Study The Effects And Mechanism Of ?-mangostin Derivatives On Vascular Dementia Rats

Background:Vascular dementia is one of the most common causes of dementia after Alzheimer's disease,causing around 15%of cases.It is the same with Alzheimer's disease is still no effective treatment.Progress in the specialty has been difficult and progn criteria,controversy over the exact nature of the relationship between cerebrovascular pathology and cognitive impairment,and the paucity of identifiable tractable treatment targets.After there is an established connection between vascular and degenerative Alzheimer's pathology,the mechanistic link between the two has not yet has been identified.The study has confirmed that the inflammatory response caused by reperfusion injury in the brain is involved in the occurrence and development of vascular dementia and is an important pathological feature of vascular dementia.a-Mangostin is a kind of ketone compounds separated from mangosteen peel,which has a wide range of biological and pharmacological activity.It exerts certain effect on differentiation of neural stem cell because of the similar structure with tacrine.Base on it,Through the previous experiments,it was found that the derivative had better anti-inflammatory and anti-oxidation and promote the activity of neural differentiation.At the same time,the advantages of this derivative is to enhance the activity while maintaining a good blood-brain barrier transmittance,So it is one of the potential candidate compound for the treatment of vascular dementia.Objective:In this study,rat model of dementia was established by middle cerebral artery occlusion(MCAO).Intraperitoneal injection thread embolization and drug intervention was carried out using the ?-mangostin derivative.Evaluation of efficacy by animal behavioral experiment like Open field experiment and Morris water maze experiment.At the same time,the mechanism was explored by enzyme-linked immunosorbent assay(ELISA)and Western blotting(WB).provide new ideas and experimental basis for the compound treatment of VD.Methods:this study can be divided into three parts:(1)MCAO method induced vascular dementia animal model,then the rats were randomly divided into VD group(intraperitoneal injection of saline),high dose group(20 mg/kg),middle dose group(10 mg/kg),low dose group(5mg/kg),positive drug group(1mg/kg donepezil.HCl)and CON group(intraperitoneal injection of saline).(2)At the end of the drug treatment,Morris water maze experiment and open field experiment were used to observe the spatial learning and memory ability,autonomous behavior and exploratory behavior of the rats in each group.The use of brain tissue morphology means Nissl staining to compare the pathological changes in brain tissue of rats in each group.(3)The expressions of ikka,NFkB and TRAF3 were detected by western blotting.IL1?,IL6 and TNF? were detected by enzyme-linked immunosorbent assay(ELISA).Preliminary explore the mechanism of drugs.Results:(1)After MCAO was used to produce the vascular dementia model,they were divided into VD group(physiologic saline);high doses group(20mg/kg MGD1);middle doses group(10mg/kg MGD1);low doses group(5mg/kg MGD1);positive group(lmg/kg Donepezil HCl)and CON group(physiologic saline).All the groups had 8 rats.(2)Nissl staining showed a significant reduction in the number of neurons in the VD group,the ELISA showed that the levels of IL-1?,IL-6 and TNF-a in the VD group were significantly higher than those in the CON group(P<0.05).Compared with the VD group,The levels of IL-1?,IL-6 and TNF-a in the brain were decreased(P<0.05)in MGD1 group.The WB data showed that the expression of IKKa in the VD group was significantly higher than that in the CON group(P<0.05).The expression of IKK? in the MGD1 group was significantly lower than that in the VD group(P<0.05).Compared with the VD group,the expression of NF-?B in the nucleus was significantly higher than that in the CON group(P<0.05).The expression of NF-?B in the MGD1 group was significantly lower than that in the VD group(P<0.05).The expression of TRAF6 in WB was higher than that in CON group,and the high dose of 20mg/kg group was lower than that of VD group(P<0.05).Conclusion:(1)MGD1 could effectively improve VD rat behavior disorders.(2)MGD1 could regulate its inflammation-related function through IKK/NF-?B signaling pathway,reduce inflammatory injury and improve caused by MCAO and treat vascular dementia in rats.