The Mechanism Study Of Platelet Involving In Learning And Memory Disfunction Induced By Increased Blood Pressure Variability In Rats

BackgroundClinical studies showed that increased blood pressure variability can lead to learning and memory dysfunction,but the specific mechanism is not clear.Previous studies have shown that platelets release clusterin and beta amyloid.Clusterin and beta amyloid could interact with platelets to form the fibrillar beta amyloid,which may deposit in the cerebral vascular endothelium and caused learning and memory dysfunction.Based on our previous studies that ‘increased blood pressure can activate platelet',so we hypothesized that: increased blood pressure can lead to learning and memory dysfunction,and the mechanism of platelet was involved in.AimsOur study was designed to investigate the effect of increased blood pressure variability on learning and memory function in rats,the mechanism of platelet and intervention with nimodipine.Methods(1)The model of sinoaortic denervation(SAD)were prepared in SD rats.Rats were divided into 3 groups: sham operation(Sham)group,SAD group,and SAD + nimodipine group.After two weeks of SAD,hemodynamics were measured continuously in conscious,freely-moving rats.Behavioral experiments such as novel object recognition trial,passive avoidance trial and Morris water maze were carried out at 2nd week,4th week,8th week and 16 th week after SAD,respectively.Then the animals was anesthetized and blood,hippocampus and cerebral cortex were collected.Next,we detected the level of beta amyloid in the hippocampus and cortex,beta amyloid and clusterin in plasma,amyloid precursor protein in platelet,beta amyloid and clusterin released from platelet and percent of fibrillar beta amyloid after incubation with platelet.Moreover,percent of beta amyloid deposited in cerebral vascular endothelium was tested with immunofluorescence methods.(2)SD rats were divided into two groups randomly: SAD and Sham group.Two weeks after operation,SAD group was randomly divided into SAD group and nimodipine(20 mg /kg/d)group.Nimodipine was given by gavage for 30 days.The indexes were determinated with the above methods.Results1.Hemodynamic results: There was no significant difference in SBP,DBP and MBP between SAD and Sham group,but SBPV,DBPV and MBPV were increased significantly(P<0.01),which indicating that SAD rats showed simple blood pressure variability;SAD rats showed decrease of baroreflex sensitivity(P<0.05)and heart rates less than 20 beats per minute with blood pressure of 50 mmHg,suggesting that SAD model were successful.2.The behavioral results:(1)The Morris water maze test results showed that in space navigation experiment,escape latency was prolonged at 8th week and 16 th week after SAD(P<0.05,P<0.01).In space exploration experiment,seek times of crossing the platform was decreased significantly at 8th week and 16 th week after SAD compared with Sham group(P<0.05).However,there was no significant differences in the swimming speed between two groups.(2)The passive avoidance trial results showed that after shock,the latency period of SAD group was decreased significantly at 2nd week,4th week,8th week and 16 th week after SAD compared with Sham group(P<0.05).(3)The novel object recognition trial results showed that the identification index of the object in SAD group was decreased significantly at 16 th week after SAD compared with the Sham group(P<0.05).(4)After administration of nimodipine in SAD rats,escape latency was shortened(P<0.05),seek times of crossing the platform was increased(P<0.05),the latency period was prolonged(P<0.01),the identification index of the object in SAD group was increased(P<0.05).3.Plasm index results: The level of beta amyloid and clusterin in plasm was increased at 8th week and 16 th week after SAD compared with the Sham group(P<0.05,P<0.01).However,level of beta amyloid and clusterin in plasm of SAD rats decreased after treatment with nimodipine(P<0.05).4.Platelet index results: The level of amyloid precursor protein in platelet was decreased at 2nd week and 4th week,and increased at 8th week and 16 th week after SAD compared with Sham group(P<0.05,P<0.01).The level of clusterin released from platelet was increased at 4th week,8th week and 16 week(P<0.01).The concentration of beta amyloid released from platelets was increased at 8th week and 16 th week(P<0.05).Ratio of fibrillar beta amyloid formation was increased at 2nd week,4th week,8th week and 16 th week(P<0.01).After administration of nimodipine in SAD rats,the level of amyloid precursor protein in platelet,clusterin and beta amyloid released from platelet,and ratio of fibrillar beta amyloid was all significantly decreased(P<0.05,P<0.01).5.Brain index results: The concentration of beta amyloid in the hippocampus was increased at 8th week and 16 th week after SAD(P<0.05,P<0.01),while the concentration of beta amyloid in cerebral cortex was increased at 4th week,8th week and 16 th week(P<0.05,P<0.01).The ratio of beta amyloid deposited in cerebral vascular endothelium was increased at 2nd week,4th week,8th week and 16 th week of SAD rats(P<0.01).After treatment with nimodipine in SAD rats,the concentration of beta amyloid in the hippocampus and cerebral cortex and ratio of beta amyloid deposited in cerebral vascular endothelium was decreased(P<0.01).Conclusion1.Increased blood pressure variability may lead to learning and memory dysfunction in SAD rats,which may be associated with the increased release of clusterin and beta amyloid from platelet,the increased formation of fibrillar beta amyloid,and the increased deposition of beta amyloid in cerebral vascular endothelium.2.Nimodipine may improve learning and memory dysfunction induced by increased blood pressure variability in SAD rats.This effect may be related to the inhibition of platelet release,deposition of beta amyloid in cerebral vessels endothelium.