吡格列酮对AD大鼠模型学习记忆及GSK-3β、p-tau蛋白的影响
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摘要
目的:将吡格列酮用于阿尔茨海默病(AD)大鼠模型,观察其对AD大鼠模型学习记忆能力及糖原合成激酶-3β(GSK-3β)、tau蛋白磷酸化(p-tau)的影响,初步探讨吡格列酮对AD大鼠模型的疗效及可能的作用机制。
方法:
1.AD大鼠模型的制备。根据大鼠脑立体定位图谱,用脑立体定位仪定位,向大鼠右侧海马CA1区微量注射冈田酸(OA),隔日一次,共4次,制备AD大鼠模型。
2.吡格列酮制成混悬液灌胃,各组大鼠分别于灌胃前、后尾静脉采血,微量血糖仪测定外周血糖。
3.用Morris水迷宫行大鼠行为学检测。
4.GSK-3β与tau蛋白磷酸化表达的研究。采用免疫组化法观察大鼠海马内GSK-3β的表达及tau蛋白磷酸化的表达。
结果:
1.外周血糖测定:各组大鼠灌胃前、后血糖相比较无显著差异(P>0.05)。
2.Morris水迷宫检测结果:模型组大鼠平均逃避潜伏期较对照组明显延长(P<0.05),且较对照组游泳平台象限的路径长度占总路径长度的百分比明显减少(P<0.05);低、高吡格列酮组大鼠平均逃避潜伏期较模型组明显缩短(P<0.05),且较模型组游泳平台象限的路径长度占总路径长度的百分比明显增大(P<0.05),但低、高吡格列酮组大鼠二者比较无显著差异(P>0.05)。
3.大鼠海马GSK-3β的表达:模型组大鼠较对照组GSK-3β的阳性表达明显增多,平均灰度值明显降低(P<0.05);低、高吡格列酮组大鼠较模型组GSK-3β的阳性表达明显减少,平均灰度值明显增高(P<0.05),但二者比较无显著差异(P>0.05)。
4.大鼠海马tau蛋白磷酸化的表达:模型组大鼠较对照组tau蛋白磷酸化的阳性表达明显增多,平均灰度值明显降低(P<0.05);低、高吡格列酮组大鼠较模型组tau蛋白磷酸化的阳性表达明显减少,平均灰度值明显增高(P<0.05),但二者比较无显著差异(P>0.05)。
结论:
1.大鼠右侧海马CA1区多次微量注射OA制备AD动物模型,成功模拟了AD学习记忆能力的减退及tau蛋白过度磷酸化的病理改变。
2.吡格列酮用于AD大鼠模型,对其血糖无显著影响,但提高了其学习记忆能力,减少了GSK-3β及tau蛋白过度磷酸化的表达,可认为AD的发生与胰岛素信号传导系统异常有关。吡格列酮通过调整胰岛素信号传导系统功能,增加胰岛素敏感性,降低GSK-3β的活性,可减少tau蛋白的过度磷酸化。
3.吡格列酮用于AD大鼠模型有效,可为AD的临床防治提供一条新的思路。
Objective：To investigate the effect of Pioglitazone on the learning memory and glycogensynthase kinase-3β、tau protein phosphorylation in model of Alzheimer’s disease rats, andexplore the therapeutical effect on AD rats and the potential mechanism of action ofPioglitazone.
Methods：
1. Establishment of AD rats model. Okadaic acid (OA) was injected into the hippocampus CA1region overnight, four times totally.
2. Pioglitazone made suspension to intragastric administration; the rats were measured bloodglucose.
3. Behavior was tested by the Morris water maze.
4. Research the relationship between GSK-3βand tau protein phosphorylation. The GSK-3βandtau protein hyperphosphorylation were detected by immunohistochemistry staining.
Results：
1. Determination of peripheral blood glucose: blood glucose of rats compared with before andafter using medicine were no significant difference(P>0.05).
2. The Morris water maze test manifested: compared with the control group, the model grouprats have longer escape latency(P<0.05), moreover, the percentage of terrace quadrantswimming path length occupying total path length is the shorter than the control group(P<0.05);compared with the model group, low and high dose of Pioglitazone group rats have shorterescape latency(P<0.05), the percentage of terrace quadrant swimming path length occupyingtotal path length is the longer than the model group(P<0.05), but there is no significantdifference between two groups rats(P>0.05).
3. The activity of GSK-3β: compared with the control group, the model group rats haveobviously positive cells, the grey scale is lower(P<0.05); compared with the model group, lowand high dose of Pioglitazone group rats have not obviously positive cells, the grey scale ishigher(P<0.05), but there is no significant difference between two groups(P>0.05).
4. The activity of tau protein phosphorylation: compared with the control group, the model grouprats have obviously positive cells, the grey scale is lower(P<0.05); compared with the modelgroup, low and high dose of Pioglitazone group rats have not obviously positive cells, the grey scale is higher(P<0.05), but there is no significant difference between two groups(P>0.05).
Conclusion：
1. AD rats were successfully induced by injected OA into the hippocampus CA1 region.
2. Pioglitazone can improve the learning and memory ability of AD rats, it may reduce tauprotein phosphorylation by reducing the activity of GSK-3β, AD may be related with insulinsignal transduction.
3. Pioglitazone is effective for AD rats, moreover it provide a new idea for Alzheimer’s disease.
方法:
1.AD大鼠模型的制备。根据大鼠脑立体定位图谱,用脑立体定位仪定位,向大鼠右侧海马CA1区微量注射冈田酸(OA),隔日一次,共4次,制备AD大鼠模型。
2.吡格列酮制成混悬液灌胃,各组大鼠分别于灌胃前、后尾静脉采血,微量血糖仪测定外周血糖。
3.用Morris水迷宫行大鼠行为学检测。
4.GSK-3β与tau蛋白磷酸化表达的研究。采用免疫组化法观察大鼠海马内GSK-3β的表达及tau蛋白磷酸化的表达。
结果:
1.外周血糖测定:各组大鼠灌胃前、后血糖相比较无显著差异(P>0.05)。
2.Morris水迷宫检测结果:模型组大鼠平均逃避潜伏期较对照组明显延长(P<0.05),且较对照组游泳平台象限的路径长度占总路径长度的百分比明显减少(P<0.05);低、高吡格列酮组大鼠平均逃避潜伏期较模型组明显缩短(P<0.05),且较模型组游泳平台象限的路径长度占总路径长度的百分比明显增大(P<0.05),但低、高吡格列酮组大鼠二者比较无显著差异(P>0.05)。
3.大鼠海马GSK-3β的表达:模型组大鼠较对照组GSK-3β的阳性表达明显增多,平均灰度值明显降低(P<0.05);低、高吡格列酮组大鼠较模型组GSK-3β的阳性表达明显减少,平均灰度值明显增高(P<0.05),但二者比较无显著差异(P>0.05)。
4.大鼠海马tau蛋白磷酸化的表达:模型组大鼠较对照组tau蛋白磷酸化的阳性表达明显增多,平均灰度值明显降低(P<0.05);低、高吡格列酮组大鼠较模型组tau蛋白磷酸化的阳性表达明显减少,平均灰度值明显增高(P<0.05),但二者比较无显著差异(P>0.05)。
结论:
1.大鼠右侧海马CA1区多次微量注射OA制备AD动物模型,成功模拟了AD学习记忆能力的减退及tau蛋白过度磷酸化的病理改变。
2.吡格列酮用于AD大鼠模型,对其血糖无显著影响,但提高了其学习记忆能力,减少了GSK-3β及tau蛋白过度磷酸化的表达,可认为AD的发生与胰岛素信号传导系统异常有关。吡格列酮通过调整胰岛素信号传导系统功能,增加胰岛素敏感性,降低GSK-3β的活性,可减少tau蛋白的过度磷酸化。
3.吡格列酮用于AD大鼠模型有效,可为AD的临床防治提供一条新的思路。
Objective：To investigate the effect of Pioglitazone on the learning memory and glycogensynthase kinase-3β、tau protein phosphorylation in model of Alzheimer’s disease rats, andexplore the therapeutical effect on AD rats and the potential mechanism of action ofPioglitazone.
Methods：
1. Establishment of AD rats model. Okadaic acid (OA) was injected into the hippocampus CA1region overnight, four times totally.
2. Pioglitazone made suspension to intragastric administration; the rats were measured bloodglucose.
3. Behavior was tested by the Morris water maze.
4. Research the relationship between GSK-3βand tau protein phosphorylation. The GSK-3βandtau protein hyperphosphorylation were detected by immunohistochemistry staining.
Results：
1. Determination of peripheral blood glucose: blood glucose of rats compared with before andafter using medicine were no significant difference(P>0.05).
2. The Morris water maze test manifested: compared with the control group, the model grouprats have longer escape latency(P<0.05), moreover, the percentage of terrace quadrantswimming path length occupying total path length is the shorter than the control group(P<0.05);compared with the model group, low and high dose of Pioglitazone group rats have shorterescape latency(P<0.05), the percentage of terrace quadrant swimming path length occupyingtotal path length is the longer than the model group(P<0.05), but there is no significantdifference between two groups rats(P>0.05).
3. The activity of GSK-3β: compared with the control group, the model group rats haveobviously positive cells, the grey scale is lower(P<0.05); compared with the model group, lowand high dose of Pioglitazone group rats have not obviously positive cells, the grey scale ishigher(P<0.05), but there is no significant difference between two groups(P>0.05).
4. The activity of tau protein phosphorylation: compared with the control group, the model grouprats have obviously positive cells, the grey scale is lower(P<0.05); compared with the modelgroup, low and high dose of Pioglitazone group rats have not obviously positive cells, the grey scale is higher(P<0.05), but there is no significant difference between two groups(P>0.05).
Conclusion：
1. AD rats were successfully induced by injected OA into the hippocampus CA1 region.
2. Pioglitazone can improve the learning and memory ability of AD rats, it may reduce tauprotein phosphorylation by reducing the activity of GSK-3β, AD may be related with insulinsignal transduction.
3. Pioglitazone is effective for AD rats, moreover it provide a new idea for Alzheimer’s disease.
引文
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[5] Bialojan C, Takai A. Inhibitory effect of a marine-sponge toxin, okadaic acid, on proteinphosphatases-Specificity and kinetics[J]. Biochem J, 1988, 256: 283-290
[6] Tanimukai H, Grundke-Iqbal I, Iqbal K. Up-regulation of inhibitors of proteinphosphatase-2A in Alzheimer’s disease[J]. Am J Pathol, 2005, 166(6): 1761-1771
[7] Arendt T, Holzer M, Fruth R, et al. Paired helical filament-like phosphorylation of tau,deposition ofβ/A4-amyloid and memory impairment in rat induced by chronic inhibition ofphosphatase 1 and 2A[J]. Neuroscience, 1995, 69: 691-698
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