Prostaglandin F2α FP receptor inhibitor reduces demyelination and motor dysfunction in a cuprizone-induced multiple sclerosis mouse model
Prostaglandin F2α FP receptor inhibitor reduces demyelination and motor dysfunction in a cuprizone-induced multiple sclerosis mouse model
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DOI：
10.1016/j.plefa.2014.08.004
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发表时间：
2014-11-01
影响因子：
3
通讯作者：
Yoshikawa, K.
中科院分区：
文献类型：
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作者：
Iwasa, K.;Yamamoto, S.;Yoshikawa, K.
此前，我们已经证明前列腺酰胺/PGF合酶在髓鞘和培养的少突胶质细胞中组成型表达，其催化前列腺素（PG）H-2还原为PGF（2α），表明PGF（2α）在髓鞘形成少突胶质细胞中具有功能意义。为了研究 PGF(2α)/FP 受体信号传导对脱髓鞘的影响，我们给暴露于铜宗的小鼠（多发性硬化症模型）施用 FP 受体激动剂和拮抗剂。小鼠被喂食含有 0.2% 铜宗的饮食 5 周，这会诱导严重的脱髓鞘、胶质细胞活化、促炎细胞因子表达和运动功能障碍。给予 FP 受体拮抗剂 AL-8810 可减轻铜宗诱导的脱髓鞘、神经胶质活化和胼胝体中 TNF α 的表达，并改善运动功能。这些数据表明，在铜宗诱导的脱髓鞘过程中，PGF(2α)/FP 受体信号传导有助于神经胶质活化、神经炎症和脱髓鞘，从而导致运动功能障碍。因此，FP 受体抑制可能是多发性硬化症的有效对症治疗。 (C) 2014 Elsevier Ltd. 保留所有权利。
Previously, we have demonstrated that prostamide/PGF synthase, which catalyzes the reduction of prostaglandin (PG) H-2 to PGF(2 alpha) is constitutively expressed in myelin sheaths and cultured oligodendrocytes, suggesting that PGF(2 alpha) has functional significance in myelin-forming oligodendrocytes. To investigate the effects of PGF(2 alpha)/FP receptor signaling on demyelination, we administrated FP receptor agonist and antagonist to cuprizone-exposed mice, a model of multiple sclerosis. Mice were fed a diet containing 0.2% cuprizone for 5 weeks, which induces severe demyelination, glial activation, proinflammatory cytokine expression, and motor dysfunction. Administration of the FP receptor antagonist AL-8810 attenuated cuprizone-induced demyelination, glial activation, and TNF alpha expression in the corpus callosum, and also improved the motor function. These data suggest that during cuprizone-induced demyelination, PGF(2 alpha)/FP receptor signaling contributes to glial activation, neuroinflammation, and demyelination, resulting in motor dysfunction. Thus, FP receptor inhibition may be a useful symptomatic treatment in multiple sclerosis. (C) 2014 Elsevier Ltd. All rights reserved.