| Due to the increasing life expectancy,the management of dementia has become one of the most significant public health problems.Vascular dementia is the second most prevalent cause of dementia.Considering the high occurrence rates of stroke and other vascular diseases,the prevention and treatment of vascular dementia in China is an enormous challenge.However,up to now,there are no effective treatments proven to stop or reverse the progression of the disease except for some primary and secondary preventive methods.Traditional Chinese medicine has a long history of treating dementia.Syndrome studies nowadays have found that deficiency in kidney essence,turbid phlegm blocking the clear orifices and blood stasis obstructing the collaterals are the most commen syndromes in vascular dementia patients.Thus,Bushentongluo therapy(kidney-tonifying and meridian-dredging therapy)is usually applied clinically for the treatment of vascular dementia.In this study,we intent to evaluate the efficacy and safety of kidney-tonifying and meridian-dredging therapy through systematic review and clinical research as well as investigate the putative mechanisms underlying this therapy based on NLRP3 inflammasome pathway.Objective 1.To systematically assess the effectiveness and safety of Bushentongluo therapy(kidney-tonifying and meridian-dredging therapy)for vascular dementia.2.To investigate the effectiveness and safety of Yizhitongmai Decoction for vascular dementia clinically.3.To investigate the underlying mechanism of Yizhitongmai Decoction in treating vascular dementia based on the NLRP3 inflammasome.Methods 1.Literature Reasearch Data Sources:All published English and Chinese articles were searched using databases including Pubmed,EMBASE,China national knowledge infrastructure(CNKI),Wanfang database and VIP database from inception to June 2017.Search terms included vascular dementia,arteriosclerotic dementia,multi-infarct dementia,small vessel dementia,strategic infarct dementia,haemorrhagic dementia,hereditary dementia,CADASIL,vascular cognitive impairment,randomized controlled trial(RCT),controlled clinical trial and random allocation.Study Selection: Only RCTs of herbal medicine using kidney-tonifying and meridian-dredging therapy with or without western medicine vs western medicine or placebo were included.The measures were the effectiveness and/or safety of the therapy.Data extraction and analysis: Study selection and data extraction were performed by two independent researchers.Epidata 3.1 was used for data recording.The Cochrane Handbook was used to estimation of risk of bias in individual studies.Revman 5.1 software was used to synthesize the main outcomes of the included studies.2.Clinical Research Participants with vascular dementia meeting the including critetia from Department of Traditional Chinese Medicine in Shandong Provincial Hospital affiliated to Shandong University from December 2015 to June 2017 were randomized into two groups,the experimental group(38 cases)and the control group(38 cases).The control group received donepezil(5 mg/d)per day by oral administration,while the experimental group received donepezil plus Yizhitongmai Decoction,both for 24 weeks.The outcome measures included CIBIC-plus,ADAS-Cog,MMSE,ADL and BBS scores.The measures were collected before the treatment,12 weeks after the treatment and 24 weeks after the treatment.ITT and PP methods were both used to analyze the outcomes.3.Experimental research 8-12 weeks male Wistar rats were randomized into six groups including sham-operation group,model group,vehicle group,si NLRP3 group,Yizhitongmai Decoction group and nimodipine group.After a week of adaption,vehicle group and si NLRP3 group received injection of lentivirus(5μL)or lentivirus-mediated NLRP3 si RNA(5μL)in hippocampus.After 7 days,all groups except for sham-operation group received 2-VO operation to establish chronic cerebral ischemia models,while the sham-operation group only received separation of bilateral common carotid arteries.After the operation,the Yizhitongmai group received intragastric administration of Yizhitongmai Decoction(0.646 g/m L,2 m L,i.g.,qd),while the minodipine group received intragastric administration of nimodipine(0.938 g/m L,2 m L,i.g.,qd)for 28 days.After the treatment,Morris water maze were used to investigate the learning/memory function of the rats.Western-Blotting was used to test the expression of NLRP3、Caspase-1、IL-1β、IL-18、NF-κB and BDNF in the hippocampus of the rats.Results 1.Liturature research Compared with the placebo group,kidney-tonifying and meridian-dredging medicine could significantly improve the MMSE score(MD=5.68,P<0.00001)and decrease the ADL score(MD=-6.05,P<0.0001),indicating that kidney-tonifying and meridian-dredging medicine could improve the cognitive function and overall performance of Va D patients.Compared with the donepezil group,the effects of kidney-tonifying and meridian-dredging medicine on changes of MMSE(P=0.02)、BBS(P=0.48)、Mo CA(P=0.77)scores were not significant,indicating that the cognition-improving effect of kidney-tonifying and meridian-dredging medicine has no advantage compared with denepezil.However,the kidney-tonifying and meridian-dredging medicine could significantly reduce the ADL scores compared with donepezil,suggesting that it might have some advantage in improving daily performance.When using kidney-tonifying and meridian-dredging medicine and donepezil simultaneously,the amelioration in MMSE(MD=2.14,P=0.0005),HDS(MD=3.56,P<0.00001),WMS(MD=5.38,P=0.001)scores were significantly better compared with those using donepezil alone.Besides,according to the current studies,kidney-tonifying and meridian-dredging medicine was relatively safe in use.However,the quality of the included reports in this study were generally low,leading to the deficiency in the potency of evidence.2.Clinical research According to the ITT-LOCF and PP analysis,after 24 weeks of intervention,the experimental group and control group showed no significant difference in CIBIC-plus scores improvement,and the CIBIC-plus improvement were not significant within the groups.According to ITT-LOCF analysis,the experimental group showed significant improvement in TCM scores compared with baseline as well as control group.3.Experimental research According to Morris water maze,compared with sham-operation group,the model group showed significant prolonged escape latency and reduce in number of platform-crossing and time in the target quadrant,indicating that the learning/memory ability of the rats in model group was decreased.However,this effects could be partially reversed in si NLRP3 group,indicating that target silencing of NLRP3 gene have some protective effects on chronic cerebral ischemia.The vehicle group showed no difference in these aspects compared with model group.The Yizhitongmai group showed significant improvement in the aspects of escape latency and platform-crossing number compared with the model group,suggesting that the Yizhitongmai decoction might have some protective effect on chronic cerebral ischemia,while the nimodipine group had no such effects.Western-blotting results showed that compared with the sham-operation group,the expression of NLRP3,IL-1β,IL-18,and caspase-1 in model group were increased,while these effects were reveres in si NLRP3 group,suggesting that target silencing of NLRP3 gene could partially down-regulate the expression of NLRP3-associated pathways.The vehicle group showed no such effect.Compared with the model group,the Yizhitongmai group showed no significant change in NLRP3,IL-1β,IL-18 and caspase-1 expressions,but the BDNF expression were increased,suggesting the neuro-protective effects of Yizhitongmai decoction might not be associated with anti-inflammatory mechanism but might be associated with improving the expression of neurotrophin. |
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