Abnormal chloride homeostasis in the substancia nigra pars reticulata contributes to locomotor deficiency in a model of acute liver injury.
Abnormal chloride homeostasis in the substancia nigra pars reticulata contributes to locomotor deficiency in a model of acute liver injury.
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黑质网状部的氯化物稳态异常导致急性肝损伤模型中的运动缺陷
DOI：
10.1371/journal.pone.0065194
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Wang YY
中科院分区：
文献类型：
--
作者：
Yang YL;Li JJ;Ji R;Wei YY;Chen J;Dou KF;Wang YY
背景氯稳态改变被认为是几种脑部疾病的危险因素，而对其在肝脏疾病中的作用则关注较少。本研究利用谷氨酸脱羧酶67-绿色荧光蛋白敲入转基因小鼠，分析了黑质GABA能神经元氯离子稳态改变在急性肝功能衰竭脑病模型运动障碍中的作用及其可能机制。方法采用小鼠肝性脑病(HE)低运动模型，观察SNR区GABA能神经元细胞内氯离子浓度的变化及氯离子稳态调节基因KCC2和NKCC1表达的变化。评价药物阻断和/或激活KCC2和NKCC1功能及其特异性抑制剂和/或激活剂对运动活动的影响。结果在我们建立的小鼠急性肝损伤模型中，氯化物成像显示SNR-GABA能神经元内局部氯离子浓度升高。此外，KCC2的mRNA和蛋白水平降低，尤其是在神经元细胞膜上；相反，NKCC1的表达没有受到影响。此外，阻断KCC2降低了正常小鼠的运动活动，并导致HE小鼠运动功能进一步恶化。阻断NKCC1不能使肝功能衰竭小鼠的运动活动恢复正常。结论血氯平衡改变可能参与了HE后低氧血症的病理生理学过程。旨在恢复正常氯平衡的药物将是治疗肝功能衰竭的一种潜在方法。
Background Altered chloride homeostasis has been thought to be a risk factor for several brain disorders, while less attention has been paid to its role in liver disease. We aimed to analyze the involvement and possible mechanisms of altered chloride homeostasis of GABAergic neurons within the substantia nigra pars reticulata (SNr) in the motor deficit observed in a model of encephalopathy caused by acute liver failure, by using glutamic acid decarboxylase 67 - green fluorescent protein knock-in transgenic mice. Methods Alterations in intracellular chloride concentration in GABAergic neurons within the SNr and changes in the expression of two dominant chloride homeostasis-regulating genes, KCC2 and NKCC1, were evaluated in mice with hypolocomotion due to hepatic encephalopathy (HE). The effects of pharmacological blockade and/or activation of KCC2 and NKCC1 functions with their specific inhibitors and/or activators on the motor activity were assessed. Results In our mouse model of acute liver injury, chloride imaging indicated an increase in local intracellular chloride concentration in SNr GABAergic neurons. In addition, the mRNA and protein levels of KCC2 were reduced, particularly on neuronal cell membranes; in contrast, NKCC1 expression remained unaffected. Furthermore, blockage of KCC2 reduced motor activity in the normal mice and led to a further deteriorated hypolocomotion in HE mice. Blockade of NKCC1 was not able to normalize motor activity in mice with liver failure. Conclusion Our data suggest that altered chloride homeostasis is likely involved in the pathophysiology of hypolocomotion following HE. Drugs aimed at restoring normal chloride homeostasis would be a potential treatment for hepatic failure.
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影响因子：
25.7
作者：
Jayakumar, Arumugam R.;Valdes, Vanessa;Norenberg, Michael D.
通讯作者：
Norenberg, Michael D.
影响因子：
6.1
作者：
DICHIARA, G;MORELLI, M;GESSA, GL
通讯作者：
GESSA, GL
DOI：
10.1111/j.1440-1746.2007.04988.x
发表时间：
2008-07-01
影响因子：
4.1
作者：
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通讯作者：
Lee, Shou-Dong
影响因子：
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作者：
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通讯作者：
Norenberg, M. D.
影响因子：
25.7
作者：
Jover, R;Compañy, L;Pérez-Mateo, M
通讯作者：
Pérez-Mateo, M