Altered glutamate reuptake in relapsing-remitting and secondary progressive multiple sclerosis cortex: Correlation with microglia infiltration, demyelination, and neuronal and synaptic damage
Altered glutamate reuptake in relapsing-remitting and secondary progressive multiple sclerosis cortex: Correlation with microglia infiltration, demyelination, and neuronal and synaptic damage
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DOI：
10.1097/nen.0b013e31812571b0
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发表时间：
2007-08-01
影响因子：
3.2
通讯作者：
Cavalla, Paola
中科院分区：
文献类型：
--
作者：
Vercellino, Marco;Merola, Aristide;Cavalla, Paola
多发性硬化症（MS）的皮质受累正在成为疾病进展的重要决定因素。负责MS皮质病理学的机制尚未完全表征。本研究的目的是评估兴奋性毒性在MS皮质中的作用，评价兴奋性氨基酸转运蛋白（EAAT）表达及其与脱髓鞘、炎症、神经胶质增生、神经元和突触病理学的关系。EAAT在维持低细胞外谷氨酸浓度和防止兴奋性毒性中是必不可少的。通过免疫组织化学法评估了10例MS脑（3例复发缓解型MS病例和7例继发性进展型MS病例）的髓鞘碱性蛋白、CD 68、HLA-DR、EAAT 1、EAAT 2、胶质纤维酸性蛋白、磷酸化c-Jun N-末端激酶（pJNK）、突触素和神经丝。在MS脑中经常观察到不同数量和范围的皮质病变。在皮质病变中，活化的小胶质细胞浸润与EAAT 1、EAAT 2和突触素免疫染色的局灶性丢失相关，并且与pJNK（一种参与兴奋性毒性损伤反应的蛋白质）的神经元免疫染色相关。在没有激活的小胶质细胞的情况下，在脱髓鞘皮质中没有观察到EAAT或突触素免疫染色的减少。在存在活化小胶质细胞的皮质MS病变中发现谷氨酸再摄取机制的改变，并与提示兴奋性毒性的神经元和突触损伤体征相关。兴奋性毒性可能参与MS皮质脱髓鞘和神经元和突触损伤的发病机制。
Cortical involvement in multiple sclerosis (MS) is emerging as an important determinant of disease progression. The mechanisms responsible for MS cortical pathology are not fully characterized. The objective of this study was to assess the role of excitotoxicity in MS cortex, evaluating excitatory amino acid transporter (EAAT) expression and its relationship with demyelination, inflammation, gliosis, and neuronal and synaptic pathology. EAATs are essential in maintaining low extracellular glutamate concentrations and preventing excitotoxicity. Ten MS brains (3 relapsing-remitting MS cases and 7 secondary progressive MS cases) were evaluated by immumohistochernistry for myelin basic protein, CD68, HLA-DR, EAAT1, EAAT2, glial fibrillary acidic protein, phosphorylated c-Jun N-terminal kinase (pJNK), synaptophysin, and neurofilaments. Cortical lesions were frequently observed in MS brains in variable numbers and extensions. In cortical lesions, activated microglia infiltration correlated with focal loss of EAAT1, EAAT2, and synaptophysin immunostaining, and with neuronal immunostaining for pJNK, a protein involved in response to excitotoxic injury. No reduction of EAATs or synaptophysin immunostaining was observed in demyelinated cortex in the absence of activated microglia. Alterations of the mechanisms of glutamate reuptake are found in cortical MS lesions in the presence of activated microglia and are associated with signs of neuronal and synaptic damage suggestive of excitotoxicity. Excitotoxicity may be involved in the pathogenesis of demyelination and of neuronal and synaptic damage in MS cortex.