Elevated dopamine induces minimal hepatic encephalopathy by activation of astrocytic NADPH oxidase and astrocytic protein tyrosine nitration
Elevated dopamine induces minimal hepatic encephalopathy by activation of astrocytic NADPH oxidase and astrocytic protein tyrosine nitration
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多巴胺升高通过激活星形细胞 NADPH 氧化酶和星形细胞蛋白酪氨酸硝化诱导轻微肝性脑病
DOI：
10.1016/j.biocel.2014.09.003
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发表时间：
2014-10-01
影响因子：
4
通讯作者：
Zhuge, Qichuan
中科院分区：
文献类型：
--
作者：
Ding, Saidan;Yang, Jianjing;Zhuge, Qichuan
背景：我们先前已经证明，多巴胺(DA)超负荷可能是大鼠发生微小肝性脑病(MHE)的一个关键机制。已有研究表明，轻度脑水肿和氧化应激在MHE的发病机制中起重要作用。本研究旨在研究DA诱导的大脑皮层氧化损伤。方法：采用MHE大鼠模型。脑室注射DA(i.c.v.)并加入到原代皮质星形胶质细胞(PCA)中。结果：MHE组和10-DA组大鼠均出现认知障碍和脑水肿。DA可增加星形胶质细胞肿胀。DA诱导星形胶质细胞蛋白酪氨酸硝化(PTN)。DA诱导的PTN对L-NMMA不敏感，但可被载脂蛋白、超氧化物歧化酶、过氧化氢酶和尿酸钝化。DA可显著增加星形胶质细胞NADPH氧化酶亚基水平，诱导P47(Phox)磷酸化和活性氧的产生，但降低神经元型一氧化氮合酶(NNOS)的表达和活性。结论：DA诱导的PTN可能与NADPH氧化酶有关，而不是nNOS所致，可能改变星形胶质细胞的功能，从而导致MHE事件的发生。(C)2014爱思唯尔有限公司。保留所有权利。
Background: We previously demonstrated that dopamine (DA) overload may be a key mechanism behind development of minimal hepatic encephalopathy (MHE) in rats. It has been shown that low-grade cerebral oedema and oxidative stress play important roles in the pathogenesis of MHE. In the current study, DA-triggered oxidative injury in cerebral cortex was studied.Methods: An MHE rat model was used. DA was injected intracerebroventricularly (i.c.v.) into rats and added to primary cortical astrocytes (PCAs). Immunoblotting, immunoprecipitation and immunostaining were conducted after DA injection.Results: Cognitive impairment and cerebral edema were observed in MHE rats and rats injected with 10 DA. Astrocyte swelling was increased by DA. Astrocytic protein tyrosine nitration (PTN) was induced by DA. DA-induced PTN was insensitive to L-NMMA but was blunted by apocynin, superoxide dismutase, catalase and uric acid. Exposure to DA substantially increased levels of astrocytic NADPH oxidase subunits and induced p47(Phox) phosphorylation and reactive oxygen species production but decreased the expression and activity of neuronal-type nitric oxide synthase (nNOS).Conclusions: PTN induced by DA, which was attributed to NADPH oxidase and not to nNOS, may alter astrocyte function and thereby contribute to the precipitation of MHE episodes. (C) 2014 Elsevier Ltd. All rights reserved.