergic neurons, and GABAergic neuron is activated in SN reticular part, while Dopaminergic neuron is not activated in SN compact part. These results suggest that GABAergic neuron may be one of the target cells in the nervous lesion in the manganism. Besides, some expressions of Fos don’t colocate with either GABAergic neuron or Dopaminergic neuron, suggesting neurotoxicity of manganism may be caused by other neurons falling into neither Dopaminergic neuron nor GABAergic neuron category.
3. The treatment of KCC2 inhibitor can improve the motor behavior to some extent after manganism. The possible mechanism is that KCC2, existing in SN reticular part, specifically affects Dopaminergic neuron in SN compact part through the regulation of GABAergic neuron in SN reticular part, which in time influences the motor behavior of mice.
4. The significantly decreased number of Dopaminergic neurons in SN after manganism, coupled with the slight change of microtubular structure in Dopaminergic neuron suggests that the structure change of microtubule may be one of the factors causing the decrease in the number of Dopaminergic neurons. In addition, the significantly increased expression of phosphorylated tau suggests that hyperphosphorylation of tau may contribute to the structure change of microtubule.
引文
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