Aggression behaviour induced by oral administration of the Janus-kinase inhibitor tofacitinib, but not oclacitinib, under stressful conditions
Aggression behaviour induced by oral administration of the Janus-kinase inhibitor tofacitinib, but not oclacitinib, under stressful conditions
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DOI：
10.1016/j.ejphar.2015.06.060
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发表时间：
2015-10-05
影响因子：
5
通讯作者：
Baeumer, Wolfgang
中科院分区：
文献类型：
--
作者：
Fukuyama, Tomoki;Tschernig, Thomas;Baeumer, Wolfgang
最近开发了用于过敏性疾病的 Janus 激酶 (JAK) 抑制剂。我们重点关注 2 种不同的 JAK 抑制剂：托法替尼（对 JAK3 选择性）和奥拉替尼（对 JAK1 和 2 选择性），以阐明这些药物的抗炎和止痒功效机制。在检测抗瘙痒功效的过程中，我们观察到托法替布治疗的小鼠表现出攻击行为。本文报道的研究目的是通过使用过敏性皮炎小鼠模型和常驻入侵者测试来研究托法替布诱导的攻击行为。对于过敏性皮炎模型，用甲苯-2,4-二异氰酸酯（TDI）对雌性 BALB/c 小鼠进行局部致敏和攻击。在 TDI 攻击前 30 分钟口服载体托法替尼或奥拉替尼。在 TDI 攻击后 60 分钟内立即监测抓挠、攻击和站立行为。另一组用赋形剂、托法替尼或奥拉替尼治疗的雄性 BALB/c 小鼠在常驻入侵者测试中进行评估，并获取大脑以确定血脑屏障的渗透性。在过敏性皮炎模型中，仅托法替布治疗组的攻击性和站立行为显着增加。在非致敏小鼠中没有效果，但在雄性常驻入侵者测试中，托法替布也诱导了类似的攻击行为。在托法替尼和奥拉替尼治疗的小鼠中观察到血脑屏障的穿透。这些结果表明，在某种压力环境下，托法替布会诱发攻击行为。这项研究表明 JAK-STAT 通路在调节攻击行为中可能发挥作用。 (C) 2015 Elsevier B.V. 保留所有权利。
Janus kinase (JAK) inhibitors have recently been developed for allergic diseases We focused on the 2 different JAK inhibitors, tofacitinib (selective for JAK3) and oclacitinib (selective for JAK1 and 2), to clarify the mechanism of anti-inflammatory and anti-itching potency of these drugs. In the process of detecting anti-itching potency, we observed that tofacitinib treated mice showed aggression behaviour. The objective of the study reported here was to investigate the aggressive behaviour induced by tofacitinib by using a mouse model of allergic dermatitis and the resident intruder test. For the allergic dermatitis model, female BALB/c mice were sensitised and challenged topically with toluene-2,4-diisocyanate (TDI). Vehicle, tofacitinib or oclacitinib, was administered orally 30 min before TDI challenge. Scratching, aggression and standing behaviours were monitored in the 60 min period immediately following challenge of TDI. Another group of male BALB/c mice treated with vehicle, tofacitinib or oclacitinib was evaluated in the resident intruder test and brains were obtained to determine blood brain barrier penetration. In the allergic dermatitis model, a significant increase in aggression and standing behaviour was only obvious in the tofacitinib treatment group. There was no effect in non sensitised mice, but similar aggression was also induced by tofacitinib in male resident intruder test. Penetration of blood brain barrier was observed both in tofacitinib and oclacitinib treated mice. These results suggest that aggression was induced by tofacitinib under some kind of stressful environment. This study indicates a possible role of the JAK-STAT pathway in modulation of aggression behaviour. (C) 2015 Elsevier B.V. All rights reserved.