| Objective:Stroke,characterized by high morbidity,mortality and disability,is the second leading cause of death and the third leading cause of the loss of Disability-adjusted Life Year following ischemic heart disease.With the development of clinical research and medical treatment,strategies of stroke prevention and treatment have made great progress.However,the large number of stroke survivors are at great risk of cognitive decline and even dementia,which severely affects their quality of life and imposes a heavy medical burden on society.Chronic cerebral hypoperfusion(CCH)is an important pathophysiological basis of neurodegenerative disease Alzheimer’s disease(AD)and vascular cognitive impairment(VCI)following stroke,but its mechanism remains elusive.Brain specific angiogenesis inhibitor(BAI1),which is highly expressed in brain tissue,has been widely studied for its anti-angiogenesis,anti-tumor and immunophagocytic effects.Recent studies have found that BAI1 also plays an important role in synaptogenesis and synaptic plasticity.Our previous studies have found that CCH inducing cognitive impairment are associated with alterations of hippocampal silent synapse and functional synapse,mitochondrial aging,abnormal expression and structure of cofilin rods.The research establishes CCH model rats by adopting the method of the permanent bilateral common carotid artery occlusion(BCCAO),and the cognitive and behavioral changes,BAI1 expression and synaptic function of the hippocampal structure in experimental animals were observed dynamically for 3 month.Combined with the effect of chronic treatment with simvastatin on modulating synaptic plasticity to further clarify that(1)the changes of cognitive function in rats after chronic cerebral hypoperfusion status lasting for 3 months;(2)the expression of presynaptic membrane protein synaptophysin(SYN)and postsynaptic membrane protein postsynaptic density 95(PSD95)under chronic cerebral hypoperfusion;(3)the protein expression of BAI1 in rats with chronic cerebral hypoperfusion and the changes after intervention with simvastatin;(4)discussing the possible implications of BAI1 in early identification of VCI.Material and method:Forty-eight male SD rats were randomly divided into chronic cerebral hypoperfusion model group(CCH group,n=12),sham operation control group(Sham group,n=12),solvent group(n=12),and simvastatin intervention group(SV group,n=12).(1)CCH group: bilateral common carotid artery ligation;(2)Sham group:modeling steps were consistent with CCH group except bilateral common carotid artery ligation.(3)solvent group:rats were given 0.5% sodium carboxymethyl cellulose by gavage for 3 months after modeling,in order to eliminate the interference of the solvent.(4)administration group: the rats were given simvastatin suspension by gavage for 3 months after modeling.The cognitive function of rats in each group was examined by behavioral test,and the protein expression of BAI1,SYN and PSD95 were detected by western blot.Results:1.Sustaining impaired learning and memory function in rats induced by CCH: In the open field test,the total distance of movement within 5 minutes in CCH group was shorter than the Sham group(CCH group 898.92± 142.39 cm vs.Sham group 1268.54± 210.52 cm,P<0.01).From the first day to the fifth day of the acquired training in the place navigation test,the reference memory escape latency of the CCH group was longer than that of Sham group,the difference was statistically significant(P<0.05),and the trend of gradual decrease was observed in all of them.In the spatial probe test,the times of crossing the platform and the target quadrant time of rats in CCH group were decreased compared with Sham group(CCH group 2.58±1.44 vs.Sham group 3.50±1.73 in,P<0.05;CCH group14.73±2.18 vs.Sham group 24.54±7.33,P<0.01).In the working memory experiment,there was no significant difference in the woking memory escape latency between rats in CCH group and Sham group on the first day,and the difference was statistically significant on the second day(P<0.05),and even more significant on the third and fourth days(P<0.01).2.Simvastatin can effectively protect the cognitive function of CCH rats: In the open field test,the total distance of movement within 5 minutes in SV group increased compared with solvent group(SV group 1228.10± 258.70 cm vs.solvent group 918.35± 208.97 cm,P<0.01).From the first day to the fifth day of the acquired training in the place navigation test,the reference memory escape latency in SV group was shorter than that in the solvent group(P<0.05),and the difference was statistically significant(P<0.05).In the spatial probe test,the times of crossing the platform and the target quadrant time of rats in the SV group were increased compared with solvent group(SV group 3.33±1.67 vs.solvent group2.50±1.17,P<0.05;SV group 24.08±3.70 vs.solvent group 15.03±5.05,P<0.01).In the working memory experiment,there was no significant difference between SV group and the solvent group in the woking memory escape latency on the first day,the time of the SV group was shorter on the second day,the difference was statistically significant(P<0.05),and the difference was even more significant on the third and the fourth day(P<0.01).3.Protein expression of BAI1 decreased in rats after chronic cerebral hypoperfusion status lasting for 3 months: Western blot results showed that the protein expression of BAI1 in the hippocampal CA1 region of the CCH model group rats was lower than Sham group,and the parameters showed a significant difference(CCH group 1 vs.Sham group1.3641±0.0460,P<0.01).4.Protein expression of BAI1 increased in CCH model rats after intervention with simvastatin: The results of western blot experiments showed that protein expression of BAI1 in the hippocampal CA1 region of SV group rats was higher than the solvent group,and the parameters showed a significant difference(1.3302±0.0319 in the SV group vs.0.9946±0.0264 in the solvent group,P<0.01).5.The variation tendency of protein expression of BAI1 was consistent with the key protein of presynaptic membrane SYN and the key protein of postsynaptic membrane PSD95:The protein expression of BAI1 in CCH group and the solvent group was lower compared respectively with Sham group and the SV group,and the protein expression change tendency of BAI1 in CCH group and the solvent group were similar to the protein expression change tendency of SYN、PSD95(SYN: CCH group 1 vs.Sham group 1.4138±0.0689,P<0.01;SV group 1.3763±0.0532 vs.solvent group 0.9800±0.0459,P<0.01;PSD95: CCH group 1 vs.Sham group 1.4969±0.0812,P<0.01;SV group 1.4295±0.0580 vs.solvent group1.0642±0.1204,P<0.01)Conclusion:1.The abilities of rats in independent exploration and spatial learning and memory were still significantly impaired after chronic cerebral hypoperfusion status lasting for 3 months,and there were significant synaptic loss in the hippocampal CA1 region of the CCH model rats.2.Simvastatin can effectively protect CCH model rats from the continuous cognitive impairment;3.In the process of chronic cerebral hypoperfusion leading to sustaining cognitive impairment in rats,the protein expression of BAI1 in the hippocampal CA1 region was decreased,while the protein expression of BAI1 increased after applying the intervention of simvastatin,which indicated that the decreased BAI1 expression was related to the occurrence of cognitive impairment following chronic cerebral hypoperfusion.4.The variation trend of BAI1 is consistent with the change of synaptic key proteins,which revealed that BAI1 were expected to be a novel biological target for early identification and intervention for vascular cognitive impairment. |
PDF Full Text Request