N-Methyl-D-Aspartate Receptor and Neuronal Nitric Oxide Synthase Activation Mediate Bilirubin-Induced Neurotoxicity
N-Methyl-D-Aspartate Receptor and Neuronal Nitric Oxide Synthase Activation Mediate Bilirubin-Induced Neurotoxicity
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DOI：
10.2119/molmed.2009.00152
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发表时间：
2010-09-01
影响因子：
5.7
通讯作者：
Brites, Dora
中科院分区：
文献类型：
--
作者：
Brito, Maria A.;Vaz, Ana R.;Brites, Dora
高胆红素血症可能导致神经毒性和神经元死亡。虽然未结合胆红素（UCB）的神经细胞损伤的机制似乎涉及破坏氧化还原状态和兴奋性毒性，一氧化氮（NO）和N-甲基-D-天冬氨酸（NMDA）谷氨酸受体的贡献尚不清楚。我们研究了NO和NMDA谷氨酸受体在UCB致神经细胞死亡途径中的作用。将神经元与100 μ mol/L UCB在100 μ mol/L人血清白蛋白存在下于37 ℃孵育4 h，单独或与N-ω-硝基-L-精氨酸甲酯（L-NAME）联合孵育。（神经元型一氧化氮合酶（nNOS）的抑制剂）、血红蛋白（NO清除剂）或（+）-5-甲基-10，11-二氢-5H-二苯并（a，d）环庚烯-5，10-亚胺马来酸盐（MK-801）（一种NMDA受体拮抗剂）暴露于UCB导致nNOS表达增加以及NO和环鸟苷3 '，5'-单磷酸（cGMP）的产生增加，沿着蛋白质氧化和谷胱甘肽耗竭，这些事件同时发生细胞功能障碍和死亡，并被L-NAME抵消。此外，血红蛋白消除了UCB诱导的神经元活力丧失，而MK-801抵消了nNOS的激活以及NO和cGMP的产生，从而显著保护细胞功能障碍和死亡。这些结果通过显示UCB引起的神经细胞损伤由NO介导，因此被NO抑制剂或清除剂抵消，从而加强了氧化应激的参与。我们的研究结果强烈表明nNOS的激活和神经毒性通过NMDA受体的参与发生。这些数据揭示了谷氨酸受体过度刺激在介导UCB氧化损伤中的作用（C）2010 Feinstein医学研究所，www.feinsteininstitute.org
Hyperbilirubinemia may lead to neurotoxicity and neuronal death. Although the mechanisms of nerve cell damage by unconjugated bilirubin (UCB) appear to involve a disruption of the redox status and excitotoxicity, the contribution of nitric oxide (NO) and of N-methyl-D-aspartate (NMDA) glutamate receptors is unclear. We investigated the role of NO and NMDA glutamate receptors in the pathways of nerve cell demise by UCB Neurons were incubated with 100 mu mol/L UCB, in the presence of 100 mu mol/L human serum albumin for 4 h at 37 degrees C, alone or in combination with N-omega-nitro-L-arginine methyl ester (L-NAME) (an inhibitor of neuronal nitric oxide synthase (nNOS)), hemoglobin (an NO scavenger) or (+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine maleate (MK-801) (an NMDA-receptor antagonist) Exposure to UCB led to increased expression of nNOS and production of both NO and cyclic guanosine 3',5'-monophosphate (cGMP), along with protein oxidation and depletion of glutathione These events concurred for cell dysfunction and death and were counteracted by L-NAME. Moreover, the UCB-induced loss of neuronal viability was abolished by hemoglobin, whereas the activation of nNOS and production of both NO and cGMP were counteracted by MK-801, resulting in significant protection from cell dysfunction and death These results reinforce the involvement of oxidative stress by showing that nerve cell damage by UCB is mediated by NO. and therefore is counteracted by NO. inhibitors or scavengers. Our findings strongly suggest that the activation of nNOS and neurotoxicity occur through the engagement of NMDA receptors These data reveal a role for overstimulation of glutamate receptors in mediating oxidative damage by UCB (C) 2010 The Feinstein Institute for Medical Research, www.feinsteininstitute.org