Inhibition of MAO-A and stimulation of behavioural activities in mice by the inactive prodrug form of the anti-influenza agent oseltamivir.
Inhibition of MAO-A and stimulation of behavioural activities in mice by the inactive prodrug form of the anti-influenza agent oseltamivir.
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通过抗激素剂Oseltamivir的无活性前药形式抑制MAO-A和刺激小鼠行为活性。
DOI：
10.1111/bph.12102
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发表时间：
2013-05
影响因子：
7.3
通讯作者：
Kuzuhara T
中科院分区：
文献类型：
--
作者：
Hiasa M;Isoda Y;Kishimoto Y;Saitoh K;Kimura Y;Kanai M;Shibasaki M;Hatakeyama D;Kirino Y;Kuzuhara T
奥司他韦是最常用的抗流感药物。然而，据报告，在极少数情况下，它会刺激青少年的行为活动。本研究的目的是确定负责这些行为活动的分子机制。我们使用活性形式-奥司他韦羧酸酯（OC）或无活性前药-奥司他韦乙酯（OEE）对负责神经递质降解的MAO-A进行了体外测定。我们还分析了MAO-A与OEE或OC的计算机对接。 使用自动视频和计算机分析监测OEE或OC给药后的小鼠行为。OEE，而不是OC，竞争性和选择性抑制人MAO-A。估算的Ki值与MAO-A的天然底物的Km值相当。基于MAO-A三级结构的计算机对接模拟表明，OEE可以适合酶的内口袋。使用自动视频分析的行为监测进一步显示，OEE而不是OC显著增强了小鼠的自发行为活动，如跳跃、直立、嗅闻、转身和行走。我们的多层次分析表明OEE是与奥司他韦相关的副作用的原因，并揭示了在某些情况下由奥司他韦诱导的刺激行为的分子机制。
Oseltamivir is the most widely prescribed anti-influenza medication. However, in rare instances, it has been reported to stimulate behavioural activities in adolescents. The goal of this study was to determine the molecular mechanism responsible for these behavioural activities. We performed an in vitro assay of MAO-A, the enzyme responsible for neurotransmitter degradation, using either the active form – oseltamivir carboxylate (OC) or the inactive prodrug – oseltamivir ethyl ester (OEE). We also analysed the docking of MAO-A with OEE or OC in silico. Mouse behaviours after OEE or OC administration were monitored using automated video and computer analysis. OEE, but not OC, competitively and selectively inhibited human MAO-A. The estimated Ki value was comparable with the Km values of native substrates of MAO-A. Docking simulations in silico based on the tertiary structure of MAO-A suggested that OEE could fit into the inner pocket of the enzyme. Behavioural monitoring using automated video analysis further revealed that OEE, not OC, significantly enhanced spontaneous behavioural activities in mice, such as jumping, rearing, sniffing, turning and walking. Our multilevel analyses suggested OEE to be the cause of the side effects associated with oseltamivir and revealed the molecular mechanism underlying the stimulated behaviours induced by oseltamivir in some circumstances.
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影响因子：
3.7
作者：
Iwai Y;Murakami K;Gomi Y;Hashimoto T;Asakawa Y;Okuno Y;Ishikawa T;Hatakeyama D;Echigo N;Kuzuhara T
通讯作者：
Kuzuhara T
影响因子：
2.5
作者：
Hatori, Akiko;Yui, Joji;Zhang, Ming-Rong
通讯作者：
Zhang, Ming-Rong
影响因子：
3.1
作者：
Hatori, Akiko;Arai, Takuya;Zhang, Ming-Rong
通讯作者：
Zhang, Ming-Rong
影响因子：
2.9
作者：
Crain, SM;Shen, KF
通讯作者：
Shen, KF
影响因子：
4.8
作者：
Chen, K;Holschneider, DP;Shih, JC
通讯作者：
Shih, JC