四逆散的有效组分改善睡眠作用的5-HT机制研究
摘要
目的：探讨四逆散的有效组分改善睡眠作用的5-HT机制。
方法：
1.采用戊巴比妥钠协同睡眠实验,以小鼠翻正反射为观测指标,考察了在本实验条件下戊巴比妥钠所致小鼠睡眠的闽上剂量和阈下剂量
2.采用戊巴比妥钠协同睡眠实验,以小鼠睡眠潜伏期和睡眠持续时间为观测指标考察了四逆散的有效组分联合阈上剂量和阈下剂量戊巴比妥钠对小鼠睡眠的影响。
3.运用酶联免疫吸附法对小鼠中枢与睡眠相关脑区(前额叶皮质、下丘脑和海马区)5-HT的含量进行测定。
4.考察四逆散的有效组分联合5-HT合成的前体物质,对小鼠睡眠潜伏期和睡眠持续时间的影响。
5.考察了四逆散的有效组分联合5-HT合成酶的抑制剂,对小鼠睡眠持续时间和睡眠潜伏期的影响。
6.Elisa法测定了四逆散的有效组分对小鼠中枢不同脑区5-HT合成的限速酶色氨酸羟化酶含量的影响。
7.应用酶免试剂盒测定了四逆散的有效组分对小鼠中枢与睡眠相关脑区5-HT的代谢产物5-HIAA的含量的影响并推算出5-HIAA/5-HT的比值。
8.应用RT-PCR技术考察了四逆散的有效组分对小鼠下丘脑5-HT转运体编码基因表达的影响。
9.应用RT-PCR技术考察了四逆散的有效组分对小鼠下丘脑5-HT1A受体编码基因表达的影响。
结果：
1.戊巴比妥钠所致小鼠睡眠阈上、阈下剂量的确定
在确定阈上剂量的研究中,在所设的3个剂量中(55mg/kg、50mg/kg和45mg/kg,i.g.,4days),最终确定阈上剂量为50mg/kg,该剂量下,所有给药小鼠翻正反射均消失。在确定阈下剂量的研究中,在所设的4个剂量中(45mg/kg、40mg/kg、35mg/kg和30mg/kg,i.g.,4days),最终确定阈下剂量为35mg/kg,该剂量下,所有给药小鼠翻正反射均未消失。
2.四逆散四个有效组分混合与单个组分改善睡眠作用的比较研究
实验结果表明,与空白组比较,四逆散四个有效组分混合组、辛弗林组、甘草次酸组和异丙嗪(阳性药)组小鼠睡眠潜伏期明显缩短(P<0.05),睡眠持续时间均显著延长(P<0.05),尤其以四逆散有效组分组和异丙嗪组作用最为明显。另外,溶媒组和空白组比较无论是在睡眠潜伏期和睡眠持续时间上都无明显改变(P>0.05)。
3.四逆散有效组分联合阈下剂量戊巴比妥钠对小鼠睡眠的影响
实验结果显示,腹腔注射阈下剂量的戊巴比妥钠,空白组小鼠无翻正反射消失,异丙嗪组几乎所有小鼠的翻正反射都消失,四逆散有效组分组小鼠的翻正反射消失率66.7%。
4.四逆散有效组分对小鼠不同脑区5-HT含量的影响
实验结果表明,与空白组相比,四逆散有效组分组小鼠前额叶皮质区和下丘脑部位5-HT的浓度明显升高(P<0.05),而海马区的5-HT浓度虽有升高的趋势,但无明显变化(P>0.05)。
5.四逆散有效组分联合阈下剂量5-HTP对戊巴比妥钠所致小鼠睡眠的影响
实验结果表明,与空白组比较,四逆散有效组分组以及5-HTP组小鼠睡眠潜伏期有缩短的趋势,但无显著性差异(P>0.05)；在睡眠持续时间上均有延长的趋势,但统计学上是无显著性的变化(P>0.05),当阈下剂量四逆散和5-HTP联合应用时,与空白组相比,小鼠的睡眠潜伏期明显缩短(P<0.05),睡眠持续时间显著延长(P<0.05)。
6.四逆散有效组分对小鼠不同脑区色氨酸羟化酶(TPH)的含量影响
实验结果表明,与空白组相比,四逆散有效组分组小鼠海马区和下丘脑部位以及前额叶皮质区TPH的浓度均显著升高(P<0.05)。
7.四逆散有效组分联合PCPA对戊巴比妥钠所致小鼠睡眠的影响
睡眠潜伏期的实验结果表明,与空白组比较,四逆散有效组分组小鼠睡眠的潜伏期明显缩短(P<0.05),但是其他组与空白组比较,统计学上无显著性差异(P>0.05)。
睡眠持续时间的实验结果表明,与空白组相比,阈剂量的四逆散有效组分组可以显著延长小鼠睡眠时间(P<0.05)。PCPA组的睡眠持续时间明显缩短(P<0.05)。当四逆散有效组分联合PCPA组给药时,小鼠的睡眠时间与四逆散有效组分相比明显缩短(P<0.05),睡眠持续时间接近空白组小鼠。
8.四逆散有效组分对小鼠不同脑区5-HIAA含量以及5-HIAA/5-HT比值的影响
实验结果表明,与空白组相比,四逆散有效组分组小鼠前额叶皮质脑区和下丘脑部位的5-HIAA浓度显著升高(P<0.05),海马部位5-HIAA的浓度虽然都有升高的趋势,但是统计学上无显著性差异(P>0.05)。
与空白组相比,四逆散有效组分组小鼠前额叶皮质脑区和下丘脑部位的5-HIAA/5-HT比值显著升高(P<0.05),海马区的5-HIAA/5-HT比值虽有上升的趋势,但是在统计学上无显著性差异(P>0.05)。
9.四逆散有效组分对小鼠下丘脑Slc6a4(5-HT转运体)编码基因和Htr1a (5-HT1A受体)编码基因基因表达的影响
实验结果表明,与空白组相比,给药组小鼠下丘脑部位Slc6a4基因表达明显降低,而Htr1a基因表达显著升高。
结论：四逆散的有效组分通过5-HT能神经系统来发挥改善睡眠的作用。
Clinical practice and basic experiments showed that traditional compound Chinese medicine SNS has significant improvements in sleep, but the mechanism in improving sleep is not clear. Earlier studies about the mechanism of SNS almost based on multiple-targets in the organs or nervous systems. There is no in-depth study about it. The present research based on5-HTergic nervous system to investigate the mechanism of sleep improvement of SNS. In the first section, the experiment began with sodium pentobarbital collaborative experiment, which was to definite the suprathreshold dose and the subthreshold dose in mice. Then, compared the potency of both the combined active priciples and single active priciple. After that the impact of active priciples of SNS combined with the subthreshold dose sodium pentobarbital on the sleep of mice was studied. In the second section, sodium pentobarbital collaborative experiment, enzyme linked immunosorbent assay and RT-PCR were used to clarify the mechanism of SNS in improving sleep. The present study from multiple perspectives(synthetic and metabolic of5-HT,5-HT transmitter and5-HT receptor) to investigate the mechanism of SNS.
The results:
1. determine threshold dose of sodium pentobarbital in mice. In the established three dose(55mg/kg、50mg/kg and45mg/kg, i.g.,4days), the suprathreshold dose of sodium pentobarbital was50mg/kg. Injecting with this dose the righting reflex of all the mice was abolition. In the established four dose(45mg/kg、40mg/kg、35mg/kg and30mg/kg, i.g.,4days), the subthreshold dose of sodium pentobarbital was35mg/kg. Injecting with this dose the righting reflex of all the mice was not abolition.
2. Compared the potency of both the combined active priciples and single active priciple.
Compared with vehicle group, the sleep latence of mice in the combined active priciples group, synephrine group enoxolone group and promethazine group significantly shorted (P<0.05), while sleep duration of mice in the4groups increased obviously (P<0.05). Combined active priciples group and promethazine group showed the best potency. Additionally, solvent group showed no significance either in sleep latence nor in sleep duration (P>0.05)
3. Impact of subthreshold doses of sodium pentobarbital combined with SNS active priciples and single active priciple on sleep in mice.
The results indicated that after injecting subthreshold doses of sodium pentobarbital, mice in vehicle group showed no righting reflex abolition, while almost all the mice in promethazine group showed righting reflex abolition. The proportion of righting reflex abolition in SNS active priciples group was66.7%.
4. Impact of SNS active priciples on concentration of5-HT in the brain of mice.
Compared with vehicle group, the concentration of5-HT in cortex of frontal lobe and hypothalamus of mice in SNS active priciples group increased obviously (P<0.05). however, there was a tendency to increase, the concentration of5-HT in hippocampus did not show significance (P>0.05)
5. Impact of SNS active priciples combined with5-HTP on sleep latency and sleep duration.
However mice in Subthreshold doses of SNS active priciples group and5-HTP group showed the tendency to increase in sleep duration and to decrease in sleep latency, there is no significance (P>0.05). when SNS active priciples group combined application of5-HT precursor5-HTP can significantly prolong sodium pentobarbital-induced sleep duration (P<0.05) and short the sleep latency (P<0.05) in mice, which showing a certain synergy.
6. Impact of SNS active priciples on concentration of TPH in the brain of mice.
Compared with vehicle group, the concentration of TPH in cortex of frontal lobe, hippocampus and hypothalamus of mice in SNS active priciples group increased obviously (P<0.05)
7. Impact of SNS active priciples combined with PCPA on sleep latency and sleep duration.
Compared with vehicle group, mice in SNS active priciples group showed shorter sleep latency (P<0.05). There was no significance among other groups (P>0.05)
Compared with vehicle group, mice in SNS active priciples group showed longer sleep duration (P<0.05) while mice in PCPA group showed shorter sleep duration (P<0.05). The potency of SNS prolongs sodium pentobarbital-induced sleep time in mice can interdiction by PCPA(compared with SNS active priciples group, P<0.05). The sleep duration of mice in SNS active priciples combined PCPA group approach to the vehicle group.
8. Impact of SNS active priciples on the concentration of5-HIAA and the ratio of5-HIAA/5-HT in the brain of mice.
Compared with vehicle group, the concentration of5-HIAA in cortex of frontal lobe and hypothalamus of mice in SNS active priciples group increased obviously (P<0.05). however, there was a tendency to increase, the concentration of5-HIAA in hippocampus did not show significance (P>0.05)
Also compared with vehicle group, the ratio of5-HIAA/5-HT in cortex of frontal lobe and hypothalamus of mice in SNS active priciples group increased obviously (P<0.05). however, there was a tendency to increase, the ratio of5-HIAA/5-HT in hippocampus did not show significance (P>0.05)
9. Impact of SNS active priciples on the gene of Slc6a4and Htrla.
Compared with vehicle group, the expression of Htr1a gene markedly increased while the expression of Slc6a4gene significantly decreased of mice in SNS active priciples group.
Summary:
Based on the above results that SNS active priciples improves sleep through increasing5-HT in various of regions of the brain. SNS active priciples can affect the synthesis, rate-limiting enzyme, metabolic, transmitter and receptor of5-HT in the brain.
方法：
1.采用戊巴比妥钠协同睡眠实验,以小鼠翻正反射为观测指标,考察了在本实验条件下戊巴比妥钠所致小鼠睡眠的闽上剂量和阈下剂量
2.采用戊巴比妥钠协同睡眠实验,以小鼠睡眠潜伏期和睡眠持续时间为观测指标考察了四逆散的有效组分联合阈上剂量和阈下剂量戊巴比妥钠对小鼠睡眠的影响。
3.运用酶联免疫吸附法对小鼠中枢与睡眠相关脑区(前额叶皮质、下丘脑和海马区)5-HT的含量进行测定。
4.考察四逆散的有效组分联合5-HT合成的前体物质,对小鼠睡眠潜伏期和睡眠持续时间的影响。
5.考察了四逆散的有效组分联合5-HT合成酶的抑制剂,对小鼠睡眠持续时间和睡眠潜伏期的影响。
6.Elisa法测定了四逆散的有效组分对小鼠中枢不同脑区5-HT合成的限速酶色氨酸羟化酶含量的影响。
7.应用酶免试剂盒测定了四逆散的有效组分对小鼠中枢与睡眠相关脑区5-HT的代谢产物5-HIAA的含量的影响并推算出5-HIAA/5-HT的比值。
8.应用RT-PCR技术考察了四逆散的有效组分对小鼠下丘脑5-HT转运体编码基因表达的影响。
9.应用RT-PCR技术考察了四逆散的有效组分对小鼠下丘脑5-HT1A受体编码基因表达的影响。
结果：
1.戊巴比妥钠所致小鼠睡眠阈上、阈下剂量的确定
在确定阈上剂量的研究中,在所设的3个剂量中(55mg/kg、50mg/kg和45mg/kg,i.g.,4days),最终确定阈上剂量为50mg/kg,该剂量下,所有给药小鼠翻正反射均消失。在确定阈下剂量的研究中,在所设的4个剂量中(45mg/kg、40mg/kg、35mg/kg和30mg/kg,i.g.,4days),最终确定阈下剂量为35mg/kg,该剂量下,所有给药小鼠翻正反射均未消失。
2.四逆散四个有效组分混合与单个组分改善睡眠作用的比较研究
实验结果表明,与空白组比较,四逆散四个有效组分混合组、辛弗林组、甘草次酸组和异丙嗪(阳性药)组小鼠睡眠潜伏期明显缩短(P<0.05),睡眠持续时间均显著延长(P<0.05),尤其以四逆散有效组分组和异丙嗪组作用最为明显。另外,溶媒组和空白组比较无论是在睡眠潜伏期和睡眠持续时间上都无明显改变(P>0.05)。
3.四逆散有效组分联合阈下剂量戊巴比妥钠对小鼠睡眠的影响
实验结果显示,腹腔注射阈下剂量的戊巴比妥钠,空白组小鼠无翻正反射消失,异丙嗪组几乎所有小鼠的翻正反射都消失,四逆散有效组分组小鼠的翻正反射消失率66.7%。
4.四逆散有效组分对小鼠不同脑区5-HT含量的影响
实验结果表明,与空白组相比,四逆散有效组分组小鼠前额叶皮质区和下丘脑部位5-HT的浓度明显升高(P<0.05),而海马区的5-HT浓度虽有升高的趋势,但无明显变化(P>0.05)。
5.四逆散有效组分联合阈下剂量5-HTP对戊巴比妥钠所致小鼠睡眠的影响
实验结果表明,与空白组比较,四逆散有效组分组以及5-HTP组小鼠睡眠潜伏期有缩短的趋势,但无显著性差异(P>0.05)；在睡眠持续时间上均有延长的趋势,但统计学上是无显著性的变化(P>0.05),当阈下剂量四逆散和5-HTP联合应用时,与空白组相比,小鼠的睡眠潜伏期明显缩短(P<0.05),睡眠持续时间显著延长(P<0.05)。
6.四逆散有效组分对小鼠不同脑区色氨酸羟化酶(TPH)的含量影响
实验结果表明,与空白组相比,四逆散有效组分组小鼠海马区和下丘脑部位以及前额叶皮质区TPH的浓度均显著升高(P<0.05)。
7.四逆散有效组分联合PCPA对戊巴比妥钠所致小鼠睡眠的影响
睡眠潜伏期的实验结果表明,与空白组比较,四逆散有效组分组小鼠睡眠的潜伏期明显缩短(P<0.05),但是其他组与空白组比较,统计学上无显著性差异(P>0.05)。
睡眠持续时间的实验结果表明,与空白组相比,阈剂量的四逆散有效组分组可以显著延长小鼠睡眠时间(P<0.05)。PCPA组的睡眠持续时间明显缩短(P<0.05)。当四逆散有效组分联合PCPA组给药时,小鼠的睡眠时间与四逆散有效组分相比明显缩短(P<0.05),睡眠持续时间接近空白组小鼠。
8.四逆散有效组分对小鼠不同脑区5-HIAA含量以及5-HIAA/5-HT比值的影响
实验结果表明,与空白组相比,四逆散有效组分组小鼠前额叶皮质脑区和下丘脑部位的5-HIAA浓度显著升高(P<0.05),海马部位5-HIAA的浓度虽然都有升高的趋势,但是统计学上无显著性差异(P>0.05)。
与空白组相比,四逆散有效组分组小鼠前额叶皮质脑区和下丘脑部位的5-HIAA/5-HT比值显著升高(P<0.05),海马区的5-HIAA/5-HT比值虽有上升的趋势,但是在统计学上无显著性差异(P>0.05)。
9.四逆散有效组分对小鼠下丘脑Slc6a4(5-HT转运体)编码基因和Htr1a (5-HT1A受体)编码基因基因表达的影响
实验结果表明,与空白组相比,给药组小鼠下丘脑部位Slc6a4基因表达明显降低,而Htr1a基因表达显著升高。
结论：四逆散的有效组分通过5-HT能神经系统来发挥改善睡眠的作用。
Clinical practice and basic experiments showed that traditional compound Chinese medicine SNS has significant improvements in sleep, but the mechanism in improving sleep is not clear. Earlier studies about the mechanism of SNS almost based on multiple-targets in the organs or nervous systems. There is no in-depth study about it. The present research based on5-HTergic nervous system to investigate the mechanism of sleep improvement of SNS. In the first section, the experiment began with sodium pentobarbital collaborative experiment, which was to definite the suprathreshold dose and the subthreshold dose in mice. Then, compared the potency of both the combined active priciples and single active priciple. After that the impact of active priciples of SNS combined with the subthreshold dose sodium pentobarbital on the sleep of mice was studied. In the second section, sodium pentobarbital collaborative experiment, enzyme linked immunosorbent assay and RT-PCR were used to clarify the mechanism of SNS in improving sleep. The present study from multiple perspectives(synthetic and metabolic of5-HT,5-HT transmitter and5-HT receptor) to investigate the mechanism of SNS.
The results:
1. determine threshold dose of sodium pentobarbital in mice. In the established three dose(55mg/kg、50mg/kg and45mg/kg, i.g.,4days), the suprathreshold dose of sodium pentobarbital was50mg/kg. Injecting with this dose the righting reflex of all the mice was abolition. In the established four dose(45mg/kg、40mg/kg、35mg/kg and30mg/kg, i.g.,4days), the subthreshold dose of sodium pentobarbital was35mg/kg. Injecting with this dose the righting reflex of all the mice was not abolition.
2. Compared the potency of both the combined active priciples and single active priciple.
Compared with vehicle group, the sleep latence of mice in the combined active priciples group, synephrine group enoxolone group and promethazine group significantly shorted (P<0.05), while sleep duration of mice in the4groups increased obviously (P<0.05). Combined active priciples group and promethazine group showed the best potency. Additionally, solvent group showed no significance either in sleep latence nor in sleep duration (P>0.05)
3. Impact of subthreshold doses of sodium pentobarbital combined with SNS active priciples and single active priciple on sleep in mice.
The results indicated that after injecting subthreshold doses of sodium pentobarbital, mice in vehicle group showed no righting reflex abolition, while almost all the mice in promethazine group showed righting reflex abolition. The proportion of righting reflex abolition in SNS active priciples group was66.7%.
4. Impact of SNS active priciples on concentration of5-HT in the brain of mice.
Compared with vehicle group, the concentration of5-HT in cortex of frontal lobe and hypothalamus of mice in SNS active priciples group increased obviously (P<0.05). however, there was a tendency to increase, the concentration of5-HT in hippocampus did not show significance (P>0.05)
5. Impact of SNS active priciples combined with5-HTP on sleep latency and sleep duration.
However mice in Subthreshold doses of SNS active priciples group and5-HTP group showed the tendency to increase in sleep duration and to decrease in sleep latency, there is no significance (P>0.05). when SNS active priciples group combined application of5-HT precursor5-HTP can significantly prolong sodium pentobarbital-induced sleep duration (P<0.05) and short the sleep latency (P<0.05) in mice, which showing a certain synergy.
6. Impact of SNS active priciples on concentration of TPH in the brain of mice.
Compared with vehicle group, the concentration of TPH in cortex of frontal lobe, hippocampus and hypothalamus of mice in SNS active priciples group increased obviously (P<0.05)
7. Impact of SNS active priciples combined with PCPA on sleep latency and sleep duration.
Compared with vehicle group, mice in SNS active priciples group showed shorter sleep latency (P<0.05). There was no significance among other groups (P>0.05)
Compared with vehicle group, mice in SNS active priciples group showed longer sleep duration (P<0.05) while mice in PCPA group showed shorter sleep duration (P<0.05). The potency of SNS prolongs sodium pentobarbital-induced sleep time in mice can interdiction by PCPA(compared with SNS active priciples group, P<0.05). The sleep duration of mice in SNS active priciples combined PCPA group approach to the vehicle group.
8. Impact of SNS active priciples on the concentration of5-HIAA and the ratio of5-HIAA/5-HT in the brain of mice.
Compared with vehicle group, the concentration of5-HIAA in cortex of frontal lobe and hypothalamus of mice in SNS active priciples group increased obviously (P<0.05). however, there was a tendency to increase, the concentration of5-HIAA in hippocampus did not show significance (P>0.05)
Also compared with vehicle group, the ratio of5-HIAA/5-HT in cortex of frontal lobe and hypothalamus of mice in SNS active priciples group increased obviously (P<0.05). however, there was a tendency to increase, the ratio of5-HIAA/5-HT in hippocampus did not show significance (P>0.05)
9. Impact of SNS active priciples on the gene of Slc6a4and Htrla.
Compared with vehicle group, the expression of Htr1a gene markedly increased while the expression of Slc6a4gene significantly decreased of mice in SNS active priciples group.
Summary:
Based on the above results that SNS active priciples improves sleep through increasing5-HT in various of regions of the brain. SNS active priciples can affect the synthesis, rate-limiting enzyme, metabolic, transmitter and receptor of5-HT in the brain.
引文
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