柴胡皂苷抗抑郁作用及其机制的研究
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摘要
抑郁症(Depression)是一种严重危害人类身心健康的常见疾病,随着人们生活压力的增大及工作节奏加快,抑郁症的发病率逐年上升,该病不仅困扰患者的生活和工作,也对其家庭和社会带来沉重的负担,因此对于该病的治疗及发病机制的研究也日益受到重视。目前,中医药治疗该病已经取得了令人满意的效果,与广泛应用于临床的西药相比,有着诸多优势,但由于中草药化学成分的复杂性,研究成果尚未受到国际学术界的认可。本课题试图建立稳定的、符合人类抑郁症发病特点的抑郁动物模型,在此基础上,对柴胡的有效成分柴胡皂苷治疗该病的疗效进行探索,并研究其抗抑郁的可能机制,期望为中药提取物治疗抑郁症提供有价值的参考依据。
本课题首先通过慢性应激性刺激配合孤养的方法造出抑郁症大鼠模型,通过记录大鼠体重、糖水消耗量、游泳不动时间、敞箱实验评分等行为学表现等抑郁评价指标情况,成功制备出抑郁症大鼠模型。在此模型的基础上,应用柴胡皂苷进行干预治疗,同时记录给药期间各项抑郁评价指标,最后采用高效液相色谱法、免疫组化、RT-PCR等技术,研究了抑郁模型大鼠及柴胡皂苷干预大鼠脑内单胺类神经递质和脑源性神经营养因子(BDNF)含量的变化。
研究结果表明,我们通过孤养加不可预见的刺激成功的复制出抑郁症大鼠的模型,发现其脑内单胺类神经递质及其代谢产物5-羟色胺(5-HT)、去甲肾上腺素(NE)、多巴胺(DA)、高香草酸(HVA)含量的下降以及脑源性神经营养因子(BDNF)表达的下调,本实验结果支持了抑郁症发病的单胺类神经递质假说及神经营养这两种假说。柴胡皂苷治疗干预后,上述指标均有显著改善,发现了柴胡皂苷的抗抑郁作用,且表明其抗抑郁作用可能与调节脑内单胺类神经递质及神经营养因子有关,为中药提取物治疗抑郁症提供了有价值的科学依据。
Depression is a disorder of impaired emotion regulation.Sustained negative affect and a persistent reduction in positive affect are the hallmark features of a diagnosis of a major depressive episode. it has become common diseases harmful to human health, social problems and economic losses caused by depression are very serious. Consequently,the researchers have paid more attention to pathogenesy and therapy of depression, however, its mechanism is not clear so far. Indeed, studies have suggested that depression is closely related to monoamine neurotransmitters, neurotrophic factors, signal transduction and other factors. The majority of drug treatment rely to chemotherapy, antidepressant drugs commonly used at present have too much shortage, such as drug resistance, adverse effect and so on. From this perspective, we need to find out a new type of antidepressant drugs, while the vegetable drug have stable antidepressant curative effect and few adverse effect. Bupleurum is a traditional drug of frequently used in our country, we extracted the major active component of bupleurum-saikoside.Then, investigated its antidepressant effect and corresponding mechanisms based on depression animal models.
1. establishment of depression rat model and observation of rats′ethology variation cured by saikoside.
Two classical type included stress and raised alone were applied in our study, we raised the rats alone with each other in a single cage, this method deprived the characteristics of rat’s social life. and the rats were given a series of unpredictable medium intensity stress which made them depressive state. weight gain, sacchar consumption, open field test, swim aplanetic time were used to assess the depressive extent.Then observed the index above mentioned after treatment of saikoside.
According to open-field test score, we selected 60 rats whose score were proximalis, divided them into 6 groups randomly, each group have 10 rats. The 6 groups were saikoside low dose group(SsLDG 5ml/kg), saikoside middle dose group(SsMDG 10ml/kg), saikoside high dose group(SsHDG 15ml/kg), depression group(1ml liquor natrii chloridi isotonicus), fluoxetine group, normal group. The normal group were raised together, other rats were raised lonely with each other. We used 7 different stimulates on them, a stimulate were used once a day. 28days later, drug groups were given corresponding drug, different dose of saikoside and fluoxetine.In the 56days of experiment, the stress stimulate used on rats were successive. Record the weight gain once a week, sacchar consumption, open field test and swim aplanetic time fortnightly.
After 4 weeks of experiment, the result suggested that the rats’body weight gain of depression model group were slow, sacchar consumption, open field test score were tapered, swim aplanetic time were increased. Compared with normal group, the differences were significant (P<0.05).The results illustrated that our depressive rat model were successful. After 56days of experiment, the differences between SsMDG, SsHDG and fluoxetine group were not significant(P>0.05), compared with depressive rat group,the differences were significant(P<0.05).The results suggested that saikoside could improve rat’s appetite, curiosity and despair degree in dangerous condition. Saikoside have outstanding effect of curing depression, and the drug action of it is similar with fluoxetine.
2. Influence of saikosaponina on monamine neurotransmitters and the corresponding metabolin compositions in depressed rats’brain
Existing findings showed that morbidity of depressive disorder were closely correlated with monoamine neurotransmitter and its corresponding metabolin compositions, such as homovanillic acid(HVA), noradrenaline(NE), dihydroxyphenylethylamine(DA), 5-hydroxy- tryptamine(5-HT).The high performance liquid chromatography was applied to investigate the influence of the saikosaponina on monamine neurotransmitter in the depressed rats’brain. It is shown from analytical results that in the depressed rats’brain, the contents of homovanillic acid, noradrenaline, dihydroxyphenyl ethylamine and 5-HT increase in the presence of the saikosaponin A. These results can help to clarify the mechanism of saikosaponin A in curing the depression.
At the end of the experiment, take out of the rats’brain on ice quickly.
Then put the brain into homogenizer, add perchloric acid, homogenate on waterbath, take out of the homogenate into centrifuge tube, put them into refrigerated centrifuge, after a few time, take the clear supernatant into.
condition of -70℃. The high performance liquid chromatography and fluorescence detection was applied to investigate the variation of HVA, NE, DA, 5-HT in the rats’brain.
Experimental result showed that the content of HVA, NE, DA and 5-HT in depression rats’brain were degraded compared with the normal group. While the content of them in saikoside group were higher than depression group, the results were similar to fluoxetine group. So we found that our depression rats model was successful which used alonely raised and medium intensity stress, and the monoamine neurotransmitter in brain were degraded, this result confirmed the neurotransmitter hypothesis of depression. At the same time, we also found that saikoside could reversed the variation of HVA, NE, DA, 5-HT in the rats’brain.That may be the mechanism of antidepression of saikoside.
3. Influence of saikosaponina on BDNF expression in depressed rats’cornu ammonis.
Neurotrophy hypothesis presumes that the loss of BDNF level in patients’brain can cause depression, heightening the BDNF level used various kinds of approach can treat the depression. RT-PCR and immunohistochemical methods were applied to investigate the influence of the saikosaponina on brain-derived neurotrophic factor in rats’brain, we want to find its antidpression effect and possible mechanisms.
We found that the cellula nervosa disposed indiscriminate and pultaceous, part of caryon was destroyed in depressed rats’cornu ammonis. The cell population of them was fewer than normal group, masculine BDNF cells were degraded significantly, expression was weakened, size of cells was not uniformity, collocation was anomalism. While the cellula nervosa of SsMDG and SsHDG rats’cornu ammonis were completed, collocation was regularity, drum dyeing was dark, content of BDNF was high. Compared with fluoxetine group, the difference is not significant. It showed that some cellula nervosa was died and destroyed in depressed rats’brain, and content of BDNF was degraded. Saikoside could protect cellula nervosa in cornu ammonis,set up the content of BDNF. That may be the mechanism of antidepression of saikoside.
Above all, we used stress and raising alone in our study,extended experiment time, depressed rats model were establishened successfully. The depressed rats’body weight gain, sacchar-consumption and open-field test score degraded,swimming immobility time increased. This type of depression model is stable. It is valuable on the study of depression nosogenesis and thymoleptics. Saikoside can improve depressed appearance, especially when used middle and high dose, the effect is optimization. The nosogenesis of depressive disorder is related with the content of HVA, NE, DA, 5-HT and BDNF in rats’brain. Saikoside can regulate them. That may be the mechanism of antidepression of saikoside.
本课题首先通过慢性应激性刺激配合孤养的方法造出抑郁症大鼠模型,通过记录大鼠体重、糖水消耗量、游泳不动时间、敞箱实验评分等行为学表现等抑郁评价指标情况,成功制备出抑郁症大鼠模型。在此模型的基础上,应用柴胡皂苷进行干预治疗,同时记录给药期间各项抑郁评价指标,最后采用高效液相色谱法、免疫组化、RT-PCR等技术,研究了抑郁模型大鼠及柴胡皂苷干预大鼠脑内单胺类神经递质和脑源性神经营养因子(BDNF)含量的变化。
研究结果表明,我们通过孤养加不可预见的刺激成功的复制出抑郁症大鼠的模型,发现其脑内单胺类神经递质及其代谢产物5-羟色胺(5-HT)、去甲肾上腺素(NE)、多巴胺(DA)、高香草酸(HVA)含量的下降以及脑源性神经营养因子(BDNF)表达的下调,本实验结果支持了抑郁症发病的单胺类神经递质假说及神经营养这两种假说。柴胡皂苷治疗干预后,上述指标均有显著改善,发现了柴胡皂苷的抗抑郁作用,且表明其抗抑郁作用可能与调节脑内单胺类神经递质及神经营养因子有关,为中药提取物治疗抑郁症提供了有价值的科学依据。
Depression is a disorder of impaired emotion regulation.Sustained negative affect and a persistent reduction in positive affect are the hallmark features of a diagnosis of a major depressive episode. it has become common diseases harmful to human health, social problems and economic losses caused by depression are very serious. Consequently,the researchers have paid more attention to pathogenesy and therapy of depression, however, its mechanism is not clear so far. Indeed, studies have suggested that depression is closely related to monoamine neurotransmitters, neurotrophic factors, signal transduction and other factors. The majority of drug treatment rely to chemotherapy, antidepressant drugs commonly used at present have too much shortage, such as drug resistance, adverse effect and so on. From this perspective, we need to find out a new type of antidepressant drugs, while the vegetable drug have stable antidepressant curative effect and few adverse effect. Bupleurum is a traditional drug of frequently used in our country, we extracted the major active component of bupleurum-saikoside.Then, investigated its antidepressant effect and corresponding mechanisms based on depression animal models.
1. establishment of depression rat model and observation of rats′ethology variation cured by saikoside.
Two classical type included stress and raised alone were applied in our study, we raised the rats alone with each other in a single cage, this method deprived the characteristics of rat’s social life. and the rats were given a series of unpredictable medium intensity stress which made them depressive state. weight gain, sacchar consumption, open field test, swim aplanetic time were used to assess the depressive extent.Then observed the index above mentioned after treatment of saikoside.
According to open-field test score, we selected 60 rats whose score were proximalis, divided them into 6 groups randomly, each group have 10 rats. The 6 groups were saikoside low dose group(SsLDG 5ml/kg), saikoside middle dose group(SsMDG 10ml/kg), saikoside high dose group(SsHDG 15ml/kg), depression group(1ml liquor natrii chloridi isotonicus), fluoxetine group, normal group. The normal group were raised together, other rats were raised lonely with each other. We used 7 different stimulates on them, a stimulate were used once a day. 28days later, drug groups were given corresponding drug, different dose of saikoside and fluoxetine.In the 56days of experiment, the stress stimulate used on rats were successive. Record the weight gain once a week, sacchar consumption, open field test and swim aplanetic time fortnightly.
After 4 weeks of experiment, the result suggested that the rats’body weight gain of depression model group were slow, sacchar consumption, open field test score were tapered, swim aplanetic time were increased. Compared with normal group, the differences were significant (P<0.05).The results illustrated that our depressive rat model were successful. After 56days of experiment, the differences between SsMDG, SsHDG and fluoxetine group were not significant(P>0.05), compared with depressive rat group,the differences were significant(P<0.05).The results suggested that saikoside could improve rat’s appetite, curiosity and despair degree in dangerous condition. Saikoside have outstanding effect of curing depression, and the drug action of it is similar with fluoxetine.
2. Influence of saikosaponina on monamine neurotransmitters and the corresponding metabolin compositions in depressed rats’brain
Existing findings showed that morbidity of depressive disorder were closely correlated with monoamine neurotransmitter and its corresponding metabolin compositions, such as homovanillic acid(HVA), noradrenaline(NE), dihydroxyphenylethylamine(DA), 5-hydroxy- tryptamine(5-HT).The high performance liquid chromatography was applied to investigate the influence of the saikosaponina on monamine neurotransmitter in the depressed rats’brain. It is shown from analytical results that in the depressed rats’brain, the contents of homovanillic acid, noradrenaline, dihydroxyphenyl ethylamine and 5-HT increase in the presence of the saikosaponin A. These results can help to clarify the mechanism of saikosaponin A in curing the depression.
At the end of the experiment, take out of the rats’brain on ice quickly.
Then put the brain into homogenizer, add perchloric acid, homogenate on waterbath, take out of the homogenate into centrifuge tube, put them into refrigerated centrifuge, after a few time, take the clear supernatant into.
condition of -70℃. The high performance liquid chromatography and fluorescence detection was applied to investigate the variation of HVA, NE, DA, 5-HT in the rats’brain.
Experimental result showed that the content of HVA, NE, DA and 5-HT in depression rats’brain were degraded compared with the normal group. While the content of them in saikoside group were higher than depression group, the results were similar to fluoxetine group. So we found that our depression rats model was successful which used alonely raised and medium intensity stress, and the monoamine neurotransmitter in brain were degraded, this result confirmed the neurotransmitter hypothesis of depression. At the same time, we also found that saikoside could reversed the variation of HVA, NE, DA, 5-HT in the rats’brain.That may be the mechanism of antidepression of saikoside.
3. Influence of saikosaponina on BDNF expression in depressed rats’cornu ammonis.
Neurotrophy hypothesis presumes that the loss of BDNF level in patients’brain can cause depression, heightening the BDNF level used various kinds of approach can treat the depression. RT-PCR and immunohistochemical methods were applied to investigate the influence of the saikosaponina on brain-derived neurotrophic factor in rats’brain, we want to find its antidpression effect and possible mechanisms.
We found that the cellula nervosa disposed indiscriminate and pultaceous, part of caryon was destroyed in depressed rats’cornu ammonis. The cell population of them was fewer than normal group, masculine BDNF cells were degraded significantly, expression was weakened, size of cells was not uniformity, collocation was anomalism. While the cellula nervosa of SsMDG and SsHDG rats’cornu ammonis were completed, collocation was regularity, drum dyeing was dark, content of BDNF was high. Compared with fluoxetine group, the difference is not significant. It showed that some cellula nervosa was died and destroyed in depressed rats’brain, and content of BDNF was degraded. Saikoside could protect cellula nervosa in cornu ammonis,set up the content of BDNF. That may be the mechanism of antidepression of saikoside.
Above all, we used stress and raising alone in our study,extended experiment time, depressed rats model were establishened successfully. The depressed rats’body weight gain, sacchar-consumption and open-field test score degraded,swimming immobility time increased. This type of depression model is stable. It is valuable on the study of depression nosogenesis and thymoleptics. Saikoside can improve depressed appearance, especially when used middle and high dose, the effect is optimization. The nosogenesis of depressive disorder is related with the content of HVA, NE, DA, 5-HT and BDNF in rats’brain. Saikoside can regulate them. That may be the mechanism of antidepression of saikoside.
引文
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