中药SXY-006的抗抑郁作用及其机制
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摘要
抑郁症是一种以显著而持久的心境低落为主要临床特征的常见的情感性精神疾病,已成为现代社会的常见病、多发病。研究表明,抑郁症状的发生、发展与神经内分泌系统、免疫系统和基因表达调节的异常有关。抑郁症的治疗主要是药物治疗,目前临床上主要用药有以氟西汀为代表的5-羟色胺(5-HT)再摄取抑制剂(SSRIs),以阿米替林为代表的三环类抗抑郁药(TCA)和以吗氯贝胺为代表的单胺氧化酶抑制剂(MAOI),这些化工合成的药物均有一定疗效,但也均有不同程度的副作用和依赖性,有的甚至反而加重病人抑郁状态。因此,开发疗效确切、毒副作用小的中药,正成为当前国内外抗抑郁药物研发的热点。
本文由中药新药SXY-006的抗抑郁作用评价及其抗抑郁机制研究两部分组成,旨在通过一系列经典行为学和形态学实验,对中药新药SXY-006进行抗抑郁作用研究,并探讨其抗抑郁作用的机制,为其投入临床应用提供理论和实验依据。
第一部分中药SXY-006的抗抑郁作用
目的:研究中药SXY-006的抗抑郁作用
方法:通过小鼠悬尾实验、小鼠强迫游泳实验、大鼠单次及多次给药后强迫游泳实验,观察中药SXY-006对实验动物不动时间的影响;通过制作大鼠慢性轻度不可预见性应激(CUMS)抑郁症模型,进行敞箱(open-field)实验,观察SXY-006对实验动物水平得分和垂直得分的影响。
结果:SXY-006中剂量(100 mg/kg)、高剂量(300 mg/kg)均能明显减少小鼠悬尾实验和强迫游泳实验的不动时间(p<0.01); SXY-006低(25 mg/kg)、中(100 mg/kg)、高(300 mg/kg)剂量均能减少大鼠单次和多次给药后强迫游泳实验的不动时间(p<0.05),均能增加大鼠慢性不可预知性应激抑郁症造模后大鼠的水平得分(p<0.05)和垂直得分(p<0.01)。
结论:中药新药SXY-006具有抗抑郁作用
第二部分中药SXY-006抗抑郁作用的机制
目的:研究中药SXY-006抗抑郁作用的机制
方法:通过5-羟色胺酸(5-HTP)诱导的小鼠甩头实验观察SXY-006对小鼠甩头次数的影响;通过利血平引起的小鼠睁眼不能以及运动不能实验观察SXY-006对小鼠眼睑闭合和自主运动的影响;通过HE染色观察海马神经元形态学的变化,免疫组织化学技术检测5-HT2受体、c-fos蛋白的表达。
结果:SXY-006低剂量(25 mg/kg)、中剂量(100 mg/kg)和高剂量(300 mg/kg)均能显著增加5-HTP诱导的甩头实验中小鼠甩头次数(p<0.01),均能拮抗利血平引起的小鼠的睁眼不能和运动不能(p<0.05);抑郁症模型组大鼠海马神经元形态异常,顶叶皮层5-HT2受体、海马c-fos蛋白表达增加,而SXY-006各剂量组大鼠海马神经元形态基本正常,5-HT2受体、c-fos蛋白表达无明显变化。
结论:中药SXY-006的抗抑郁作用可能与其①阻断突触间隙单胺类递质再摄取或抑制单胺氧化酶,②对海马神经元的保护作用,③下调5-HT2受体和c-fos受体的作用有关。
Depression is a common and debilitating thymogenic mental disorder in clinic, characterized by marked and long-lasting depressed mood. Previous studies show that the pathogenesis of depression correlates with the abnormity of neuroendocrine and immune system and the expression of certain genes. Depression is primarily treated by drug therapy. The clinically used medications include selective serotonin reuptake inhibitors(SSRIs, e.g. fluoxetine)、TCAs (e.g. amitripramine) and monoamine oxidase inhibitor (MAOIs, e.g. maclobemide). All of the drugs are effective in treating some subpopulation of depression patients, however, they also have certain side effects or physical dependence, and under some conditions they even aggravate the process. Therefore, it is necessary to find new drug, which has good antidepressive effect and less adverse reaction.
The thesis consists of two parts: preclinical evaluation of the antidepressant efficacy of new TCM SXY-006 and the investigation of its mechanism. By using several behavioral and morphological experiment for antidepressants, the goal of this series of studies is to evaluate the antidepressant effects of SXY-006 and elucidate its mechanisms, thus to provide convinced preclinical information for NDA (New Drug Application).
Part I Antidepressant effects of traditional Chinese medicine“SXY-006”
Objective: To evaluate the antidepressant effects of traditional Chinese medicine“SXY-006”
Methods: The effect of SXY-006 on immobility time was investigated by the tail suspension test and force swimming test of mice or rats after single and multiple administrations. The effect of SXY-006 on horizontal and vertical score was studied through the open-field test after the establishment of chronic unpredictable mild stress (CUMS) model of rats.
Results: Moderate (100 mg/kg) and high (300 mg/kg) doses of SXY-006 can obviously decrease the immobility time in the tail suspension and forced swimming tests of mice (p<0.01). All of SXY-006 in different doses can markedly reduce the immobility time in forced swimming tests of rats after both the single and multiple administrations of the medicine (p<0.05), and raise the horizontal score (p<0.05) and vertical score (p<0.01) in chronic unpredictable mildstress model of rats.
Conclusion: The new TCM SXY-006“SXY-006”has good antidepressant effect.
PartⅡAntidepressant mechanisms of traditional Chinese medicine“SXY-006”
Objective: To investigate antidepressant mechanisms of traditional Chinese medicine“SXY-006”
Methods: The effect of SXY-006 on the times of 5-HTP induced head-twitches and reserpine induced eyes shutting and independence movement were observed. HE stain was applied to observe the morphological change of hippocampal neurons. The expression of the 5-HT2 and c-fos were analyzed by immunohistochemistry experiment.
Results: Different doses of SXY-006 can markedly increase the times of head-twitches induced by 5-HTP of mice (p<0.01). It can antagonize the inability of eyes opening and akinesia evoked by reserpine (p<0.05). In the depression model group, the morphology of neurons in the hippocampus is aberrant, and the expression of 5-HT2 and c-fos increase significantly in parietal cortex and hippocampus. However, SXY-006 improve the morphology of neurons in the hippocampus, and different SXY-006 groups had no changes in the expression of 5-HT2 and c-fos.
Conclusion: The traditional Chinese medicine“SXY-006”exerts antidepressant effect probably through①inhibiting the reuptake of monoamine in synaptic cleft or inhibiting monoaminoxidase,②protecting hippocampal neurons,③decreasing the expression of 5-HT_2 and c-fos.
本文由中药新药SXY-006的抗抑郁作用评价及其抗抑郁机制研究两部分组成,旨在通过一系列经典行为学和形态学实验,对中药新药SXY-006进行抗抑郁作用研究,并探讨其抗抑郁作用的机制,为其投入临床应用提供理论和实验依据。
第一部分中药SXY-006的抗抑郁作用
目的:研究中药SXY-006的抗抑郁作用
方法:通过小鼠悬尾实验、小鼠强迫游泳实验、大鼠单次及多次给药后强迫游泳实验,观察中药SXY-006对实验动物不动时间的影响;通过制作大鼠慢性轻度不可预见性应激(CUMS)抑郁症模型,进行敞箱(open-field)实验,观察SXY-006对实验动物水平得分和垂直得分的影响。
结果:SXY-006中剂量(100 mg/kg)、高剂量(300 mg/kg)均能明显减少小鼠悬尾实验和强迫游泳实验的不动时间(p<0.01); SXY-006低(25 mg/kg)、中(100 mg/kg)、高(300 mg/kg)剂量均能减少大鼠单次和多次给药后强迫游泳实验的不动时间(p<0.05),均能增加大鼠慢性不可预知性应激抑郁症造模后大鼠的水平得分(p<0.05)和垂直得分(p<0.01)。
结论:中药新药SXY-006具有抗抑郁作用
第二部分中药SXY-006抗抑郁作用的机制
目的:研究中药SXY-006抗抑郁作用的机制
方法:通过5-羟色胺酸(5-HTP)诱导的小鼠甩头实验观察SXY-006对小鼠甩头次数的影响;通过利血平引起的小鼠睁眼不能以及运动不能实验观察SXY-006对小鼠眼睑闭合和自主运动的影响;通过HE染色观察海马神经元形态学的变化,免疫组织化学技术检测5-HT2受体、c-fos蛋白的表达。
结果:SXY-006低剂量(25 mg/kg)、中剂量(100 mg/kg)和高剂量(300 mg/kg)均能显著增加5-HTP诱导的甩头实验中小鼠甩头次数(p<0.01),均能拮抗利血平引起的小鼠的睁眼不能和运动不能(p<0.05);抑郁症模型组大鼠海马神经元形态异常,顶叶皮层5-HT2受体、海马c-fos蛋白表达增加,而SXY-006各剂量组大鼠海马神经元形态基本正常,5-HT2受体、c-fos蛋白表达无明显变化。
结论:中药SXY-006的抗抑郁作用可能与其①阻断突触间隙单胺类递质再摄取或抑制单胺氧化酶,②对海马神经元的保护作用,③下调5-HT2受体和c-fos受体的作用有关。
Depression is a common and debilitating thymogenic mental disorder in clinic, characterized by marked and long-lasting depressed mood. Previous studies show that the pathogenesis of depression correlates with the abnormity of neuroendocrine and immune system and the expression of certain genes. Depression is primarily treated by drug therapy. The clinically used medications include selective serotonin reuptake inhibitors(SSRIs, e.g. fluoxetine)、TCAs (e.g. amitripramine) and monoamine oxidase inhibitor (MAOIs, e.g. maclobemide). All of the drugs are effective in treating some subpopulation of depression patients, however, they also have certain side effects or physical dependence, and under some conditions they even aggravate the process. Therefore, it is necessary to find new drug, which has good antidepressive effect and less adverse reaction.
The thesis consists of two parts: preclinical evaluation of the antidepressant efficacy of new TCM SXY-006 and the investigation of its mechanism. By using several behavioral and morphological experiment for antidepressants, the goal of this series of studies is to evaluate the antidepressant effects of SXY-006 and elucidate its mechanisms, thus to provide convinced preclinical information for NDA (New Drug Application).
Part I Antidepressant effects of traditional Chinese medicine“SXY-006”
Objective: To evaluate the antidepressant effects of traditional Chinese medicine“SXY-006”
Methods: The effect of SXY-006 on immobility time was investigated by the tail suspension test and force swimming test of mice or rats after single and multiple administrations. The effect of SXY-006 on horizontal and vertical score was studied through the open-field test after the establishment of chronic unpredictable mild stress (CUMS) model of rats.
Results: Moderate (100 mg/kg) and high (300 mg/kg) doses of SXY-006 can obviously decrease the immobility time in the tail suspension and forced swimming tests of mice (p<0.01). All of SXY-006 in different doses can markedly reduce the immobility time in forced swimming tests of rats after both the single and multiple administrations of the medicine (p<0.05), and raise the horizontal score (p<0.05) and vertical score (p<0.01) in chronic unpredictable mildstress model of rats.
Conclusion: The new TCM SXY-006“SXY-006”has good antidepressant effect.
PartⅡAntidepressant mechanisms of traditional Chinese medicine“SXY-006”
Objective: To investigate antidepressant mechanisms of traditional Chinese medicine“SXY-006”
Methods: The effect of SXY-006 on the times of 5-HTP induced head-twitches and reserpine induced eyes shutting and independence movement were observed. HE stain was applied to observe the morphological change of hippocampal neurons. The expression of the 5-HT2 and c-fos were analyzed by immunohistochemistry experiment.
Results: Different doses of SXY-006 can markedly increase the times of head-twitches induced by 5-HTP of mice (p<0.01). It can antagonize the inability of eyes opening and akinesia evoked by reserpine (p<0.05). In the depression model group, the morphology of neurons in the hippocampus is aberrant, and the expression of 5-HT2 and c-fos increase significantly in parietal cortex and hippocampus. However, SXY-006 improve the morphology of neurons in the hippocampus, and different SXY-006 groups had no changes in the expression of 5-HT2 and c-fos.
Conclusion: The traditional Chinese medicine“SXY-006”exerts antidepressant effect probably through①inhibiting the reuptake of monoamine in synaptic cleft or inhibiting monoaminoxidase,②protecting hippocampal neurons,③decreasing the expression of 5-HT_2 and c-fos.
引文
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