Glutamate receptor expression in multiple sclerosis lesions
Glutamate receptor expression in multiple sclerosis lesions
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DOI：
10.1111/j.1750-3639.2007.00101.x
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发表时间：
2008-01-01
期刊：
影响因子：
6.4
通讯作者：
Smith, Terence
中科院分区：
文献类型：
--
作者：
Newcombe, Jia;Uddin, Alim;Smith, Terence
阻断兴奋性神经递质谷氨酸受体可改善CNS炎性脱髓鞘疾病多发性硬化症（MS）模型的神经学临床体征。为了研究谷氨酸兴奋毒性是否在MS发病机制中起作用，检查了谷氨酸及其受体、转运蛋白和酶的细胞定位。谷氨酸受体（GluR）1，钙++渗透离子型AMPA受体亚基的表达上调少突胶质细胞在活跃的MS病变边界，但钙++不渗透AMPA GluR 2亚基水平没有增加。活性斑块中的反应性星形胶质细胞表达AMPA GluR 3和代谢型mGluR 1、2/3和5受体以及GLT-1转运蛋白，并且亚群用谷氨酸抗体进行免疫染色。活化的小胶质细胞和巨噬细胞对GluR 2、GluR 4和NMDA受体亚单位1呈免疫阳性。红藻氨酸受体GluR 5 -7免疫组化显示内皮细胞和营养不良的轴突。星形胶质细胞和巨噬细胞群体表达谷氨酸代谢酶和出乎意料的EAAC 1转运蛋白，这可能在病变中的谷氨酸摄取中发挥作用。因此，MS白色病变中的反应性星形胶质细胞在隔离和代谢细胞外谷氨酸中具有保护作用。然而，他们可能无法维持谷氨酸在足够低的水平，以保护少突胶质细胞容易受到兴奋性毒性损伤，因为GluR 1上调。
Blockade of receptors for the excitatory neurotransmitter glutamate ameliorates neurological clinical signs in models of the CNS inflammatory demyelinating disease multiple sclerosis (MS). To investigate whether glutamate excitoxicity may play a role in MS pathogenesis, the cellular localization of glutamate and its receptors, transporters and enzymes was examined. Expression of glutamate receptor (GluR) 1, a Ca++-permeable ionotropic AMPA receptor subunit, was up-regulated on oligodendrocytes in active MS lesion borders, but Ca++-impermeable AMPA GluR2 subunit levels were not increased. Reactive astrocytes in active plaques expressed AMPA GluR3 and metabotropic mGluR1, 2/3 and 5 receptors and the GLT-1 transporter, and a subpopulation was immunostained with glutamate antibodies. Activated microglia and macrophages were immunopositive for GluR2, GluR4 and NMDA receptor subunit 1. Kainate receptor GluR5-7 immunostaining showed endothelial cells and dystrophic axons. Astrocyte and macrophage populations expressed glutamate metabolizing enzymes and unexpectedly the EAAC1 transporter, which may play a role in glutamate uptake in lesions. Thus, reactive astrocytes in MS white matter lesions are equipped for a protective role in sequestering and metabolizing extracellular glutamate. However, they may be unable to maintain glutamate at levels low enough to protect oligodendrocytes rendered vulnerable to excitotoxic damage because of GluR1 up-regulation.