P2X7 antagonist activity of the anti-allergic agent oxatomide
P2X7 antagonist activity of the anti-allergic agent oxatomide
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抗过敏药奥沙米特的 P2X7 拮抗剂活性
DOI：
10.1016/j.ejphar.2015.10.002
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Isao Matsuoka
中科院分区：
文献类型：
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作者：
Kazuki Yoshida;Masaaki Ito;Isao Matsuoka
细胞外ATP对P2 X7受体的激活与包括过敏性炎症在内的各种免疫应答相关。已知抗过敏药，如H1-抗组胺药，可抑制不同化学介质如乙酰胆碱和血小板活化因子的作用。因此，我们假设一些抗过敏药物可能会影响P2 X7受体功能。使用表达功能性P2 X7受体的N18 TG 2和J774细胞，通过监测ATP诱导的细胞内Ca 2+浓度（[Ca 2 +]i）增加来研究几种抗过敏剂对P2 X7受体功能的影响。在测试的各种药物中，奥沙米特以浓度依赖性方式显著抑制P2 X7受体介导的[Ca 2 +]i升高，而不影响N18 TG 2和J774细胞中P2 Y2受体介导的反应。因此，奥沙米特抑制P2 X7受体介导的膜电流和下游反应，如丝裂原活化蛋白激酶激活，炎症相关基因诱导和细胞死亡。此外，oxatomide抑制P2 X7受体介导的小鼠骨髓源性肥大细胞脱颗粒。在表达人、小鼠和大鼠P2 X7受体的HEK 293细胞中进行的全细胞膜片钳分析显示，奥沙米特对ATP诱导电流的抑制作用对人P2 X7受体最为显著，对大鼠P2 X7受体几乎不存在。在内源性表达P2 X7受体的RPMI 8226人B细胞样骨髓瘤细胞中证实了奥沙米特对人P2 X7受体介导的功能的强效抑制作用。我们的研究结果表明，抗组胺药奥沙米特也作为P2 X7受体拮抗剂。因此，未来的研究应评估P2 X7受体拮抗作用是否有助于奥沙米特的抗过敏作用。
Activation of the P2X7 receptor by extracellular ATP is associated with various immune responses including allergic inflammation. Anti-allergic agents, such as H1-antihistamines, are known to inhibit the effects of different chemical mediators such as acetylcholine and platelet-activating factor. Therefore, we hypothesized that some anti-allergic agents might affect P2X7 receptor function. Using N18TG2 and J774 cells, which express functional P2X7 receptors, the effects of several anti-allergic agents on P2X7 receptor function were investigated by monitoring the ATP-induced increase in intracellular Ca2+concentrations ([Ca2+]i). Among the various agents tested, oxatomide significantly inhibited P2X7 receptor-mediated [Ca2+]i elevation in a concentration-dependent manner without affecting the P2Y2receptor-mediated response in both N18TG2 and J774 cells. Consistently, oxatomide inhibited P2X7 receptor-mediated membrane current and downstream responses such as mitogen-activated protein kinase activation, inflammation-related gene induction, and cell death. In addition, oxatomide inhibited P2X7 receptor-mediated degranulation in mouse bone marrow-derived mast cells. Whole cell patch clamp analyses in HEK293 cells expressing human, mouse, and rat P2X7 receptors revealed that the inhibitory effect of oxatomide on ATP-induced current was most prominent for the human P2X7 receptor and almost non-existent for the rat P2X7 receptor. The potent inhibitory effects of oxatomide on human P2X7 receptor-mediated function were confirmed in RPMI8226 human B cell-like myeloma cells, which endogenously express the P2X7 receptor. Our results demonstrated that the antihistamine oxatomide also acts as a P2X7 receptor antagonist. Future studies should thus evaluate whether P2X7 receptor antagonism contributes to the anti-allergic effects of oxatomide.