Synthesis of neurotransmitter GABA via the neuronal tricarboxylic acid cycle is elevated in rats with liver cirrhosis consistent with a high GABAergic tone in chronic hepatic encephalopathy
Synthesis of neurotransmitter GABA via the neuronal tricarboxylic acid cycle is elevated in rats with liver cirrhosis consistent with a high GABAergic tone in chronic hepatic encephalopathy
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DOI：
10.1111/j.1471-4159.2011.07244.x
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发表时间：
2011-06-01
影响因子：
4.7
通讯作者：
Waagepetersen, Helle S.
中科院分区：
文献类型：
--
作者：
Leke, Renata;Bak, Lasse K.;Waagepetersen, Helle S.
肝性脑病（HE）是肝脏疾病的神经精神并发症.已知氨在HE的发病机制中起作用，并且GABA能系统的紊乱与HE有关。GABA的合成通过谷氨酸的脱羧作用发生，谷氨酸是由星形胶质细胞衍生的谷氨酰胺脱酰胺形成的。已知一部分谷氨酸直接脱羧为GABA（称为直接途径），一部分经历转氨作用形成α-酮戊二酸。后一部分在用于GABA合成（间接途径）之前通过神经元三羧酸循环（一种能量产生途径）循环。我们以前已经表明，氨诱导神经元三羧酸循环活性的升高。因此，本研究的目的是确定是否增加氨水平增加GABA的合成通过间接途径在大鼠模型的肝性脑病诱导的胆管结扎和共培养的神经元和星形胶质细胞暴露于氨。采用13 C-标记的前体和随后的质谱分析，我们证明了更多的GABA是通过间接途径在胆管结扎大鼠和共培养物进行氨水平升高合成。由于间接途径与囊泡GABA的合成有关，这可能解释HE中GABA能张力增加。
P>Hepatic encephalopathy (HE) is a neuropsychiatric complication to liver disease. It is known that ammonia plays a role in the pathogenesis of HE and disturbances in the GABAergic system have been related to HE. Synthesis of GABA occurs by decarboxylation of glutamate formed by deamidation of astrocyte-derived glutamine. It is known that a fraction of glutamate is decarboxylated directly to GABA (referred to as the direct pathway) and that a fraction undergoes transamination with formation of alpha-ketoglutarate. The latter fraction is cycled through the neuronal tricarboxylic acid cycle, an energy-generating pathway, prior to being employed for GABA synthesis (the indirect pathway). We have previously shown that ammonia induces an elevation of the neuronal tricarboxylic acid cycle activity. Thus, the aims of the present study were to determine if increased levels of ammonia increase GABA synthesis via the indirect pathway in a rat model of HE induced by bile-duct ligation and in co-cultures of neurons and astrocytes exposed to ammonia. Employing 13C-labeled precursors and subsequent analysis by mass spectrometry, we demonstrated that more GABA was synthesized via the indirect pathway in bile duct-ligated rats and in co-cultures subjected to elevated ammonia levels. Since the indirect pathway is associated with synthesis of vesicular GABA, this might explain the increased GABAergic tone in HE.