地黄、苏合香对大鼠早期肝性脑病的神经保护作用
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摘要
肝性脑病(Hepatic encephalopathy, HE)是由肝脏功能严重障碍引起的以代谢紊乱为基础的中枢神经系统功能失调综合征。患者的主要临床表现包括性格和睡眠-清醒循环改变,认知功能障碍和运动状态的改变等。HE的病因很多,但最终后果是以氨为主的多种毒性物质在血内的聚集、假性神经递质生成、氨基酸比例失衡、γ-氨基丁酸／苯二氮卓(GABA/BZ)受体增多等。目前公认氨中毒仍是HE发病机制的主要因素,高血氨可使脑内一些神经递质浓度发生变化,干扰神经递质间平衡,因而导致中枢神经系统的功能紊乱。血氨可激活外周型苯二氮卓受体PBRs,增加其结合位点,刺激神经激素产生,这些神经激素能扩大GABA的作用。近期一些研究还表明,高血氨和炎症反应共同作用引起HE认知功能障碍。
目前,HE的发病机制仍不十分明确,对HE的治疗亦缺乏有效手段,虽然有许多西药用于临床治疗肝性脑病,但主要还是仿制国外产品,尚存在着适应不良和副作用,因此,越来越多的研究将重点转移到中草药,原因是中草药来源于天然,比合成药物更安全。而且中草药的成分复杂,对于病理机制复杂的疾病,可能具有更好的疗效。此外,中草药的代谢谱对于药物活性成分筛选具有重要价值,为药物的研发及作用机制阐述提供了线索。在本研究中,我们将地黄、苏合香提取物(Rehmannia&storesin extracts, RS,以下简称地苏合剂)用于治疗四氯化碳(CCl4)诱导的HE大鼠,同时使用乳果糖(Lactulose)作为阳性对照药,观察RS治疗是否能对早期HE大鼠模型起到神经保护作用,在整体水平评价RS的治疗效果,并探讨其作用机制,为开发安全有效的防治HE的新药提供依据。
1.地苏合剂是一种含有多种成分的混合物。其中具有芳香开窍作用的苏合香,其主要成分由高效液相色谱(high performance liquid chromatography, HPLC)显示。
2.成年Wistar大鼠随机分为6组(n=10×6)：(1)对照组(Control);(2)模型组(Model);(3)阳性药乳果糖组(Lactulose)(6g/kg, i.g)；(4)地苏合剂低剂量(RS-L)组(地黄提取物0.5g/kg+苏合香0.008g/kg, i.g.);(5)地苏合剂中剂量组(RS-M)(地黄提取物1g/kg+苏合香0.016g/kg, i.g.);(6)地苏合剂高剂量组(RS-H)(地黄提取物2g/kg+苏合香0.032g/kg, i.g.)。除正常对照组外,其余组采用经典的CCl4诱发肝纤维化模型(50%CCl41ml/kg, i.g.),每周2次,连续12周。
3.实验过程中大鼠每周测体重一次,实验结束时模型组大鼠体重明显低于对照组(P<0.01),经过阳性药和地苏合剂治疗后,乳果糖组和RS-H组大鼠的体重与模型组相比有明显改善(P<0.05)。
4.行为学实验结果显示：①模型组大鼠自发运动总距离较对照组显著减少(P<0.01),乳果糖组(P<0.01)和RS-H组(P<0.05)明显改善；模型组大鼠自发运动跨格次数较对照组显著减少(P<0.01),乳果糖组(P<0.05)明显改善,RS组的跨格次数较模型组增加,但并无统计学差异；模型组大鼠在中心场的停留时间较对照组显著缩短(P<0.01),RS-H组大鼠在中心场的停留时间明显延长(P<0.05)；模型组大鼠直立次数较对照组显著减少(P<0.01),乳果糖和RS治疗后直立次数增加,但无统计学差异。②Morris水迷宫实验中,在连续训练的几天内,随着训练次数的增加,各组动物的寻台潜伏期缩短。末次实验中,模型组大鼠寻台潜伏期较对照组显著延长(P<0.01),乳果糖治疗组和RS-H组大鼠寻台潜伏期较模型组明显缩短(P<0.05)；模型组大鼠游泳速度减慢,但差异没有达到统计学意义。模型组大鼠在十字高架迷宫实验中进入开放臂的次数与对照组相比显著减少(P<0.05),乳果糖和RS治疗后进入开放臂次数增加,但无统计学差异；模型组大鼠进入开放臂的时间与对照组相比减少,但各组间无统计学差异。与对照组相比,模型组大鼠的Y迷宫正确选择率有所下降,但未达到统计学差异标准。以上实验证明RS可以增加HE大鼠自发活动,改善其学习记忆能力。
5.实验结束后各组大鼠肝脏湿重与对照组相比所得肝指数,模型组大鼠较对照组显著降低(P<0.01),乳果糖治疗组、RS-M组和RS-H组大鼠肝指数较模型组明显升高(P<0.05)；模型组大鼠脾指数较对照组显著升高(P<0.01), RS-M组大鼠脾指数较模型组明显降低(P<0.05)。
6.生化学检测结果显示：模型组大鼠ALT、Amm、NO、TNOS和iNOS水平较对照组均显著升高(P<0.01),乳果糖组和RS组大鼠ALT、Amm、TNOS和iNOS水平较模型组明显降低(P<0.01,P<0.05)。模型组大鼠血清AST水平有所升高,但未达到统计学差异标准。模型组大鼠总蛋白水平较对照组显著降低(P<0.05),其余各组间无统计学差异。模型组大鼠白蛋白水平较对照组显著降低(P<0.01),乳果糖组和RS治疗组大鼠白蛋白水平较模型组有不同程度的升高。
7. ELISA结果显示：模型组大鼠TNF-α水平较对照组显著升高(P<0.01),乳果糖组(P<0.01)、RS-M组(P<0.05)和RS-H组(P<0.01)大鼠TNF-α水平较模型组明显降低。
8.受体活性检测结果显示：模型组大鼠PBRs和NMDA受体的结合位点均显著增加,Bmax值较对照组明显升高(P<0.01),乳果糖组和RS-H组大鼠Bmax值较模型组明显降低(P<0.01)。
9.形态学结果显示：肝脏HE染色提示,模型组大鼠可见肝硬化表现。乳果糖组及RS治疗组大鼠肝细胞变性和坏死程度显著减轻。与对照组相比,模型组大鼠脑海马BrdU、NeuN和GFAP阳性细胞数显著下降(P<0.01),乳果糖组和RS治疗组较模型组有不同程度增加。本研究结果证实,地苏合剂能够在一定程度上提高HE大鼠自发运动次数和学习记忆能力；减轻CCl4诱导的肝损伤,治疗肝硬化；解除脑内氨毒性作用,抑制脑内PBRs和NMDA受体结合位点的增加,促进海马区神经发生,促进神经干细胞增殖和分化,延缓HE的发生和发展,并为开发安全有效的神经保护新药提供了重要的实验依据。
Hepatic encephalopathy (HE) is defined as a disturbance in central nervous system function because of hepatic insufficiency. This broad definition reflects the existence of a spectrum of neuropsychiatric manifestations from minimal changes in personality or altered sleep-waking cycle to altered cognitive function and motor activity and coordination.
The main tenet of all theories of the pathogenesis of HE is firmly accepted: nitrogenous substances derived from the gut adversely affect brain function. These compounds gain access to the systemic circulation as a result of decreased hepatic function. Once in brain tissue, they produce alterations of neurotransmission that affect consciousness and behavior. A large body of work points at ammonia as a key factor in the pathogenesis of HE. Furthermore, the alterations in neurotransmission induced by ammonia also occur after the metabolism of this toxin into astrocytes, resulting in a series of neurochemical events caused by the functioning alteration of this cell. Ammonia activates peripheral-type benzodiazepine receptors with subsequent stimulation of the GABA-ergic system, an effect also induced directly by ammonia. Recent reports support the idea that hyperammonemia and inflammation cooperate in inducing the neurological alterations in HE.
At present, the mechanisms of HE are still unclear, and there is no definitive treatment or cure for HE. A large segment of the public findings solace in herbs, in part believing that herbs are natural and hence safer than synthetic drugs, and that a complex mixture of herbs can effectively treat complex diseases. In addition, the metabolite profile of herbal medicine is important for screening its active constituents, thus providing a valuable contribution to the drug discovery process and elucidation of the underlying mechanism of action. In the present study, the neuroprotective effect of RS against CCl4-induced impairment was observed in vivo. We used RS to treat the rats i.g. with CCl4, lactulose as the positive conrol. The results suggested RS could be considered as a potential agent for preventing or retarding the development or progression of HE.
1. There were multiple components in RS. The main components of Storesin were analyzed by HPLC.
2. The animals were randomly distributed in the following groups:control, model, lactulose (i.g. treated with lactulose6g/kg), RS-L (i.g. treated with R:0.5+S:0.008g/kg), RS-M (i.g. treated with R:1.0+S:0.016g/kg) and RS-H (i.g. treated with R:2.0+S:0.032g/kg). To induce hepatic encephalopathy, all the rats except the ones in control group were treated with a mixture of CCl4and olive oil (1:1vol/vol, at a dose of1ml/kg) by a gavage tube twice a week for12weeks. Control animals were treated with the solvent alone.
3. The weight of rats was monitored every week. The body weight changed since the3rd week. There was a significant weight loss in model animals compared with control group (P<0.01). The RS-H treatment significantly reversed the changes of the body weight (P<0.05).
4. Total distances, square crossing times, times in inner zone and rearing frequency in open field test revealed a significant decrease (P<0.01) for the model group in comparison to the control group. RS-H-treated rats exhibited longer distance than that of the model (P<0.05). RS treatment inreased the square crossing times and rearing frequeny, but the improvement did not achieve statistical significance. Morris water maze data showed that model animals exhibited obviously longer escape latencies. The lactulose and RS-H significantly shortened escape latenies (P<0.05). The swim speed of model rats slowed down. The model rats exhibited a decreased OE of EPM(P<0.05).
5. The hepatosomatic index significantly decreased in model rats compared with control group (P<0.01), and the RS-M and RS-H treatment effectively increased the hepatosomatic index (P<0.05); the spleen index significantly increased in model rats compared with control group (P<0.01), and the RS-M treatment effectively decreased the spleen index (P<0.05).
6. The level of serum ALT、Amm、NO、TNOS and iNOS significantly increased in model rats compared with control group (P<0.01), which could be decreased by RS treatment. The level of serum total protein and albumin decreased compared with control group (P<0.05, P<0.01), RS treatment could improve these indexes without statistical significance.
7. ELISA results indicated the TNF-a level significantly increased compared with control group (P<0.01), which was decreased by RS-M and RS-H treatment (P<0.05, P<0.01)
8. Our findings showed that compared with control group, there was a significant increase in the Bmax value of both PBRs and NMDA-R (P<0.01), which was reduced by RS-H treatment (P<0.01).
9. Immunohistostaining results indicated liver cirrhosis in model group, RS treatment reduced the cell degeneration and necrosis. Compared with control group, the number of BrdU, NeuN and GFAP positive cells in model rats hippocampus decreased (P<0.01), RS treatment could increased the number of positive cells.
The results of presnet study incicate that RS treatment leads to the increase of spontaneous movement and the improvement of learning and memory ability; mitigates the liver damage induced by CCl4; ablates the toxic effect caused by hyperammonemia, inhibits the increase of both PBRs and NMDA receptors, promotes hippocampal neurogenesis and the proliferation and differentiation of NSC.
目前,HE的发病机制仍不十分明确,对HE的治疗亦缺乏有效手段,虽然有许多西药用于临床治疗肝性脑病,但主要还是仿制国外产品,尚存在着适应不良和副作用,因此,越来越多的研究将重点转移到中草药,原因是中草药来源于天然,比合成药物更安全。而且中草药的成分复杂,对于病理机制复杂的疾病,可能具有更好的疗效。此外,中草药的代谢谱对于药物活性成分筛选具有重要价值,为药物的研发及作用机制阐述提供了线索。在本研究中,我们将地黄、苏合香提取物(Rehmannia&storesin extracts, RS,以下简称地苏合剂)用于治疗四氯化碳(CCl4)诱导的HE大鼠,同时使用乳果糖(Lactulose)作为阳性对照药,观察RS治疗是否能对早期HE大鼠模型起到神经保护作用,在整体水平评价RS的治疗效果,并探讨其作用机制,为开发安全有效的防治HE的新药提供依据。
1.地苏合剂是一种含有多种成分的混合物。其中具有芳香开窍作用的苏合香,其主要成分由高效液相色谱(high performance liquid chromatography, HPLC)显示。
2.成年Wistar大鼠随机分为6组(n=10×6)：(1)对照组(Control);(2)模型组(Model);(3)阳性药乳果糖组(Lactulose)(6g/kg, i.g)；(4)地苏合剂低剂量(RS-L)组(地黄提取物0.5g/kg+苏合香0.008g/kg, i.g.);(5)地苏合剂中剂量组(RS-M)(地黄提取物1g/kg+苏合香0.016g/kg, i.g.);(6)地苏合剂高剂量组(RS-H)(地黄提取物2g/kg+苏合香0.032g/kg, i.g.)。除正常对照组外,其余组采用经典的CCl4诱发肝纤维化模型(50%CCl41ml/kg, i.g.),每周2次,连续12周。
3.实验过程中大鼠每周测体重一次,实验结束时模型组大鼠体重明显低于对照组(P<0.01),经过阳性药和地苏合剂治疗后,乳果糖组和RS-H组大鼠的体重与模型组相比有明显改善(P<0.05)。
4.行为学实验结果显示：①模型组大鼠自发运动总距离较对照组显著减少(P<0.01),乳果糖组(P<0.01)和RS-H组(P<0.05)明显改善；模型组大鼠自发运动跨格次数较对照组显著减少(P<0.01),乳果糖组(P<0.05)明显改善,RS组的跨格次数较模型组增加,但并无统计学差异；模型组大鼠在中心场的停留时间较对照组显著缩短(P<0.01),RS-H组大鼠在中心场的停留时间明显延长(P<0.05)；模型组大鼠直立次数较对照组显著减少(P<0.01),乳果糖和RS治疗后直立次数增加,但无统计学差异。②Morris水迷宫实验中,在连续训练的几天内,随着训练次数的增加,各组动物的寻台潜伏期缩短。末次实验中,模型组大鼠寻台潜伏期较对照组显著延长(P<0.01),乳果糖治疗组和RS-H组大鼠寻台潜伏期较模型组明显缩短(P<0.05)；模型组大鼠游泳速度减慢,但差异没有达到统计学意义。模型组大鼠在十字高架迷宫实验中进入开放臂的次数与对照组相比显著减少(P<0.05),乳果糖和RS治疗后进入开放臂次数增加,但无统计学差异；模型组大鼠进入开放臂的时间与对照组相比减少,但各组间无统计学差异。与对照组相比,模型组大鼠的Y迷宫正确选择率有所下降,但未达到统计学差异标准。以上实验证明RS可以增加HE大鼠自发活动,改善其学习记忆能力。
5.实验结束后各组大鼠肝脏湿重与对照组相比所得肝指数,模型组大鼠较对照组显著降低(P<0.01),乳果糖治疗组、RS-M组和RS-H组大鼠肝指数较模型组明显升高(P<0.05)；模型组大鼠脾指数较对照组显著升高(P<0.01), RS-M组大鼠脾指数较模型组明显降低(P<0.05)。
6.生化学检测结果显示：模型组大鼠ALT、Amm、NO、TNOS和iNOS水平较对照组均显著升高(P<0.01),乳果糖组和RS组大鼠ALT、Amm、TNOS和iNOS水平较模型组明显降低(P<0.01,P<0.05)。模型组大鼠血清AST水平有所升高,但未达到统计学差异标准。模型组大鼠总蛋白水平较对照组显著降低(P<0.05),其余各组间无统计学差异。模型组大鼠白蛋白水平较对照组显著降低(P<0.01),乳果糖组和RS治疗组大鼠白蛋白水平较模型组有不同程度的升高。
7. ELISA结果显示：模型组大鼠TNF-α水平较对照组显著升高(P<0.01),乳果糖组(P<0.01)、RS-M组(P<0.05)和RS-H组(P<0.01)大鼠TNF-α水平较模型组明显降低。
8.受体活性检测结果显示：模型组大鼠PBRs和NMDA受体的结合位点均显著增加,Bmax值较对照组明显升高(P<0.01),乳果糖组和RS-H组大鼠Bmax值较模型组明显降低(P<0.01)。
9.形态学结果显示：肝脏HE染色提示,模型组大鼠可见肝硬化表现。乳果糖组及RS治疗组大鼠肝细胞变性和坏死程度显著减轻。与对照组相比,模型组大鼠脑海马BrdU、NeuN和GFAP阳性细胞数显著下降(P<0.01),乳果糖组和RS治疗组较模型组有不同程度增加。本研究结果证实,地苏合剂能够在一定程度上提高HE大鼠自发运动次数和学习记忆能力；减轻CCl4诱导的肝损伤,治疗肝硬化；解除脑内氨毒性作用,抑制脑内PBRs和NMDA受体结合位点的增加,促进海马区神经发生,促进神经干细胞增殖和分化,延缓HE的发生和发展,并为开发安全有效的神经保护新药提供了重要的实验依据。
Hepatic encephalopathy (HE) is defined as a disturbance in central nervous system function because of hepatic insufficiency. This broad definition reflects the existence of a spectrum of neuropsychiatric manifestations from minimal changes in personality or altered sleep-waking cycle to altered cognitive function and motor activity and coordination.
The main tenet of all theories of the pathogenesis of HE is firmly accepted: nitrogenous substances derived from the gut adversely affect brain function. These compounds gain access to the systemic circulation as a result of decreased hepatic function. Once in brain tissue, they produce alterations of neurotransmission that affect consciousness and behavior. A large body of work points at ammonia as a key factor in the pathogenesis of HE. Furthermore, the alterations in neurotransmission induced by ammonia also occur after the metabolism of this toxin into astrocytes, resulting in a series of neurochemical events caused by the functioning alteration of this cell. Ammonia activates peripheral-type benzodiazepine receptors with subsequent stimulation of the GABA-ergic system, an effect also induced directly by ammonia. Recent reports support the idea that hyperammonemia and inflammation cooperate in inducing the neurological alterations in HE.
At present, the mechanisms of HE are still unclear, and there is no definitive treatment or cure for HE. A large segment of the public findings solace in herbs, in part believing that herbs are natural and hence safer than synthetic drugs, and that a complex mixture of herbs can effectively treat complex diseases. In addition, the metabolite profile of herbal medicine is important for screening its active constituents, thus providing a valuable contribution to the drug discovery process and elucidation of the underlying mechanism of action. In the present study, the neuroprotective effect of RS against CCl4-induced impairment was observed in vivo. We used RS to treat the rats i.g. with CCl4, lactulose as the positive conrol. The results suggested RS could be considered as a potential agent for preventing or retarding the development or progression of HE.
1. There were multiple components in RS. The main components of Storesin were analyzed by HPLC.
2. The animals were randomly distributed in the following groups:control, model, lactulose (i.g. treated with lactulose6g/kg), RS-L (i.g. treated with R:0.5+S:0.008g/kg), RS-M (i.g. treated with R:1.0+S:0.016g/kg) and RS-H (i.g. treated with R:2.0+S:0.032g/kg). To induce hepatic encephalopathy, all the rats except the ones in control group were treated with a mixture of CCl4and olive oil (1:1vol/vol, at a dose of1ml/kg) by a gavage tube twice a week for12weeks. Control animals were treated with the solvent alone.
3. The weight of rats was monitored every week. The body weight changed since the3rd week. There was a significant weight loss in model animals compared with control group (P<0.01). The RS-H treatment significantly reversed the changes of the body weight (P<0.05).
4. Total distances, square crossing times, times in inner zone and rearing frequency in open field test revealed a significant decrease (P<0.01) for the model group in comparison to the control group. RS-H-treated rats exhibited longer distance than that of the model (P<0.05). RS treatment inreased the square crossing times and rearing frequeny, but the improvement did not achieve statistical significance. Morris water maze data showed that model animals exhibited obviously longer escape latencies. The lactulose and RS-H significantly shortened escape latenies (P<0.05). The swim speed of model rats slowed down. The model rats exhibited a decreased OE of EPM(P<0.05).
5. The hepatosomatic index significantly decreased in model rats compared with control group (P<0.01), and the RS-M and RS-H treatment effectively increased the hepatosomatic index (P<0.05); the spleen index significantly increased in model rats compared with control group (P<0.01), and the RS-M treatment effectively decreased the spleen index (P<0.05).
6. The level of serum ALT、Amm、NO、TNOS and iNOS significantly increased in model rats compared with control group (P<0.01), which could be decreased by RS treatment. The level of serum total protein and albumin decreased compared with control group (P<0.05, P<0.01), RS treatment could improve these indexes without statistical significance.
7. ELISA results indicated the TNF-a level significantly increased compared with control group (P<0.01), which was decreased by RS-M and RS-H treatment (P<0.05, P<0.01)
8. Our findings showed that compared with control group, there was a significant increase in the Bmax value of both PBRs and NMDA-R (P<0.01), which was reduced by RS-H treatment (P<0.01).
9. Immunohistostaining results indicated liver cirrhosis in model group, RS treatment reduced the cell degeneration and necrosis. Compared with control group, the number of BrdU, NeuN and GFAP positive cells in model rats hippocampus decreased (P<0.01), RS treatment could increased the number of positive cells.
The results of presnet study incicate that RS treatment leads to the increase of spontaneous movement and the improvement of learning and memory ability; mitigates the liver damage induced by CCl4; ablates the toxic effect caused by hyperammonemia, inhibits the increase of both PBRs and NMDA receptors, promotes hippocampal neurogenesis and the proliferation and differentiation of NSC.
引文
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