复智胶囊对血管性痴呆胆碱能系统及炎性细胞因子的影响
摘要
目的:观察复智胶囊对血管性痴呆(Vascular Dementia, VD)的临床疗效,观测复智胶囊对VD大鼠学习记忆、海马内乙酰转移酶(CHAT)表达、胆碱酯酶(AchE)活性、血清肿瘤坏死因子-α(TNF-α)、白介素-6(IL-6)的影响,探讨该药对急、慢性脑缺血所致痴呆的作用机制。
方法:临床研究按随机单盲对照方法,采用DSM IV(美国《精神病诊断和统计手册》)及NINDS-AIREN(美国国立神经系统疾病与卒中研究所和瑞士神经科学研究国际协会)关于VD的诊断标准进行病例筛选,并用临床痴呆分级量表(CDR)、简易智能状态检查(MMSE)、行为能力检查(BBS)、日常生活能力量表(ADL)及中医辨证标准对患者进行整体评定。经患者同意符合纳入标准而列入研究对象计80例,随机分为治疗组和对照组各40例;治疗组口服复智胶囊每次4粒,每日3次;对照组口服安理申,5mg/次,1次/日。两组均连续用药12周。治疗前、治疗6周后、治疗12周后对患者认知功能(MMSE-R)、行为能力(BBS)、日常生活能力(ADL)、中医证候指标进行评定。安全性观测采用血、尿、粪常规及肝、肾功、心电图监测,治疗前后各1次。
实验研究采用急性缺血再灌注及慢性缺血VD模型进行研究。前者选用4-血管阻断法制造动物模型,随机分为复智胶囊治疗组和模型组各30例,假手术组10例,在第3d、7d、4w 3个时段随机从治疗组、模型组各抽取10只检验其主动回避反应(AAR)习得率、血清TNF-α、IL-6含量及海马CHAT表达、AchE活性。后者选用双侧颈总动脉结扎法制备慢性缺血VD模型,随机分为模型组、复智胶囊高、中、低剂量治疗组、安理申对照组,以及假手术组,共6组,每组10只,治疗1月。于造模前后及用药后用水迷宫方法检测各组大鼠学习记忆情况;治疗后检测各组大鼠海马CHAT表达、AchE活性、血清TNF-α及IL-6的含量。
结果:80例患者按方案完成临床试验,无脱落及剔除病例。治疗组与对照组用药后MMSE评分较前改善(P<0.01),两者无显著差异(P>0.05)。BBS评分两组用药后均有改善(P<0.01),治疗组优于对照组(P<0.05)。用药后两组ADL评分较前改善(P<0.01),治疗组优于对照组(P<0.01)。用药后两组均降低中医证候积分(P<0.01),治疗组优于对照组,差异极显著(P<0.01)。临床疗效判定方面,MMSE、BBS、ADL评分及中医证候积分总有效率均为95%,而对照组分别为75.0%、80.0%、67.5%、72.5%,除MMSE评分无显著差异外(P>0.05),其他均有显著性差异(两组比较:BBS,P<0.05;ADL,P<0.01,中医证候积分,P<0.01)。对急性缺血再灌注VD大鼠的实验研究发现,模型动物的AAR习得率3d即显著低于对照组,7天、4w时进一步降低;造模后3d海马CHAT阳性面积及阳性面积比率即显著减少(P<0.01),第7d、4w保持在相同的低水平状态;海马AchE含量在3d时显著升高(P<0.01),第7d、4w处于低水平状态;血清IL-6造模3d时升至最高(P<0.01),7d时降低,但仍然高于假手术组(P<0.05),4w时已经接近正常水平(P>0.05);TNF-α于造模3d升高(P<0.01),7d达最高(P<0.01),4w时降低,但仍然高于假手术组(与假手术组相比,P<0.05)。复智胶囊可以提高各时段AAR习得率(P<0.05),降低IL-6在缺血早期的含量,降低各时相TNF-α含量;在早期(3d)即提高CHAT的表达,在7d时AchE活性下降且接近假手术组(P<0.05)。对慢性缺血VD大鼠的研究发现,大鼠学习记忆能力在造模后显著降低(P<0.01);海马内CHAT表达降低(P<0.01),AchE增高(P<0.01);TNF-α及IL-6含量升高(P<0.01)。与模型组比较,复智胶囊不同剂量治疗后,中、高剂量组能明显提高大鼠的学习记忆能力(P<0.05),且与对照组无显著差异(P>0.05);高剂量组可提高CHAT阳性表达(P<0.01);中、高剂量组、对照组可显著降低AchE的活性(中剂量组P<0.05,高剂量组P<0.01);低、中、高剂量组均可降低VD大鼠血清TNF-α(均P<0.01)含量,中、高剂量剂量组可降低IL-6含量,差异极显著(P<0.01),对照组无此作用(P>0.05)。
结论:复智胶囊和安理申在改善VD患者认知功能方面无显著差异;在改善非认知功能、日常生活能力及中医证候方面,复智胶囊优于安理申。实验研究表明复智胶囊能确切改善VD大鼠的学习记忆能力;可保护胆碱能系统,提高VD大鼠海马CHAT表达;可抑制血清TNF-ɑ与IL-6的过度表达,减轻缺血炎症反应损害。其机制可能为减轻缺血炎性反应对神经元的危害,并上调海马胆碱能系统低水平状态,达到改善学习记忆能力的作用。
Objective: ToinvestigatethetherapeuticefficiencyoftreatingVascularDementia(VD)by FUZHI Capsule through clinical observe,and reveal it’s action mechanism by detectingacetylcholinesterase(AchE),Cholineacetyltransferase(CHAT)inhippocampusandmerleukin-6(IL-6),tumornecrosisfactor-ɑ(TNF-ɑ)inserumwithVDrat.
Methods: In the clinical study we adopt DSM-IV,MMSE,BBS,ADL and TCMsyndrome differentiation standard and choose 80 cases who take part in this study freely andconforming with the observation criteria 80 cases are randomly divided into two groups. Thetreating method adopt simple-blinded randomize-controlled.40 cases in treated group takeFUZHI4capsuleseachtimethreetimesadayorally.40cases incontrol grouptakeDonepezil1tabletseachtimeepisodeandthestatesoftongueandpulsearerecordedeverymonthBeforetreatmentandaftertreatmentcomplexionlips, bodytype, pathologicsymptomarerecordedmeanwhilesafetyparametersareobserved.Takingmedicinecontinues12weeksandfollow-upisonetimeeverymonthBeforetakingmedicineandaftertakingmedicineMMSE,BBS,ADL,TCM on statistical analysis, especially observe MMSE,TCM episode and electroencephalogram. In the first experimental study we replicated VD rats by Pulsinelli 4-vo blockingwayandrandomlyclassifiedintotwogroupssuchas FUZHICapsulegroup,modleandgroupand sham operation group. Then examineAAR rate , hippocampal AchEactivityand CHATcontent and the content of IL-6, TNF-ɑin serum in three times(3d,7d and 4w). In thesecondexperimentalstudywereplicatedVDratsbyblockingbilateralcommoncarotidarteriespermanentlyandrandomlyclassifiedintosixgroups,namely,modelgroup, FUZHICapsulelow dose group, FUZHI Capsule middle dose group, FUZHI Capsule high dose group,Donepezil group, and sham operation group. The lasted for one month. Morris water mazewas used totest the learningand memoryabilities of these rats before and after makingmodeland after treatment. Such factors have been detected as the hippocampal AchE activity andCHATcontentandthecontentofIL-6, TNF-ɑinserumaftertreatment.
Results: In evaluation of the therapeutic efficiency and safety analysis, 80 cases hadfinishedthe clinical test accordingtoplan, there is no case hadbeen dropped off. There wasstatisticallydifference according to MMSE,BBS,ADL, TCM episode in before and aftertreatment’s assessing (P<0.01).There is no statistically difference for MMSE after treatmentbetweenthetreatedgroupandthecontrolgroup(P>0.05),whilethereisstatisticallydifferencefor BBS (P<0.05),ADL (P<0.01) and TCM episode (P<0.01) between two groups. In thetreatedgroupthetotaleffectiverateofMMSE,BBS,ADL,TCMepisodereached95.0%.Inthecontrolgroupthetotaleffectiverateoftheseindexesdifferentlyreached75.0%, 80.0%,67.5%, 72.5%. To analyze the results of therapy of two groups, there was statisticallydifference on BBS, ADL and TCM episode’s effect, while there was no statisticallydifference on MMSE’s effect. This informed that the treated groups effectiveness in behavior ability and TCM episode advantage over the control group’s effectiveness in behavior abilitythrough statistical analysis. In first experimental study ,the learning and memoryabilities ofmodel rats were obviously decreased while it was raised by FUZH in three times. Thehippocampus AchE activity were raised while CHAT positive expression were descended in3d,and the content of IL-6(3d), TNF-ɑ(7d) in serum were obviously raised compared.Aftertreatmentof FUZHIfor3d,thehippocampalCHATcontentdecreased(P<0.01).ThenFUZHI increased the content of hippocampal AchE in 7d.FUZHI obviouslydecreased thecontent of TNF-ɑin serum (3d,7d and ww) and decreased IL-6 (just 3d). In secondexperimental study ,by comparison with operated group (P<0.01) the learning and memoryabilities of model rats were obviously impaired. The hippocampus AchE activity were raisedwhile CHAT positive expression were descended ,and the content of IL-6, TNF-ɑinserum were obviously raised compared with sham operation group. After treatment of eachdosage FUZHI for one month, by comparison with model group the learning and memoryabilitiesofVDratsobviouslyimproved,Donepezilgroupincreasedtoo(P>0.05).FUZHIhighdose and Donepezil group decreased the hippocampal AchE activity (P>0.05). FUZHI highdose and middle dose can increased the hippocampal CHAT content, and there was relationbetweendoseandefect.EachdosageofFUZHIobviouslydecreasedthecontentofTNF-ɑinserum (P<0.01).FUZHI high dose and Donepezil group decreased IL-6 (P<0.01). Donepezilgroupdidn’thavesucheffect(P>0.05).
ConcIusion:FUZHICapsuleandDonepezilbothcanimprovethecognitiveabilityofVDpaitent.However FUZHI Capsule’s effectiveness in behavior ability and TCM episode werebetter than Donepezil in treating VD. Experiment has confirmed that FUZHI Capsule coulddecreasetheAchEactivityinhippocampus andincreasethepositiveexpressionofCHAT.Anddecrease the content of IL-6 and TNF-ɑin VD rats’serum. This informed that FUZHICapsule maybe lighten the injury of inflammation and increase the low level of hippocampalcocholinergicnerveafterinfraction.
方法:临床研究按随机单盲对照方法,采用DSM IV(美国《精神病诊断和统计手册》)及NINDS-AIREN(美国国立神经系统疾病与卒中研究所和瑞士神经科学研究国际协会)关于VD的诊断标准进行病例筛选,并用临床痴呆分级量表(CDR)、简易智能状态检查(MMSE)、行为能力检查(BBS)、日常生活能力量表(ADL)及中医辨证标准对患者进行整体评定。经患者同意符合纳入标准而列入研究对象计80例,随机分为治疗组和对照组各40例;治疗组口服复智胶囊每次4粒,每日3次;对照组口服安理申,5mg/次,1次/日。两组均连续用药12周。治疗前、治疗6周后、治疗12周后对患者认知功能(MMSE-R)、行为能力(BBS)、日常生活能力(ADL)、中医证候指标进行评定。安全性观测采用血、尿、粪常规及肝、肾功、心电图监测,治疗前后各1次。
实验研究采用急性缺血再灌注及慢性缺血VD模型进行研究。前者选用4-血管阻断法制造动物模型,随机分为复智胶囊治疗组和模型组各30例,假手术组10例,在第3d、7d、4w 3个时段随机从治疗组、模型组各抽取10只检验其主动回避反应(AAR)习得率、血清TNF-α、IL-6含量及海马CHAT表达、AchE活性。后者选用双侧颈总动脉结扎法制备慢性缺血VD模型,随机分为模型组、复智胶囊高、中、低剂量治疗组、安理申对照组,以及假手术组,共6组,每组10只,治疗1月。于造模前后及用药后用水迷宫方法检测各组大鼠学习记忆情况;治疗后检测各组大鼠海马CHAT表达、AchE活性、血清TNF-α及IL-6的含量。
结果:80例患者按方案完成临床试验,无脱落及剔除病例。治疗组与对照组用药后MMSE评分较前改善(P<0.01),两者无显著差异(P>0.05)。BBS评分两组用药后均有改善(P<0.01),治疗组优于对照组(P<0.05)。用药后两组ADL评分较前改善(P<0.01),治疗组优于对照组(P<0.01)。用药后两组均降低中医证候积分(P<0.01),治疗组优于对照组,差异极显著(P<0.01)。临床疗效判定方面,MMSE、BBS、ADL评分及中医证候积分总有效率均为95%,而对照组分别为75.0%、80.0%、67.5%、72.5%,除MMSE评分无显著差异外(P>0.05),其他均有显著性差异(两组比较:BBS,P<0.05;ADL,P<0.01,中医证候积分,P<0.01)。对急性缺血再灌注VD大鼠的实验研究发现,模型动物的AAR习得率3d即显著低于对照组,7天、4w时进一步降低;造模后3d海马CHAT阳性面积及阳性面积比率即显著减少(P<0.01),第7d、4w保持在相同的低水平状态;海马AchE含量在3d时显著升高(P<0.01),第7d、4w处于低水平状态;血清IL-6造模3d时升至最高(P<0.01),7d时降低,但仍然高于假手术组(P<0.05),4w时已经接近正常水平(P>0.05);TNF-α于造模3d升高(P<0.01),7d达最高(P<0.01),4w时降低,但仍然高于假手术组(与假手术组相比,P<0.05)。复智胶囊可以提高各时段AAR习得率(P<0.05),降低IL-6在缺血早期的含量,降低各时相TNF-α含量;在早期(3d)即提高CHAT的表达,在7d时AchE活性下降且接近假手术组(P<0.05)。对慢性缺血VD大鼠的研究发现,大鼠学习记忆能力在造模后显著降低(P<0.01);海马内CHAT表达降低(P<0.01),AchE增高(P<0.01);TNF-α及IL-6含量升高(P<0.01)。与模型组比较,复智胶囊不同剂量治疗后,中、高剂量组能明显提高大鼠的学习记忆能力(P<0.05),且与对照组无显著差异(P>0.05);高剂量组可提高CHAT阳性表达(P<0.01);中、高剂量组、对照组可显著降低AchE的活性(中剂量组P<0.05,高剂量组P<0.01);低、中、高剂量组均可降低VD大鼠血清TNF-α(均P<0.01)含量,中、高剂量剂量组可降低IL-6含量,差异极显著(P<0.01),对照组无此作用(P>0.05)。
结论:复智胶囊和安理申在改善VD患者认知功能方面无显著差异;在改善非认知功能、日常生活能力及中医证候方面,复智胶囊优于安理申。实验研究表明复智胶囊能确切改善VD大鼠的学习记忆能力;可保护胆碱能系统,提高VD大鼠海马CHAT表达;可抑制血清TNF-ɑ与IL-6的过度表达,减轻缺血炎症反应损害。其机制可能为减轻缺血炎性反应对神经元的危害,并上调海马胆碱能系统低水平状态,达到改善学习记忆能力的作用。
Objective: ToinvestigatethetherapeuticefficiencyoftreatingVascularDementia(VD)by FUZHI Capsule through clinical observe,and reveal it’s action mechanism by detectingacetylcholinesterase(AchE),Cholineacetyltransferase(CHAT)inhippocampusandmerleukin-6(IL-6),tumornecrosisfactor-ɑ(TNF-ɑ)inserumwithVDrat.
Methods: In the clinical study we adopt DSM-IV,MMSE,BBS,ADL and TCMsyndrome differentiation standard and choose 80 cases who take part in this study freely andconforming with the observation criteria 80 cases are randomly divided into two groups. Thetreating method adopt simple-blinded randomize-controlled.40 cases in treated group takeFUZHI4capsuleseachtimethreetimesadayorally.40cases incontrol grouptakeDonepezil1tabletseachtimeepisodeandthestatesoftongueandpulsearerecordedeverymonthBeforetreatmentandaftertreatmentcomplexionlips, bodytype, pathologicsymptomarerecordedmeanwhilesafetyparametersareobserved.Takingmedicinecontinues12weeksandfollow-upisonetimeeverymonthBeforetakingmedicineandaftertakingmedicineMMSE,BBS,ADL,TCM on statistical analysis, especially observe MMSE,TCM episode and electroencephalogram. In the first experimental study we replicated VD rats by Pulsinelli 4-vo blockingwayandrandomlyclassifiedintotwogroupssuchas FUZHICapsulegroup,modleandgroupand sham operation group. Then examineAAR rate , hippocampal AchEactivityand CHATcontent and the content of IL-6, TNF-ɑin serum in three times(3d,7d and 4w). In thesecondexperimentalstudywereplicatedVDratsbyblockingbilateralcommoncarotidarteriespermanentlyandrandomlyclassifiedintosixgroups,namely,modelgroup, FUZHICapsulelow dose group, FUZHI Capsule middle dose group, FUZHI Capsule high dose group,Donepezil group, and sham operation group. The lasted for one month. Morris water mazewas used totest the learningand memoryabilities of these rats before and after makingmodeland after treatment. Such factors have been detected as the hippocampal AchE activity andCHATcontentandthecontentofIL-6, TNF-ɑinserumaftertreatment.
Results: In evaluation of the therapeutic efficiency and safety analysis, 80 cases hadfinishedthe clinical test accordingtoplan, there is no case hadbeen dropped off. There wasstatisticallydifference according to MMSE,BBS,ADL, TCM episode in before and aftertreatment’s assessing (P<0.01).There is no statistically difference for MMSE after treatmentbetweenthetreatedgroupandthecontrolgroup(P>0.05),whilethereisstatisticallydifferencefor BBS (P<0.05),ADL (P<0.01) and TCM episode (P<0.01) between two groups. In thetreatedgroupthetotaleffectiverateofMMSE,BBS,ADL,TCMepisodereached95.0%.Inthecontrolgroupthetotaleffectiverateoftheseindexesdifferentlyreached75.0%, 80.0%,67.5%, 72.5%. To analyze the results of therapy of two groups, there was statisticallydifference on BBS, ADL and TCM episode’s effect, while there was no statisticallydifference on MMSE’s effect. This informed that the treated groups effectiveness in behavior ability and TCM episode advantage over the control group’s effectiveness in behavior abilitythrough statistical analysis. In first experimental study ,the learning and memoryabilities ofmodel rats were obviously decreased while it was raised by FUZH in three times. Thehippocampus AchE activity were raised while CHAT positive expression were descended in3d,and the content of IL-6(3d), TNF-ɑ(7d) in serum were obviously raised compared.Aftertreatmentof FUZHIfor3d,thehippocampalCHATcontentdecreased(P<0.01).ThenFUZHI increased the content of hippocampal AchE in 7d.FUZHI obviouslydecreased thecontent of TNF-ɑin serum (3d,7d and ww) and decreased IL-6 (just 3d). In secondexperimental study ,by comparison with operated group (P<0.01) the learning and memoryabilities of model rats were obviously impaired. The hippocampus AchE activity were raisedwhile CHAT positive expression were descended ,and the content of IL-6, TNF-ɑinserum were obviously raised compared with sham operation group. After treatment of eachdosage FUZHI for one month, by comparison with model group the learning and memoryabilitiesofVDratsobviouslyimproved,Donepezilgroupincreasedtoo(P>0.05).FUZHIhighdose and Donepezil group decreased the hippocampal AchE activity (P>0.05). FUZHI highdose and middle dose can increased the hippocampal CHAT content, and there was relationbetweendoseandefect.EachdosageofFUZHIobviouslydecreasedthecontentofTNF-ɑinserum (P<0.01).FUZHI high dose and Donepezil group decreased IL-6 (P<0.01). Donepezilgroupdidn’thavesucheffect(P>0.05).
ConcIusion:FUZHICapsuleandDonepezilbothcanimprovethecognitiveabilityofVDpaitent.However FUZHI Capsule’s effectiveness in behavior ability and TCM episode werebetter than Donepezil in treating VD. Experiment has confirmed that FUZHI Capsule coulddecreasetheAchEactivityinhippocampus andincreasethepositiveexpressionofCHAT.Anddecrease the content of IL-6 and TNF-ɑin VD rats’serum. This informed that FUZHICapsule maybe lighten the injury of inflammation and increase the low level of hippocampalcocholinergicnerveafterinfraction.
引文
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