Reduction of Motion Sickness Through Targeting Histamine N-Methyltransferase in the Dorsal Vagal Complex of the Brain
Reduction of Motion Sickness Through Targeting Histamine N-Methyltransferase in the Dorsal Vagal Complex of the Brain
复制标题
通过靶向大脑背侧迷走神经复合体中的组胺 N-甲基转移酶来减少晕动病
DOI：
10.1124/jpet.117.244475
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发表时间：
2018-03-01
影响因子：
3.5
通讯作者：
Jiang, Zheng-Lin
中科院分区：
文献类型：
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作者：
Chen, Miao-Miao;Xu, Li-Hua;Jiang, Zheng-Lin
为了研究组胺n -甲基转移酶（HNMT）活性在运动病（MS）发生中的作用，为MS新药的开发提供依据，本实验采用Beagle犬和Sprague-Dawley大鼠旋转模拟MS - HNMT在脑干中的表达，并测量其在dmc中的表达。观察全身应用HNMT抑制剂他克林对多发性硬化症发展的影响。此外，我们将组胺受体H1抑制剂异丙嗪微注射到DVC中，以验证组胺能神经传递是否参与MS。最后，我们将慢病毒载体微注射到DVC中，以确定HNMT表达改变对MS的影响。我们发现：1)MS不敏感的狗和大鼠延髓中HNMT的表达高于易感动物；2)他克林剂量依赖性地促进两种动物的MS，提高大鼠延髓组织胺水平；3)异丙嗪阻断DVC组胺能神经传递抑制MS；4)旋转刺激诱导HNMT表达升高，前庭训练提高MS适应过程中DVC中HNMT的基础水平；5)在体内转染包装有HNMT基因的慢病毒载体，增加了DVC中HNMT的表达，降低了MS；6)在体内微注射慢病毒载体驱动干扰HNMT基因表达，显著抑制了DVC中HNMT的表达，加重了MS。由此可见，脑干中HNMT的表达与MS的发生呈负相关。增加HNMT在DVC中的表达或刺激其活性可抑制MS。
To investigate the role of histamine N-methyltransferase (HNMT) activity in the development of motion sickness (MS) in the dorsal vagal complex (DVC) to inform the development of new drugs for MS, Beagle dogs and Sprague-Dawley rats were rotated to simulate MS. HNMT expression in the brain stem and DVC was measured. The effects of systemic application of tacrine, an HNMT inhibitor, on the development of MS were observed. Moreover, we microinjected a histamine receptor H1 inhibitor, promethazine, into the DVC to verify the involvement of histaminergic neurotransmission in MS. Finally, lentiviral vectors were microinjected into the DVC to determine the effects of altered HNMT expression on MS. We found the following: 1) HNMT expression in the medulla oblongata of dogs and rats insusceptible to MS was higher than in susceptible animals; 2) tacrine dose-dependently promoted MS in both animals and raised histamine level in rat medulla oblongata; 3) blocking histaminergic neurotransmission in the DVC with promethazine inhibited MS; 4) rotatory stimulus induced an elevation in HNMT expression, and vestibular training elevated the basal level of HNMT in the DVC during habituation to MS; 5) in vivo transfection of a lentiviral vector packaged with the HNMT gene increased HNMT expression in the DVC and reduced MS; and 6) microinjection of a lentiviral vector driving the interference of HNMT gene expression in vivo significantly inhibited HNMT expression in the DVC and exacerbated MS. In conclusion, HNMT expression in the brain stem is in versely correlated with MS development. Increasing HNMT expression or stimulating its activity in the DVC could inhibit MS.