0605的镇静催眠作用及机理研究
摘要
目的:0605是由中国协和医科大学药物研究所定向合成的化学单体,前期已对其抗精神分裂症、抗躁狂、抗焦虑及镇静催眠活性进行了筛选,结果发现其镇静催眠活性显著。由于此药还未申请专利,故其化学结构不便公开。
本论文旨在进一步明确0605的镇静催眠活性,并对其作用机理进行研究。
方法:本论文分为三部分,第一部分《0605的行为学实验研究》分别采用如下方法系统的对0605的镇静催眠效果进行了研究:自主活动试验、协同戊巴比妥钠诱导小鼠睡眠潜伏期和睡眠时间试验、增强阈下剂量戊巴比妥钠诱导小鼠睡眠试验和协同戊巴比妥钠诱导小鼠再入睡试验。
第二部分《0605对小鼠前脑单胺类神经递质的影响》采用高效液相色谱仪对小鼠脑内NE、DA、5-HT、DOPAC和5-HIAA的含量进行了检测。
第三部分《0605对大鼠不同脑区内单胺类神经递质及单胺氧化酶B(MAO-B)活性的影响》选用大鼠进行试验,在第二部分基础上,对大鼠脑组织进行分区检测了单胺类神经递质含量,并利用试剂盒对单胺氧化酶B的活性进行了检测。
结果:第一部分:0605腹腔注射给药或灌胃给药均能够明显减少小鼠的自主活动;减少戊巴比妥钠诱导小鼠的睡眠潜伏期;延长戊巴比妥钠诱导小鼠的睡眠时间;增强阈下剂量戊巴比妥钠诱导小鼠睡眠;增强戊巴比妥钠诱导小鼠的再入睡。
第二部分:与溶剂对照组相比,0605组NE含量降低了35%,具有显著性差异,P<0.01;DA含量降低了8%,但在统计上无显著性差异;DOPAC含量升高了36%, P<0.05;5-HT和5-HIAA含量无明显变化;DOPAC/DA的比值升高了43%,具有显著性差异,P<0.05。
第三部分,0605对单胺类神经递质的影响:在皮层内,0605组与对照组相比各单胺类神经递质含量均无显著性差异;在丘脑内,0605组NE含量降低了30%,DOPAC/DA的值升高了32%,P均<0.05;在纹状体内,0605组DA含量降低了21%,DOPAC/DA的值升高了43%,P均<0.01;在海马内,0605组5-HIAA含量降低了22%,P<0.01。0605对单胺氧化酶B活性的影响:与对照组相比,0605组单胺氧化酶活性升高了72%,P<0.01。
结论:1通过一系列行为学实验和神经系统生物化学试验表明:0605具有明显的镇静催眠作用。2 0605具有增强单胺氧化酶B活性的作用,从而促进了NE和DA的代谢,导致大鼠脑内NE和DA的含量降低。3我们推测0605通过降低脑内NE和DA的含量而发挥了镇静催眠作用。4 0605的镇静催眠作用可能与其对5-HT受体的影响有关。
Objective: 0605 is a compound that was oriented synthe- sized by Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College. We have examined the 0605’s activity of anti-schizophrenia, anti-mania, anti-anxiety, and found that the sedative and hypnotic activity is significant. Because the compound hasn’t been apply for a patent, so the chemical structure is classified.
This paper seeks to further clarify the sedative and hypnotic activity of compand 0605, and the mechanism for research.
Methods: This paper is divided into three parts, the first part of "The Experimental study of compound 0605 on the behavior" uses the following method to systematic study the sedative and hypnotic effects of compound 0605: the experiment of spontaneous locomotor activity, the experiment of sleep latency and sleep time induced by sodium pentobarbital, the experiment of sleep induced by subthreshold dosage of sodium pentobarbital, the experiment of again sleep induced by sodium pentobarbital.
The second part of "The effect of compound 0605 on monoamain neurotransmitters in forebrain of mice" detected the content of NE、DA、5-HT、5-HIAA and DOPAC by HPLC.
The third part of "The effect of compound 0605 on mona- main neurotransmitters and the activity of monoamine oxidase B in different parts of brain of rat " choses rats for experiment. Based on the second part, it’s further detected the content of monoamine neurotransmitters and the activity of monoamine oxidase B by kit.
Results: The first part: 0605 (intraperitoneal injection administration or intragastric administration) can significantly reduce the spontaneous locomotor activity in mice; reduce the sleep latency induced by sodium pentobarbital in mice; extension the sleep time induced by sodium pentobarbital in mice; increase the sleep induced by subthreshold dosage of sodium pentobarbital in mice; increase the again sleep induced by sodium pentobarbital in mice.
The second part: Compared with the control group, the content of NE in 0605 Group decreases by 35 percent, a significant difference, P <0.01; the content of DA decreased by 8%, but there was no significant statistical difference; the content of DOPAC increased by 36%, P <0.05; the content of 5-HT and 5-HIAA had no significant change; the ratio of DOPAC/DA increased by 43%, a significant difference, P <0.05.
The third part: the effect of 0605 on monoamine neurotransmitter: in the cortex, between the 0605 group and the control group, there is no significant difference for all monoamine neurotransmitters; in the hypothalamus, the content of NE in 0605 Group has decreased 30%, and the ratio of DOPAC/DA increased by 32%, P <0.05; in the striatum, the content of DA in 0605 group decreased by 21%, the ratio of DOPAC/DA increased by 43%, P <0.01; in the hippocampus, the content of 5-HIAA in 0605 group decreased 22%, P <0.01.
The effect of compound 0605 on the activity of monoamine oxidase B: Compared with the control group, the activity of monoamine oxidase B in 0605 group increased by 72%, P <0.01.
Conclusion: 1 Series of behavioral experiments and biochemical experiments show that: 0605 has obvious sedative and hypnotic effects on the nervous system. 2 With the enhanced monoamine oxidase B activity, 0605 contributed to the NE and DA metabolism, resulted in the decreasing of NE and DA in the brain of rat. 3 We speculate that 0605 played a sedative and hypnotic effect by reducing the content of NE and DA in brain. 4 the sedative and hypnotic effects of 0605 may be related to the impact that 5-HT played on 5-HT receptor.
本论文旨在进一步明确0605的镇静催眠活性,并对其作用机理进行研究。
方法:本论文分为三部分,第一部分《0605的行为学实验研究》分别采用如下方法系统的对0605的镇静催眠效果进行了研究:自主活动试验、协同戊巴比妥钠诱导小鼠睡眠潜伏期和睡眠时间试验、增强阈下剂量戊巴比妥钠诱导小鼠睡眠试验和协同戊巴比妥钠诱导小鼠再入睡试验。
第二部分《0605对小鼠前脑单胺类神经递质的影响》采用高效液相色谱仪对小鼠脑内NE、DA、5-HT、DOPAC和5-HIAA的含量进行了检测。
第三部分《0605对大鼠不同脑区内单胺类神经递质及单胺氧化酶B(MAO-B)活性的影响》选用大鼠进行试验,在第二部分基础上,对大鼠脑组织进行分区检测了单胺类神经递质含量,并利用试剂盒对单胺氧化酶B的活性进行了检测。
结果:第一部分:0605腹腔注射给药或灌胃给药均能够明显减少小鼠的自主活动;减少戊巴比妥钠诱导小鼠的睡眠潜伏期;延长戊巴比妥钠诱导小鼠的睡眠时间;增强阈下剂量戊巴比妥钠诱导小鼠睡眠;增强戊巴比妥钠诱导小鼠的再入睡。
第二部分:与溶剂对照组相比,0605组NE含量降低了35%,具有显著性差异,P<0.01;DA含量降低了8%,但在统计上无显著性差异;DOPAC含量升高了36%, P<0.05;5-HT和5-HIAA含量无明显变化;DOPAC/DA的比值升高了43%,具有显著性差异,P<0.05。
第三部分,0605对单胺类神经递质的影响:在皮层内,0605组与对照组相比各单胺类神经递质含量均无显著性差异;在丘脑内,0605组NE含量降低了30%,DOPAC/DA的值升高了32%,P均<0.05;在纹状体内,0605组DA含量降低了21%,DOPAC/DA的值升高了43%,P均<0.01;在海马内,0605组5-HIAA含量降低了22%,P<0.01。0605对单胺氧化酶B活性的影响:与对照组相比,0605组单胺氧化酶活性升高了72%,P<0.01。
结论:1通过一系列行为学实验和神经系统生物化学试验表明:0605具有明显的镇静催眠作用。2 0605具有增强单胺氧化酶B活性的作用,从而促进了NE和DA的代谢,导致大鼠脑内NE和DA的含量降低。3我们推测0605通过降低脑内NE和DA的含量而发挥了镇静催眠作用。4 0605的镇静催眠作用可能与其对5-HT受体的影响有关。
Objective: 0605 is a compound that was oriented synthe- sized by Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College. We have examined the 0605’s activity of anti-schizophrenia, anti-mania, anti-anxiety, and found that the sedative and hypnotic activity is significant. Because the compound hasn’t been apply for a patent, so the chemical structure is classified.
This paper seeks to further clarify the sedative and hypnotic activity of compand 0605, and the mechanism for research.
Methods: This paper is divided into three parts, the first part of "The Experimental study of compound 0605 on the behavior" uses the following method to systematic study the sedative and hypnotic effects of compound 0605: the experiment of spontaneous locomotor activity, the experiment of sleep latency and sleep time induced by sodium pentobarbital, the experiment of sleep induced by subthreshold dosage of sodium pentobarbital, the experiment of again sleep induced by sodium pentobarbital.
The second part of "The effect of compound 0605 on monoamain neurotransmitters in forebrain of mice" detected the content of NE、DA、5-HT、5-HIAA and DOPAC by HPLC.
The third part of "The effect of compound 0605 on mona- main neurotransmitters and the activity of monoamine oxidase B in different parts of brain of rat " choses rats for experiment. Based on the second part, it’s further detected the content of monoamine neurotransmitters and the activity of monoamine oxidase B by kit.
Results: The first part: 0605 (intraperitoneal injection administration or intragastric administration) can significantly reduce the spontaneous locomotor activity in mice; reduce the sleep latency induced by sodium pentobarbital in mice; extension the sleep time induced by sodium pentobarbital in mice; increase the sleep induced by subthreshold dosage of sodium pentobarbital in mice; increase the again sleep induced by sodium pentobarbital in mice.
The second part: Compared with the control group, the content of NE in 0605 Group decreases by 35 percent, a significant difference, P <0.01; the content of DA decreased by 8%, but there was no significant statistical difference; the content of DOPAC increased by 36%, P <0.05; the content of 5-HT and 5-HIAA had no significant change; the ratio of DOPAC/DA increased by 43%, a significant difference, P <0.05.
The third part: the effect of 0605 on monoamine neurotransmitter: in the cortex, between the 0605 group and the control group, there is no significant difference for all monoamine neurotransmitters; in the hypothalamus, the content of NE in 0605 Group has decreased 30%, and the ratio of DOPAC/DA increased by 32%, P <0.05; in the striatum, the content of DA in 0605 group decreased by 21%, the ratio of DOPAC/DA increased by 43%, P <0.01; in the hippocampus, the content of 5-HIAA in 0605 group decreased 22%, P <0.01.
The effect of compound 0605 on the activity of monoamine oxidase B: Compared with the control group, the activity of monoamine oxidase B in 0605 group increased by 72%, P <0.01.
Conclusion: 1 Series of behavioral experiments and biochemical experiments show that: 0605 has obvious sedative and hypnotic effects on the nervous system. 2 With the enhanced monoamine oxidase B activity, 0605 contributed to the NE and DA metabolism, resulted in the decreasing of NE and DA in the brain of rat. 3 We speculate that 0605 played a sedative and hypnotic effect by reducing the content of NE and DA in brain. 4 the sedative and hypnotic effects of 0605 may be related to the impact that 5-HT played on 5-HT receptor.
引文
1 徐叔云, 卞如濂, 陈修. 药理实验方法学. 人民卫生出版 社. 2002 年 1 月第 3 版第五次印刷
2 张均田, 张庆柱. 神经药理学研究技术与方法. 人民卫生出版社. 2005 年三月第一版
3 彭博, 刘新民, 王立为. 安神中药药理研究方法综述. 中 草药. 2005, 36(8):1257~1260
4 张均田等. 现代药理实验方法. 北京医科大学中国协和医科大学联合出版社. 19981 年 10 月北京第一次印刷
5 葛会齐, 贾天柱. 五味子炮制品镇静催眠作用研究. 辽宁 中药杂志. 2007, 34(5):636~637
1 丁虹, 乔文建. 单胺类神经递质测定方法的研究. 化学传感器, 1992, 12(2):14~19
2 姚泰等. 生理学. 人民卫生出版社. 2001 年 11 月第 5 版.
3 Duine JM, Floch F, Cann-Moisan C, et a1. Simultaneousmeasurement of monoamines, their metabolites and 2,3- and 2,5-dihydroxybenzoates by high-performance liquid chromatography with electrochemical detection. Application to rat brain dialysates. Chromatogr B Biomed Sci Appl, 1998, 716(1-2):350~353
4 Huang W, Chen Y, Shohami E, et a1.Neuroprotective effect of rasagiline, a selective moniamine oxidase-B inhibitor, against closed head injury in the mouse. Eur J Pharmacol, 1999, 366(2-3):127~135
5 Hobson JA, McCarley RW, Wyzinski PW. Sleep cycle oscillation: reciprocal discharge by two brainstem neuronal groups. Science, 1997, 189(4196):55~58
6 Jacobs BL. Single unit activity of locus coeruleus neurons in behaving animals. Prog Neurobiol, 1986, 27(2):183~194
7 Rasmussen K,. Morilak DA, Jacobs BL. Single unit activity of locus coeruleus neurons in the freely moving cat. I. During naturalistic behaviors and in response to simple and complex stimuli. Brain Res, 1986, 371(2): 324~334
8 Cespuglio R, Gomez ME, Faradji H, Jouvet M, Alterations in the sleep-waking cycle induced by cooling of the locus coeruleus area. Electroencephalogr Clin Neurophysiol, 1982, 54 (5):570~578
9 Singh S, Mallick BN. Mild electrical stimulation of pontine tegmentum around locus coeruleus reduces rapid eye movement sleep in rats. Neurosci Res, 1996, 24(3):227~235
10 Jaime MM, Daniel M. The involvement of dopamine in themodulation of sleep and waking. Sleep Med Rev, 2007, 11(2):113~133
11 Lin JS, Hou Y. Jouvet M. Potential brain neuronal targets for amphetamine-methylphenidate and modafinil-induced wakefulness, evidenced by c-fos immunocytochemistry in the cat. Proc Natl Acad Sci, 1996, 93(24):14128~14133
12 张均田等. 现代药理实验方法. 北京医科大学中国协和 医科大学联合出版社. 1998 年 10 月北京第一次印刷
13 徐叔云, 卞如濂, 陈修. 人民卫生出版社. 2002 年 1 月第 3 版第五次印刷
1 张均田等. 现代药理实验方法. 北京医科大学中国协和医科大学联合出版社. 1998 年 10 月北京第一次印刷
2 徐叔云, 卞如濂, 陈修. 人民卫生出版社. 2002 年 1 月第 3版第五次印刷
3 张均田, 张庆柱. 神经药理学研究技术与方法. 人民卫生出版社. 2005 年三月第一版
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12 Zoltowski BD, Schwerdtfeger C, Widom J, et al. Conformational switching in the fungal light sensor vivid. Science, 2007, 316(5827):1054~1057
13 Gottesmann C. Brain inhibitory mechanisms involved in basic and higher integrated sleep processes. Brain Res Rev, 2004, 45(3):230~249
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2 张均田, 张庆柱. 神经药理学研究技术与方法. 人民卫生出版社. 2005 年三月第一版
3 彭博, 刘新民, 王立为. 安神中药药理研究方法综述. 中 草药. 2005, 36(8):1257~1260
4 张均田等. 现代药理实验方法. 北京医科大学中国协和医科大学联合出版社. 19981 年 10 月北京第一次印刷
5 葛会齐, 贾天柱. 五味子炮制品镇静催眠作用研究. 辽宁 中药杂志. 2007, 34(5):636~637
1 丁虹, 乔文建. 单胺类神经递质测定方法的研究. 化学传感器, 1992, 12(2):14~19
2 姚泰等. 生理学. 人民卫生出版社. 2001 年 11 月第 5 版.
3 Duine JM, Floch F, Cann-Moisan C, et a1. Simultaneousmeasurement of monoamines, their metabolites and 2,3- and 2,5-dihydroxybenzoates by high-performance liquid chromatography with electrochemical detection. Application to rat brain dialysates. Chromatogr B Biomed Sci Appl, 1998, 716(1-2):350~353
4 Huang W, Chen Y, Shohami E, et a1.Neuroprotective effect of rasagiline, a selective moniamine oxidase-B inhibitor, against closed head injury in the mouse. Eur J Pharmacol, 1999, 366(2-3):127~135
5 Hobson JA, McCarley RW, Wyzinski PW. Sleep cycle oscillation: reciprocal discharge by two brainstem neuronal groups. Science, 1997, 189(4196):55~58
6 Jacobs BL. Single unit activity of locus coeruleus neurons in behaving animals. Prog Neurobiol, 1986, 27(2):183~194
7 Rasmussen K,. Morilak DA, Jacobs BL. Single unit activity of locus coeruleus neurons in the freely moving cat. I. During naturalistic behaviors and in response to simple and complex stimuli. Brain Res, 1986, 371(2): 324~334
8 Cespuglio R, Gomez ME, Faradji H, Jouvet M, Alterations in the sleep-waking cycle induced by cooling of the locus coeruleus area. Electroencephalogr Clin Neurophysiol, 1982, 54 (5):570~578
9 Singh S, Mallick BN. Mild electrical stimulation of pontine tegmentum around locus coeruleus reduces rapid eye movement sleep in rats. Neurosci Res, 1996, 24(3):227~235
10 Jaime MM, Daniel M. The involvement of dopamine in themodulation of sleep and waking. Sleep Med Rev, 2007, 11(2):113~133
11 Lin JS, Hou Y. Jouvet M. Potential brain neuronal targets for amphetamine-methylphenidate and modafinil-induced wakefulness, evidenced by c-fos immunocytochemistry in the cat. Proc Natl Acad Sci, 1996, 93(24):14128~14133
12 张均田等. 现代药理实验方法. 北京医科大学中国协和 医科大学联合出版社. 1998 年 10 月北京第一次印刷
13 徐叔云, 卞如濂, 陈修. 人民卫生出版社. 2002 年 1 月第 3 版第五次印刷
1 张均田等. 现代药理实验方法. 北京医科大学中国协和医科大学联合出版社. 1998 年 10 月北京第一次印刷
2 徐叔云, 卞如濂, 陈修. 人民卫生出版社. 2002 年 1 月第 3版第五次印刷
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