The in vivo effect of bilirubin on the N-methyl-D-aspartate receptor/ion channel complex in the brains of newborn piglets
The in vivo effect of bilirubin on the N-methyl-D-aspartate receptor/ion channel complex in the brains of newborn piglets
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DOI：
10.1203/00006450-199612000-00005
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发表时间：
1996-12-01
影响因子：
3.6
通讯作者：
DelivoriaPapadopoulos, M
中科院分区：
文献类型：
--
作者：
Hoffman, DJ;Zanelli, SA;DelivoriaPapadopoulos, M
由于胆红素在神经元膜中的通透性增加，胆红素的神经毒性可以通过多种机制介导。本研究检验了这样的假设：延长胆红素输注会改变新生仔猪大脑皮层中的 N-甲基-D-天冬氨酸 (NMDA) 受体/离子通道复合物。研究在 7 只对照仔猪和 6 只暴露于胆红素的 2-4 日龄仔猪中进行。胆红素组的仔猪接受 35 mg/kg 胆红素推注，然后输注 4 小时（25 mg/kg/h）含有 0.1 N NaOH、5% 人白蛋白和 0.055 Na2HPO4 以及 3 mg/dL 胆红素的缓冲溶液。胆红素组的最终平均胆红素浓度为495.9+/-85.5μmol/L(29.0+/-5.0mg/dL)。对照组接受不含胆红素的缓冲溶液。对两组动物施用磺胺异恶唑。 P-2 膜部分是从大脑皮层制备的。进行[H-3]MK-801结合测定来研究NMDA受体修饰。对照组和胆红素组的 B-max 分别为 1.20 +/- 0.10（平均值 +/- SD）和 1.32 +/- 0.14 pmol/mg 蛋白质。对照大脑中的 K-d 值为 6.97 +/- 0.80 nM，而胆红素暴露大脑中的 K-d 值为 4.80 +/- 0.28 nM (p < 0.001)。 [H-3]谷氨酸结合研究未显示两组中 NMDA 特异性谷氨酸位点的 B-max 和 K-d 存在显着差异。结果表明，体内暴露于胆红素会增加[H-3]MK-801受体的亲和力（K-d降低），表明胆红素改变了新生仔猪大脑中NMDA受体/离子通道复合物的功能。我们推测胆红素对神经元膜的亲和力导致胆红素介导的神经毒性，导致神经元功能的短期或长期破坏。
Bilirubin neurotoxicity can be mediated by numerous mechanisms due to its increased permeability in neuronal membranes. The present study tests the hypothesis that a prolonged bilirubin infusion modifies the N-methyl-D-aspartate (NMDA) receptor/ion channel complex in the cerebral cortex of newborn piglets. Studies were performed in seven control and six bilirubin-exposed piglets, 2-4 d of age. Piglets in the bilirubin group received a 35 mg/kg bolus of bilirubin followed by a 4-h infusion (25 mg/kg/h) of a buffer solution containing 0.1 N NaOH, 5% human albumin, and 0.055 Na2HPO4 with 3 mg/dL bilirubin. The final mean bilirubin concentration in the bilirubin group was 495.9 +/- 85.5 mu mol/L (29.0 +/- 5.0 mg/dL). The control group received a bilirubin-free buffer solution. Sulfisoxazole was administered to animals in both groups. P-2 membrane fractions were prepared from the cerebral cortex. [H-3]MK-801 binding assays were performed to study NMDA receptor modification. The B-max in the control and bilirubin groups were 1.20 +/- 0.10 (mean +/- SD) and 1.32 +/- 0.14 pmol/mg protein, respectively. The value for K-d in the control brains was 6.97 +/- 0.80 nM compared with 4.80 +/- 0.28 nM in the bilirubin-exposed brains (p < 0.001). [H-3]Glutamate binding studies did not show a significant difference in the B-max and K-d for the NMDA-specific glutamate site in the two groups. The results show that in vivo exposure to bilirubin increases the affinity of the receptor (decreased K-d) for [H-3]MK-801, indicating that bilirubin modifies the function of the NMDA receptor/ion channel complex in the brain of the newborn piglet. We speculate that the affinity of bilirubin for neuronal membranes leads to bilirubin-mediated neurotoxicity, resulting in either short- or long-term disruption of neuronal function.