The Mechanism Study Of The NHE1Inhibitors (Cariporide) And The Novel FKBPs Tigand(HD5-6) On SAMP8Mouse

ObjectiveIn order to explore the possible pathogenesis of Alzheimer’s disease andexplore the possible prevention and treatment methods for Alzheimer’s disease(AD), the effect of the Na+/H+exchanger1(NHE1) inhibitors, cariporide, on thechanging of the pH value of hippocampal neurons were studied. Geneexpression profiles in senescence accelerated-prone mouse8(SAMP8) werealso studied. The effect of the novel FKBPs ligand, Thiazine amides derivatives(HD5-6) on the changing of learning and memory ability, pathological and geneexpression profiles in SAMP8were observed.Methods39SAMP8mice (10-month-old) were randomly divided into Dementiagroup,HD5-6group and HOE642group which has13mice in each group.13senescence accelerated-resistant mice (SAMR1,10-Month-old) were assignedto the normal group. Each group of mice were injected by the correspondingsolution for35days. After administrated for29days, Morris water maze test wasused to assess the learning and memory abilities changes among the normalgroup, Dementia group and HD5-6group.After35days, HE staining andTUNEL assay were used to observe the pathological changes of hippocampusneuron and the neuron apoptosis index among mice of the normal group, Dementia group and HD5-6group. Non-invasive Micro-test Technique was usedto detect the hydrogen ions flow velocity of the normal group, Dementia groupand HOE642group. The differences of gene expression profiles among eachgroup were analyzed by Agilent expression profile chip. The altered mRNA inthe gene expression profiles were confirmed by real-time PCR further.ResultsMice of dementia group and HD5-6group showed significant learning andmemory deficits in Spatial acquisition compared to mice of normal group withprolonged escape latency (p<0.01). The escape latency was significantlyshortened in HD5-6group compared with dementia group (p<0.01). From HEstaining and TUNEL assay, which show that The neuron numbers inhippocampus of the dementia group decreased significantly compared withwhich in the normal group. The neuron apoptosis index of the dementia groupwas (51.734.48)%, which is obviously higher than that in normal group(28.0211.25)%(p<0.05). While these pathological changes were significantlyimproved in the HD5-6group which with the apoptosis index (20.472.25)%(p<0.05). Dementia group (0.38260.0578pmol.cm-2.s-1) has faster hydrogenions flow velocity compared with that in the normal group(0.13810.0791pmol.cm-2.s-1)(p<0.05). Compared with the dementia group,the hydrogen ions flow velocity of HOE642group(0.64980.0922pmol·cm-2·s-1)was significantly quickened (p<0.05). Compared with the dementia group, totally99mRNA had more than two fold different expressions in the HOE642group, inwhich up-regulated and down-regulated genes were5and94respectively.There are3genes up-regulated and30genes down-regulated in functionalmRNA. Compared with the dementia group, totally118mRNA had more thantwo fold different expressions in the HD5-6group, in which up-regulated anddown-regulated genes were9and109respectively. There are4genes up-regulated and21genes down-regulated in functional mRNA. The results ofreal time PCR showed the same direction with the results of Agilent expressionprofile chip and proved these alterations.ConclusionsCariporide can aggravate the degree of acid in the nervous cells of SAMP8,The gene expression profiles changes in the HOE642group is associated withthe error protein production and degradation of gene expression probablyinfluence the aging rate in SAMP8. HD5-6can improve the learning andmemory ability in SAMP8, amendment the pathological changes of thehippocampus neuron as well. The gene expression profiles changes in theHD5-6group probably play a significant anti-aging effect on SAMP8.