The TASK1 channel inhibitor A293 shows efficacy in a mouse model of multiple sclerosis
The TASK1 channel inhibitor A293 shows efficacy in a mouse model of multiple sclerosis
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DOI：
10.1016/j.expneurol.2012.08.021
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发表时间：
2012-12-01
影响因子：
5.3
通讯作者：
Meuth, Sven G.
中科院分区：
文献类型：
--
作者：
Bittner, Stefan;Bauer, Marcella A.;Meuth, Sven G.
双孔结构域钾通道TASK 1（KCNK 3）最近已成为自身免疫性CNS炎症的重要调节剂。先前，已经显示从TASK 1（-/-）小鼠获得的T淋巴细胞显示受损的T细胞效应子功能，并且TASK 1（-/-）小鼠在髓鞘少突胶质细胞糖蛋白（MOG（35-55））肽诱导的实验性自身免疫性脑脊髓炎（EAE）（多发性硬化症的动物模型）中显示疾病严重性显著降低。我们在这里评估了一种有效的和特异性的TASK 1通道抑制剂A293，它引起了T细胞效应功能（细胞因子的产生和增殖）的剂量依赖性降低。这种效应在来自TASK 1（-/-）小鼠的CD 4（+）T细胞中被消除，但在来自TASK 3（-/-）小鼠的细胞中未被消除。在电生理测量中，A293应用诱导野生型T淋巴细胞的外向电流显著降低，而在TASK 1（-/-）细胞中没有影响。A293的预防和治疗应用显著改善了野生型小鼠的EAE病程，而其在TASK 1（-/-）小鼠中没有显著作用，并且在TASK 3（-/-）小鼠中仍然部分有效。总之，我们的研究结果支持TASK 1作为自身免疫性疾病有吸引力的药物靶点的概念。(C)2012 Elsevier Inc. All rights reserved.
The two-pore domain potassium channel TASK1 (KCNK3) has recently emerged as an important modulator in autoimmune CNS inflammation. Previously, it was shown that T lymphocytes obtained from TASK1(-/-) mice display impaired T cell effector functions and that TASK1(-/-) mice show a significantly reduced disease severity in myelin oligodendrocyte glycoprotein (MOG(35-55)) peptide induced experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. We here evaluate a potent and specific TASK1 channel inhibitor, A293, which caused a dose-dependent reduction of T cell effector functions (cytokine production and proliferation). This effect was abolished in CD4(+) T cells from TASK1(-/-) mice but not in cells from TASK3(-/-) mice. In electrophysiological measurements, A293 application induced a significant reduction of the outward current of wildtype T lymphocytes, while there was no effect in TASK1(-/-) cells. Preventive and therapeutic application of A293 significantly ameliorated the EAE disease course in wildtype mice while it had no significant effect in TASK1(-/-) mice and was still partly effective in TASK3(-/-) mice. In summary, our findings support the concept of TASK1 as an attractive drug target for autoimmune disorders. (C) 2012 Elsevier Inc. All rights reserved.