Bilirubin injury to neurons: Contribution of oxidative stress and rescue by glycoursodeoxycholic acid
Bilirubin injury to neurons: Contribution of oxidative stress and rescue by glycoursodeoxycholic acid
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DOI：
10.1016/j.neuro.2007.11.002
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发表时间：
2008-03-01
期刊：
影响因子：
3.4
通讯作者：
Brites, Dora
中科院分区：
文献类型：
--
作者：
Brito, Maria A.;Lima, Silvia;Brites, Dora
高水平的未结合胆红素（UCB）对中枢神经系统具有毒性，氧化应激是UCB脑病机制中的一个相关事件。相反，亲水性胆汁酸，熊去氧胆酸（UDCA），已被报道为细胞保护和抗氧化分子。在这项研究中，我们调查，如果暴露在原代培养的大鼠神经元临床相关浓度的UCB导致氧化损伤。通过检查一氧化氮合酶抑制剂NAME是否减少NO的产生，防止氧化还原状态和神经元损伤的破坏，进一步研究了氧化应激在UCB神经毒性中的作用。此外，我们评价了甘氨熊去氧胆酸（GUDCA）（UDCA治疗患者血清中最相关的结合衍生物）消除UCB诱导的氧化损伤的能力。将培养的大鼠神经元与50或100 μ M UCB在100 μ M人血清白蛋白单独或与100 μ M NAME或与50 μ M GUDCA组合存在下在37 ℃孵育4小时。测定蛋白质羰基、4-羟基-2-壬烯醛-蛋白质加合物、细胞内谷胱甘肽含量和细胞死亡。结果表明，UCB诱导蛋白质氧化和脂质过氧化，同时减少巯基抗氧化剂防御，与细胞死亡的程度相关的事件。此外，这些事件被NAME抵消，并在GUDCA在场的情况下被废除。总的来说，这项研究表明，氧化应激是与UCB神经元活力受损相关的途径之一，GUDCA可显著防止此类效应的发生。这些发现证实了胆汁酸的抗氧化特性，并指出了一种新的治疗方法，用于UCB诱导的神经毒性，由于氧化应激。(C)2007年爱思唯尔公司All rights reserved.
It is well established that high levels of unconjugated bilirubin (UCB) can be toxic to the central nervous system, and oxidative stress is emerging as a relevant event in the mechanisms of UCB encephalopathy. In contrast, the hydrophilic bile acid, ursodeoxycholic acid (UDCA), has been reported as a cytoprotective and antioxidant molecule. In this study, we investigated if exposure of rat neurons in primary culture to clinically relevant concentrations of UCB leads to oxidative injury. The contribution of oxidative stress in UCB neurotoxicity was further investigated by examining whether the reduction of NO production by NAME, an inhibitor of nitric oxide synthase, prevents the disruption of the redox status and neuronal damage. Moreover, we evaluated the ability of glycoursodeoxycholic acid (GUDCA), the most relevant conjugated derivative in the serum of patients treated with UDCA, to abrogate the UCB-induced oxidative damage. Cultured rat neurons were incubated with 50 or 100 mu M UCB in the presence of 100 mu M human serum albumin, alone or in combination with 100 mu M NAME or with 50 mu M GUDCA, for 4 h at 37 degrees C. Protein carbonyls, 4-hydroxy-2-nonenal-protein adducts, intracellular glutathione content and cell death were determined. The results obtained showed that UCB induces protein oxidation and lipid peroxidation, while diminishes the thiol antioxidant defences, events that were correlated with the extent of cell death. Moreover, these events were counteracted by NAME and abrogated in the presence of GUDCA. Collectively, this study shows that oxidative stress is one of the pathways associated with neuronal viability impairment by UCB, and that GUDCA significantly prevents such effects from occurring. These findings corroborate the antioxidant properties of the bile acid and point to a new therapeutic approach for UCB-induced neurotoxicity due to oxidative stress. (C) 2007 Elsevier Inc. All rights reserved.