Effect Of Memantine And Rosuvastatin On Angiogenesis And Nerve Function In Rats With Vascular Dementia

ObjectiveTo analyze mechanism of the learning and memory improvement by performed Morris Water Maze(MWM) functional tests of memantine and rosuvastatin in rats with ischemic vascular dementia(Va D). To investigate the effect and underlying angiogenesis mechanism of circulating endothelial progenitor cells(EPCs), microvessel density(MVD) in hippocampus and vascular endothelial growth factor(VEGF) expression in rats with ischemic vascular dementia(Va D). To investigate the neuranagenesis and synaptic plasticity mechanism indicated by bromodeoxyuridine(Brd U) and long-term potentiation(LTP), brain-derived neurotrophic factor(BDNF) expression in hippocampus in rats with Va D.MethodsSixty adult male SD rats were equally randomized into shame operation group, Va D model group, memantine treatment group, rosuvastatin treatment group and memantine combined with rosuvastatin treatment group, 12 for each group. The method of 2-vessel occlusion(2VO)was used to extablished the Va D model. Memantine(orally, 10mg·kg-1·d-1), rosuvastatin(orally, 10mg·kg-1·d-1) and the two medications combination(orally, 10mg·kg-1·d-1) were administered respectively to the three treatment groups one week after 2VO operation for 28 consecutive days. The same volume of saline was administered orally to the Va D model group. Five weeks after the operation, the ability of spatial learning and memory was assessed with the MWM test including the average escape latency and the percentage of target quadrant. Then circulating EPCs were identified by flow cytometry. The pathologic changes of nerve cells in the hippocampus were observed by hematoxylin and eosin stain. The expression of Brd U and v WF in the hippocampus was also observed by immunohistochemistry. The CA3-CA1 LTP was measured. The expression of BDNF and VEGF was analyzed by Western blotting.ResultsThe percentage of target quadrant was significantly lower in Va D model group than that in shame group(P<0.05).The circulating EPCs level, MVD and BDNF inhippocampus as well as the percentage of target quadrant of rats with each treatment group were significantly higher than those in Va D model group(P<0.05). Compared with the memantine group and the rosuvastatin group, the combined group showed no difference in the circulating EPCs levels, microvessel density(MVD) in hippocampus and the percentage of target quadrant(P>0.05). The CA3-CA1 LTP of Va D group was greatly damaged. Memantine, rosuvastatin and the two drugs combined all could enchance CA3-CA1 LTP and BDNF in hippocampus(P<0.05). The expression of Brd U and VEGF of Va D model group were significantly increased compared with the sham group(P<0.05). Compared with the model group, Memantine, rosuvastatin and the two drugs combined can significantly upregulate the expression of Brd U and VEGF(P<0.05). The morphology of nerve cells in the hippocampus in Va D group are disordered and damaged obviously.ConclusionsMemantine, rosuvastatin and the two drugs combined at adequate dosage could improve the learning and memory ability in rats with Va D. On the one hand, they increase circulating EPCs, MVD and VEGF in hippocampus to promote angiogenesis. On the other hand, nerve repair and synaptic plasticity could be enchanced by increasing LTP and BDNF in hippocampus. The effect of the combination of the two medications was not significantly different from the effect of memantine or rosuvastatin single treatment on angiogenesis. However, on nerve repair and synaptic plasticity aspect,its more effective when use the combination of the two medications.