Dopamine from cirrhotic liver contributes to the impaired learning and memory ability of hippocampus in minimal hepatic encephalopathy
Dopamine from cirrhotic liver contributes to the impaired learning and memory ability of hippocampus in minimal hepatic encephalopathy
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DOI：
10.1007/s12072-013-9431-6
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发表时间：
2013-07-01
影响因子：
6.6
通讯作者：
Zhuge, Qichuan
中科院分区：
文献类型：
--
作者：
Ding, Saidan;Liu, Leping;Zhuge, Qichuan
研究背景学习记忆障碍是MHE的一个特征。然而，导致MHE学习/记忆能力受损的确切病理生理机制仍不清楚。方法腹腔注射TAA建立MHE大鼠模型，采用Morris水迷宫、BAEP、EEG检测。2-DE/MS检测发现，MHE大鼠肝组织中多巴胺（DA）积累相关蛋白COMT抑制剂表达上调。结果MHE组大鼠肝组织、血清及肝组织中DA水平均较对照组显著升高。通过体内脑微透析测定，在MHE大鼠的海马中，NMDA诱导的cGMP形成减少了40%。NO对sGC的激活作用降低了38%。MHE组海马NMDAR 1、CaM、nNOS和sGC的表达较对照组明显降低。慢性暴露培养的海马神经元DA（50 μ M）减少了53%的NMDA诱导的cGMP的形成。在这些神经元中，NO对sGC的激活减少了44%。与对照组相比，多巴胺处理的神经元中也检测到下调的NMDAR 1、CaM、nNOS和sGC。结论肝损伤后DA水平升高，抑制海马谷氨酸-NO-cGMP通路，可能导致MHE学习记忆能力下降。
Background Defective learning/memory ability is a feature of MHE. However, the exact pathophysiological mechanisms leading to the impairment of learning/memory ability in MHE remain not clearly understood. Methods MHE rat modeling by intraperitoneal injection of TAA was successfully established using a Morris water maze, BAEP, and EEG tests. COMT inhibitor, a protein involved in the accumulation of dopamine (DA), was found to be up-regulated in cirrhotic livers in MHE by 2-DE/MS. Results The levels of DA in cirrhotic livers, serums and hippocampuses in the MHE group were more significantly increased than in the control group. In the hippocampuses of MHE rats, NMDA-induced formation of cGMP was reduced by 40 % as determined by in vivo brain microdialysis. Activation of sGC by NO was reduced by 38 %. The expression of NMDAR1, CaM, nNOS and sGC in the hippocampus in the MHE group were more significantly decreased than in controls. Chronic exposure of cultured hippocampus neurons to DA (50 mu M) reduced by 53 % the NMDA-induced formation of cGMP. Activation of sGC by NO in these neurons was reduced by 44 %. Down-regulated NMDAR1, CaM, nNOS and sGC were also detected in neurons treated with dopamine, in contrast with the controls. Conclusions This study suggests that when the glutamate-NO-cGMP pathway in the hippocampus is inhibited by the elevation of DA from cirrhotic livers, this in turn may lead to the impairment of learning and memory ability of MHE.