Reduced astrocytic NF-κB activation by laquinimod protects from cuprizone-induced demyelination.
Reduced astrocytic NF-κB activation by laquinimod protects from cuprizone-induced demyelination.
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拉喹莫德减少星形胶质细胞 NF-κB 激活可防止铜宗诱导的脱髓鞘。
DOI：
10.1007/s00401-012-1009-1
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发表时间：
2012-09
影响因子：
12.7
通讯作者：
Wegner C
中科院分区：
文献类型：
--
作者：
Brück W;Pförtner R;Pham T;Zhang J;Hayardeny L;Piryatinsky V;Hanisch UK;Regen T;van Rossum D;Brakelmann L;Hagemeier K;Kuhlmann T;Stadelmann C;John GR;Kramann N;Wegner C
拉喹莫德（LAQ）是一种新的口服免疫调节化合物，可降低多发性硬化症（MS）的复发率、脑萎缩和残疾进展。LAQ对外周炎症的作用已得到充分证实，但对其在中枢神经系统（CNS）内的直接活性知之甚少。为了阐明LAQ对CNS内源性炎症的影响，我们研究了LAQ对体内铜腙诱导的小鼠脱髓鞘和体外原代CNS细胞的影响。在铜腙攻击后，在LAQ处理的野生型和Rag-1缺陷型小鼠中评价脱髓鞘、炎症、轴突损伤和神经胶质病理学。使用原代细胞，我们测试了LAQ对少突胶质细胞存活以及星形胶质细胞和小胶质细胞中细胞因子分泌和NF-κB活化的影响。LAQ预防cuprizone诱导的脱髓鞘，小胶质细胞活化，轴突横切，反应性胶质增生和少突胶质细胞增生在野生型和Rag-1缺陷小鼠。LAQ显着降低刺激的星形胶质细胞中的促炎因子，但不是在小胶质细胞。少突胶质细胞的存活率在体外不受LAQ的影响。NF-κB报告基因分析证实，LAQ显著降低了星形胶质细胞而非小胶质细胞的NF-κB活化。LAQ还显著降低了cuprizone处理小鼠的星形胶质细胞NF-κB活化。我们的数据表明，LAQ通过减弱星形胶质细胞NF-κB活化来防止铜腙诱导的脱髓鞘。这些作用是CNS内在的，不受外周免疫细胞介导。因此，LAQ下调星形胶质细胞促炎反应可能是其对髓鞘、少突胶质细胞和轴突保护作用的重要机制。星形胶质细胞活化的调制可能是一个有吸引力的治疗目标，以防止组织损伤在MS.这篇文章的在线版本（doi：10.1007/s 00401 -012-1009-1）包含补充材料，这是提供给授权用户。
Laquinimod (LAQ) is a new oral immunomodulatory compound that reduces relapse rate, brain atrophy and disability progression in multiple sclerosis (MS). LAQ has well-documented effects on inflammation in the periphery, but little is known about its direct activity within the central nervous system (CNS). To elucidate the impact of LAQ on CNS-intrinsic inflammation, we investigated the effects of LAQ on cuprizone-induced demyelination in mice in vivo and on primary CNS cells in vitro. Demyelination, inflammation, axonal damage and glial pathology were evaluated in LAQ-treated wild type and Rag-1-deficient mice after cuprizone challenge. Using primary cells we tested for effects of LAQ on oligodendroglial survival as well as on cytokine secretion and NF-κB activation in astrocytes and microglia. LAQ prevented cuprizone-induced demyelination, microglial activation, axonal transections, reactive gliosis and oligodendroglial apoptoses in wild type and Rag-1-deficient mice. LAQ significantly decreased pro-inflammatory factors in stimulated astrocytes, but not in microglia. Oligodendroglial survival was not affected by LAQ in vitro. Astrocytic, but not microglial, NF-κB activation was markedly reduced by LAQ as evidenced by NF-κB reporter assay. LAQ also significantly decreased astrocytic NF-κB activation in cuprizone-treated mice. Our data indicate that LAQ prevents cuprizone-induced demyelination by attenuating astrocytic NF-κB activation. These effects are CNS-intrinsic and not mediated by peripheral immune cells. Therefore, LAQ downregulation of the astrocytic pro-inflammatory response may be an important mechanism underlying its protective effects on myelin, oligodendrocytes and axons. Modulation of astrocyte activation may be an attractive therapeutic target to prevent tissue damage in MS. The online version of this article (doi:10.1007/s00401-012-1009-1) contains supplementary material, which is available to authorized users.
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影响因子：
15.3
作者：
Brambilla, R;Bracchi-Ricard, V;Hu, WH;Frydel, B;Bramwell, A;Karmally, S;Green, EJ;Bethea, JR
通讯作者：
Bethea, JR
影响因子：
4.8
作者：
Bjartmar, C;Trapp, BD
通讯作者：
Trapp, BD
影响因子：
8.3
作者：
Acarin, L;González, B;Castellano, B
通讯作者：
Castellano, B
影响因子：
158.5
作者：
Comi, Giancarlo;Jeffery, Douglas;Filippi, Massimo
通讯作者：
Filippi, Massimo
影响因子：
168.9
作者：
Comi, G.;Pulizzi, A.;Filippi, M.
通讯作者：
Filippi, M.