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【Brain】肝衰竭中脑胆碱能系统受损（已编译，欢
Brain cholinergic impairment in liver failure
Correspondence to: Javier Sáez-Valero, Instituto de Neurociencias, Universidad Miguel Hernández-CSIC, E-03550 San Juan de Alicante, Spain E-mail: j.saez@umh.es
The cholinergic system is involved in specific behavioural responses and cognitive processes. Here, we examined potential alterations in the brain levels of key cholinergic enzymes in cirrhotic patients and animal models with liver failure. An increase (30%) in the activity of the acetylcholine-hydrolyzing enzyme, acetylcholinesterase (AChE) is observed in the brain cortex from patients deceased from hepatic coma, while the activity of the acetylcholine-synthesizing enzyme, choline acetyltransferase, remains unaffected. In agreement with the human data, AChE activity in brain cortical extracts of bile duct ligated (BDL) rats was increased (20%) compared to controls. A hyperammonemic diet did not result in any further increase of AChE levels in the BDL model, and no change was observed in hyperammonemic diet rats without liver disease. Portacaval shunted rats which display increased levels of cerebral ammonia did not show any brain cholinergic abnormalities, confirming that high ammonia levels do not play a role in brain AChE changes. A selective increase of tetrameric AChE, the major AChE species involved in hydrolysis of acetylcholine in the brain, was detected in both cirrhotic humans and BDL rats. Histological examination of BDL and non-ligated rat brains shows that the subcellular localization of both AChE and choline acetyltransferase, and thus the accessibility to their substrates, appears unaltered by the pathological condition. The BDL-induced increase in AChE activity was not parallelled by an increase in mRNA levels. Increased AChE in BDL cirrhotic rats leads to a pronounced decrease (50–60%) in the levels of acetylcholine. Finally, we demonstrate that the AChE inhibitor rivastigmine is able to improve memory deficits in BDL rats. One week treatment with rivastigmine (0.6 mg/kg; once a day, orally, for a week) resulted in a 25% of inhibition in the enzymatic activity of AChE with no change in protein composition, as assessed by sucrose density gradient fractionation and western blotting analysis. In conclusion, this study is the first direct evidence of a cholinergic imbalance in the brain as a consequence of liver failure and points to the possible role of the cholinergic system in the pathogenesis of hepatic encephalopathy.
编译：
胆碱能系统与特定的行为反应及认知过程相关。因此，我们对肝硬化患者以及肝衰竭动物模型中具有潜在变化可能的脑关键胆碱能酶类浓度进行检测。结果显示在因肝昏迷致死的患者脑皮质中，乙酰胆碱水解酶（乙酰胆碱酯酶）活动度增加30%，而乙酰胆碱合成酶（胆碱乙酰基转移酶）未受影响。与人体研究数据相一致，胆管结扎（BDL）鼠脑皮质萃取物中胆碱酯酶活动度也较对照组增加20%。高氨饮食并未引起BDL鼠胆碱酯酶活性的增加，而没有肝疾病的高氨饮食鼠也未发现胆碱酯酶的变化。出现脑氨浓度增加而进行腔静脉分流的实验鼠没有显示胆碱能的异常，提示高血氨浓度并未在脑胆碱酯酶的变化中其关键作用。在肝硬化患者和BDL鼠体内均可发现乙酰胆碱酯酶四具体体选择性的增加，后者是参与脑内胆碱水解的主要胆碱能物质。BDL鼠和非胆管结扎鼠的组织学检测所提供的胆碱酯酶和胆碱乙酰基转移酶的亚细胞定位，以及以此确定的底物可接受性，均未因病理条件而改变。胆管结扎诱发的胆碱酯酶活性增加并不与mRNA浓度的增加相平行。胆管结扎肝硬化鼠增加的胆碱酯酶导致乙酰胆碱水平显著下降（50-60%）。最后，我们还证实胆碱酯酶抑制剂利凡斯的明（rivastigmine）能够改善BDL鼠的记忆缺损。通过蔗糖密度梯度分级和蛋白印迹分析测定后发现，利凡斯的明治疗一周可使25%胆碱酯酶在不改变蛋白结构的情况下活性受到抑制。结论，本研究是肝衰竭引起脑胆碱能系统失衡的首次直接证据，并指出胆碱能系统在肝性脑病致病过程中可能发挥作用。[标签:content1][标签:content2]
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作者:admin@医学,生命科学 2011-01-04 05:14
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