β-细辛醚对AD大鼠学习记忆的影响及血管保护机制研究
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摘要
目的：建立Wista大鼠阿尔茨海默病(Alzheimer's disease, AD)模型,观察AD大鼠模型学习记忆功能及血管损伤和保护性因素的变化,探讨石菖蒲活性成分β-细辛醚化痰开窍益智防治AD的药效学基础及其血管保护机制,为AD的防治提供新的思路。
方法：应用D-半乳糖(D-galactose, D-gal)联合三氯化铝(Aluminium trichloride, ALCL3)腹腔注射造成AD模型；皮下注射β-细辛醚进行治疗；应用Morris水迷宫进行行为学测试；应用激光多普勒血流仪检测脑顶叶局部脑血流量,血液流变仪检测血液流变学指标,全自动生化分析仪检测血脂四项,比色法检测皮层乳酸(Lactic acid, LA)、丙酮酸(Pyruvic acid, PA)和Na-K-ATP酶活性,real-time RT-PCR的方法检测大鼠海马ET-1、eNOS和APP mRNA的表达；应用SPSS15.0软件对实验数据进行统计分析。
结果：
1.模型组大鼠定向航行试验逃避潜伏期,空间探索试验穿越平台次数和第一次穿越平台时间,脑顶叶局部脑血流量和红细胞浓度、全血粘度、血浆粘度、红细胞压积、红细胞电泳时间和纤维蛋白原等血液流变学指标、甘油三酯(Triglyeride,TG)、低密度脂蛋白(Low density lipoprotein-cholesterol, LDL-C)和高密度脂蛋白(High density lipoprotein-cholesterol, HDL-C)、皮层LA含量、PA含量与Na-K-ATP酶活性、海马ET-1和eNOS mRNA的表达等各项实验结果与空白组比较,P<0.05；海马APP mRNA的表达与空白组比较,P>0.05,但表达水平较高；
2.与尼莫地平组相比,β-细辛醚低、中、高剂量组AD大鼠定向航行试验逃避潜伏期较短,P<0.05；与石菖蒲组相比,β-细辛醚低、中、高剂量组AD大鼠定向航行试验逃避潜伏期无差异,P>0.05；
3.与模型组相比,β-细辛醚高剂量组AD大鼠定向航行试验逃避潜伏期较短,在平台象限穿越次数较多,脑顶叶局部脑血流量和红细胞浓度较高,全血粘度、血浆粘度、红细胞压积和纤维蛋白原等指标降低,红细胞电泳时间缩短,总胆固醇(Total cholesterol, TC)降低,LDL-C降低,皮层PA降低、Na-K-ATP酶活性升高,ET-1 mRNA表达降低,P<0.05,APP和eNOS mRNA的表达与模型组比较,P>0.05,但表达水平较低；与空白组比较,β-细辛醚高剂量组AD大鼠LDL-C水平无差异,P>0.05；
4.与模型组相比,β-细辛醚中剂量组AD大鼠定向航行试验逃避潜伏期较短,全血粘度、红细胞压积和纤维蛋白原等指标降低,红细胞电泳时间缩短,TC降低,LDL-C降低,皮层PA降低,P<0.05；中剂量组AD大鼠LDL-C与空白组大鼠比较,P<0.05；
5.与模型组相比,β-细辛醚低剂量组AD大鼠定向航行试验逃避潜伏期较短,全血粘度、红细胞压积和纤维蛋白原等指标降低,红细胞电泳时间缩短,LDL-C降低,皮层PA降低,P<0.05；低剂量组AD大鼠LDL-C与空白组大鼠比较,P<0.05；
6.与模型组相比,尼莫地平组AD大鼠全血粘度、红细胞压积和纤维蛋白原等指标降低,红细胞电泳时间缩短,皮层PA降低,P<0.05；
7.与模型组相比,石菖蒲组AD大鼠全血粘度、红细胞压积和纤维蛋白原等指标降低,红细胞电泳时间缩短,TG和LDL-C降低,P<0.05；石菖蒲组AD大鼠LDL-C与空白组大鼠比较,P<0.05。
结论：
1.D-GAL (60mg/kg/d)联合ALCL3 (10mg/kg/d)腹腔注射造成的AD大鼠模型存在学习能力和记忆能力的障碍,存在多种血管性危险因素；脑代谢低下；海马ET-1和eNOSmRNA表达水平升高,APP mRNA表达水平也有升高的趋势,是研究药物血管保护作用和机制的理想AD动物模型；
2.β-细辛醚高剂量可以全面改善AD大鼠学习和记忆能力；β-细辛醚中剂量(50mg/kg/d)和低剂量(25mg/kg/d)可以改善AD大鼠的学习能力；
3.β-细辛醚高剂量可以改善AD大鼠顶叶皮层局部脑血流量、红细胞浓度的下降；
4.β-细辛醚低剂量、中剂量、高剂量组、尼莫地平和石菖蒲均可以不同程度的改善AD大鼠血液流变学,以β-细辛醚高剂量最好；
5.β-细辛醚低中高剂量均可以不同程度的降低AD大鼠的TC和LDL-C,β-细辛醚高剂量效果最好；石菖蒲可以降低AD大鼠的TG和LDL-C水平,在降低TG上优于β-细辛醚,在降低LDL-C上差于β-细辛醚高剂量；
6.β-细辛醚低中高剂量和尼莫地平可不同程度的改善脑代谢,β-细辛醚高剂量效果最好；
7.β-细辛醚具有化痰开窍益智防治痴呆的功效；
8.β-细辛醚高剂量可以抑制AD大鼠ET-1 mRNA表达水平的升高,对AD大鼠海马eNOS和APP mRNA表达水平的升高有对抗趋势,可能是其防治AD的血管保护机制之一。
Objective:
To investgate the changes of the ability of learning and memory and the vascular system in AD rats after establishing an AD model in wistar rats. And to investgate the pharmacodynamic effects and mechanisms of vascular protection of B-asarone on AD rats, so as to provide a new approach for prevention and treatment of AD.
Methods:
The rat model of AD was established by injecting both D-galactose and aluminum chloride into abdominal cavity. Their learning and memory were tested with Morris maze; Regional cerebral blood flow (rCBF) changes of right parietal lobe were measured with laser Doppler(LDP); Hemorrheologic changes were tesed by hemorheological analyser; The four reference indicators of the serum lipid were measured by full automatic biochemical analyser. The contents of lactic acid, pyruvic acid, and the activity of Na-K-ATP of cortex were measured by colorimetry. mRNA expression of ET-1,eNOS and APP was measured with real-time RT-PCR method; All the data was analyzed by SPSS 15.0.
Results:
1.The spatial navigation task latencies, the times through platform zone and the time for the first through platform zone in the target quadrant in probe task, rCBF and blood cell concentration of right parietal lobe, whole blood viscosity and plasma viscosity, hematocrit, erythrocyte electrophoretic time, fibrinogen,the levels of triglyceride, low density lipoprotein, high density lipoprotein, the contents of lactic acid, pyruvic acid, and the activity of Na-K-ATP of cortex, and ET-1 and eNOS mRNA expression in hippocampus of model control group rats were different from those of blank control group, P<0.05; The level of APP mRNA expression in model control group rats was higher than that in blank control group, though there was not a statistical difference, P>0.05;
2. Compared with nimodipine group, (?)-asarone high does group, (?)-asarone middle does group and (?)-asarone low does group rats spatial navigation task latencies were shorter, P<0.05; Compared with Acorus tatarinowii schott group, (?)-asarone high does group,β-asarone middle does group and B-asarone low does group rats spatial navigation task latencies were not shorter, P>0.05;
3. Compared with model control group, (?)-asarone high does group rats spatial navigation task latencies were shorter, in probe task the times through platform zone in the target quadrant were bigger, rCBF and blood cell concentration of right parietal lobe were higher, whole blood viscosity and plasma viscosity, hematocrit and fibrinogen were lower, erythrocyte electrophoretic time was shorter, the levels of total cholesterol and low density lipoprotein were lower, the contents of pyruvic acid was lower, the activity of Na-K-ATP was higher, and ET-1 mRNA expression in hippocampus was lower, P<0.05; The level of eNOS and APP mRNA expression in high does group rats was lower than that in model control group, though there was not a statistical difference, P>0.05; There was not a statistical difference in the level of low density lipoprotein of AD rats between high does group and blank control group, P>0.05;
4. Compared with model control group, (?)-asarone middle does group rats spatial navigation task latencies were shorter, whole blood viscosity, hematocrit and fibrinogen were lower, erythrocyte electrophoretic time was shorter, the levels of total cholesterol and low density lipoprotein were lower, and the contents of pyruvic acid was lower, P<0.05; There was a statistical difference in the level of low density lipoprotein of AD rats between acorus tatarinowii schott group and blank control group, P<0.05;
5. Compared with model control group,(?)-asarone low does group rats spatial navigation task latencies were shorter, whole blood viscosity, hematocrit and fibrinogen were lower, erythrocyte electrophoretic time was shorter, the levels of low density lipoprotein were lower, the contents of pyruvic acid was lower, P<0.05;.
6. Compared with model control group, nimodipine group rats whole blood viscosity, hematocrit and fibrinogen were lower, erythrocyte electrophoretic time was shorter, the contents of pyruvic acid was lower, P<0.05;
7. Compared with model control group, Acorus tatarinowii schott group rats whole blood viscosity and plasma viscosity, hematocrit and fibrinogen were lower, erythrocyte electrophoretic time was shorter, the levels of triglyceride and low density lipoprotein were lower, P<0.05; There was a statistical difference in the level of low density lipoprotein of AD rats between acorus tatarinowii schott group and blank control group, P<0.05;
Conclusions:
1. The rat model of AD established by injecting both D-galactose and aluminum chloride into abdominal cavity maybe have lower learning and memory, several vascular risks, cerebral metabolism dysfunction and higher ET-1 and eNOS mRNA expression in hippocampus, which might be a useful model for studies on the therapeutic effects and mechanisms of vascular protection of drugs for AD.
2. High does of (?)-asarone could enhance AD rats' learning and memory; Middle and low does of B-asarone could enhance AD rats' learning;
3. High does of (?)-asarone could enhance AD rats' rCBF and blood cell concentration of right parietal lobe;
4. Low, middle and high does of (?)-asarone, nimodipine and Acorus tatarinowii schott could improve AD rats' hemorrheology, and high does of (?)-asarone is best among them;
5. Low, middle and high does of (?)-asarone could decrease the levels of total cholesterol and low density lipoprotein, and high does of (?)-asarone is best among them; Acorus tatarinowii schott could decrease the levels of triglyceride and low density lipoprotein; and high does of B-asarone decrease the levels of low density lipoprotein better than Acorus tatarinowii schott;
6. Low, middle and high does of (?)-asarone and nimodipine could improve AD rats' cerebral metabolism, and high does of B-asarone is best among them;
7. (?)-asarone could dissipate phlegm for resuscitation and grow in intelligence and treat AD;
8. High does of (?)-asarone could downregulate ET-1 mRNA expression in hippocampus of AD Rats, and maybe downregulate eNOS and APP mRNA expression, which elucidate the mechanisms of vascular protection of (?)-asarone on AD rats.
方法：应用D-半乳糖(D-galactose, D-gal)联合三氯化铝(Aluminium trichloride, ALCL3)腹腔注射造成AD模型；皮下注射β-细辛醚进行治疗；应用Morris水迷宫进行行为学测试；应用激光多普勒血流仪检测脑顶叶局部脑血流量,血液流变仪检测血液流变学指标,全自动生化分析仪检测血脂四项,比色法检测皮层乳酸(Lactic acid, LA)、丙酮酸(Pyruvic acid, PA)和Na-K-ATP酶活性,real-time RT-PCR的方法检测大鼠海马ET-1、eNOS和APP mRNA的表达；应用SPSS15.0软件对实验数据进行统计分析。
结果：
1.模型组大鼠定向航行试验逃避潜伏期,空间探索试验穿越平台次数和第一次穿越平台时间,脑顶叶局部脑血流量和红细胞浓度、全血粘度、血浆粘度、红细胞压积、红细胞电泳时间和纤维蛋白原等血液流变学指标、甘油三酯(Triglyeride,TG)、低密度脂蛋白(Low density lipoprotein-cholesterol, LDL-C)和高密度脂蛋白(High density lipoprotein-cholesterol, HDL-C)、皮层LA含量、PA含量与Na-K-ATP酶活性、海马ET-1和eNOS mRNA的表达等各项实验结果与空白组比较,P<0.05；海马APP mRNA的表达与空白组比较,P>0.05,但表达水平较高；
2.与尼莫地平组相比,β-细辛醚低、中、高剂量组AD大鼠定向航行试验逃避潜伏期较短,P<0.05；与石菖蒲组相比,β-细辛醚低、中、高剂量组AD大鼠定向航行试验逃避潜伏期无差异,P>0.05；
3.与模型组相比,β-细辛醚高剂量组AD大鼠定向航行试验逃避潜伏期较短,在平台象限穿越次数较多,脑顶叶局部脑血流量和红细胞浓度较高,全血粘度、血浆粘度、红细胞压积和纤维蛋白原等指标降低,红细胞电泳时间缩短,总胆固醇(Total cholesterol, TC)降低,LDL-C降低,皮层PA降低、Na-K-ATP酶活性升高,ET-1 mRNA表达降低,P<0.05,APP和eNOS mRNA的表达与模型组比较,P>0.05,但表达水平较低；与空白组比较,β-细辛醚高剂量组AD大鼠LDL-C水平无差异,P>0.05；
4.与模型组相比,β-细辛醚中剂量组AD大鼠定向航行试验逃避潜伏期较短,全血粘度、红细胞压积和纤维蛋白原等指标降低,红细胞电泳时间缩短,TC降低,LDL-C降低,皮层PA降低,P<0.05；中剂量组AD大鼠LDL-C与空白组大鼠比较,P<0.05；
5.与模型组相比,β-细辛醚低剂量组AD大鼠定向航行试验逃避潜伏期较短,全血粘度、红细胞压积和纤维蛋白原等指标降低,红细胞电泳时间缩短,LDL-C降低,皮层PA降低,P<0.05；低剂量组AD大鼠LDL-C与空白组大鼠比较,P<0.05；
6.与模型组相比,尼莫地平组AD大鼠全血粘度、红细胞压积和纤维蛋白原等指标降低,红细胞电泳时间缩短,皮层PA降低,P<0.05；
7.与模型组相比,石菖蒲组AD大鼠全血粘度、红细胞压积和纤维蛋白原等指标降低,红细胞电泳时间缩短,TG和LDL-C降低,P<0.05；石菖蒲组AD大鼠LDL-C与空白组大鼠比较,P<0.05。
结论：
1.D-GAL (60mg/kg/d)联合ALCL3 (10mg/kg/d)腹腔注射造成的AD大鼠模型存在学习能力和记忆能力的障碍,存在多种血管性危险因素；脑代谢低下；海马ET-1和eNOSmRNA表达水平升高,APP mRNA表达水平也有升高的趋势,是研究药物血管保护作用和机制的理想AD动物模型；
2.β-细辛醚高剂量可以全面改善AD大鼠学习和记忆能力；β-细辛醚中剂量(50mg/kg/d)和低剂量(25mg/kg/d)可以改善AD大鼠的学习能力；
3.β-细辛醚高剂量可以改善AD大鼠顶叶皮层局部脑血流量、红细胞浓度的下降；
4.β-细辛醚低剂量、中剂量、高剂量组、尼莫地平和石菖蒲均可以不同程度的改善AD大鼠血液流变学,以β-细辛醚高剂量最好；
5.β-细辛醚低中高剂量均可以不同程度的降低AD大鼠的TC和LDL-C,β-细辛醚高剂量效果最好；石菖蒲可以降低AD大鼠的TG和LDL-C水平,在降低TG上优于β-细辛醚,在降低LDL-C上差于β-细辛醚高剂量；
6.β-细辛醚低中高剂量和尼莫地平可不同程度的改善脑代谢,β-细辛醚高剂量效果最好；
7.β-细辛醚具有化痰开窍益智防治痴呆的功效；
8.β-细辛醚高剂量可以抑制AD大鼠ET-1 mRNA表达水平的升高,对AD大鼠海马eNOS和APP mRNA表达水平的升高有对抗趋势,可能是其防治AD的血管保护机制之一。
Objective:
To investgate the changes of the ability of learning and memory and the vascular system in AD rats after establishing an AD model in wistar rats. And to investgate the pharmacodynamic effects and mechanisms of vascular protection of B-asarone on AD rats, so as to provide a new approach for prevention and treatment of AD.
Methods:
The rat model of AD was established by injecting both D-galactose and aluminum chloride into abdominal cavity. Their learning and memory were tested with Morris maze; Regional cerebral blood flow (rCBF) changes of right parietal lobe were measured with laser Doppler(LDP); Hemorrheologic changes were tesed by hemorheological analyser; The four reference indicators of the serum lipid were measured by full automatic biochemical analyser. The contents of lactic acid, pyruvic acid, and the activity of Na-K-ATP of cortex were measured by colorimetry. mRNA expression of ET-1,eNOS and APP was measured with real-time RT-PCR method; All the data was analyzed by SPSS 15.0.
Results:
1.The spatial navigation task latencies, the times through platform zone and the time for the first through platform zone in the target quadrant in probe task, rCBF and blood cell concentration of right parietal lobe, whole blood viscosity and plasma viscosity, hematocrit, erythrocyte electrophoretic time, fibrinogen,the levels of triglyceride, low density lipoprotein, high density lipoprotein, the contents of lactic acid, pyruvic acid, and the activity of Na-K-ATP of cortex, and ET-1 and eNOS mRNA expression in hippocampus of model control group rats were different from those of blank control group, P<0.05; The level of APP mRNA expression in model control group rats was higher than that in blank control group, though there was not a statistical difference, P>0.05;
2. Compared with nimodipine group, (?)-asarone high does group, (?)-asarone middle does group and (?)-asarone low does group rats spatial navigation task latencies were shorter, P<0.05; Compared with Acorus tatarinowii schott group, (?)-asarone high does group,β-asarone middle does group and B-asarone low does group rats spatial navigation task latencies were not shorter, P>0.05;
3. Compared with model control group, (?)-asarone high does group rats spatial navigation task latencies were shorter, in probe task the times through platform zone in the target quadrant were bigger, rCBF and blood cell concentration of right parietal lobe were higher, whole blood viscosity and plasma viscosity, hematocrit and fibrinogen were lower, erythrocyte electrophoretic time was shorter, the levels of total cholesterol and low density lipoprotein were lower, the contents of pyruvic acid was lower, the activity of Na-K-ATP was higher, and ET-1 mRNA expression in hippocampus was lower, P<0.05; The level of eNOS and APP mRNA expression in high does group rats was lower than that in model control group, though there was not a statistical difference, P>0.05; There was not a statistical difference in the level of low density lipoprotein of AD rats between high does group and blank control group, P>0.05;
4. Compared with model control group, (?)-asarone middle does group rats spatial navigation task latencies were shorter, whole blood viscosity, hematocrit and fibrinogen were lower, erythrocyte electrophoretic time was shorter, the levels of total cholesterol and low density lipoprotein were lower, and the contents of pyruvic acid was lower, P<0.05; There was a statistical difference in the level of low density lipoprotein of AD rats between acorus tatarinowii schott group and blank control group, P<0.05;
5. Compared with model control group,(?)-asarone low does group rats spatial navigation task latencies were shorter, whole blood viscosity, hematocrit and fibrinogen were lower, erythrocyte electrophoretic time was shorter, the levels of low density lipoprotein were lower, the contents of pyruvic acid was lower, P<0.05;.
6. Compared with model control group, nimodipine group rats whole blood viscosity, hematocrit and fibrinogen were lower, erythrocyte electrophoretic time was shorter, the contents of pyruvic acid was lower, P<0.05;
7. Compared with model control group, Acorus tatarinowii schott group rats whole blood viscosity and plasma viscosity, hematocrit and fibrinogen were lower, erythrocyte electrophoretic time was shorter, the levels of triglyceride and low density lipoprotein were lower, P<0.05; There was a statistical difference in the level of low density lipoprotein of AD rats between acorus tatarinowii schott group and blank control group, P<0.05;
Conclusions:
1. The rat model of AD established by injecting both D-galactose and aluminum chloride into abdominal cavity maybe have lower learning and memory, several vascular risks, cerebral metabolism dysfunction and higher ET-1 and eNOS mRNA expression in hippocampus, which might be a useful model for studies on the therapeutic effects and mechanisms of vascular protection of drugs for AD.
2. High does of (?)-asarone could enhance AD rats' learning and memory; Middle and low does of B-asarone could enhance AD rats' learning;
3. High does of (?)-asarone could enhance AD rats' rCBF and blood cell concentration of right parietal lobe;
4. Low, middle and high does of (?)-asarone, nimodipine and Acorus tatarinowii schott could improve AD rats' hemorrheology, and high does of (?)-asarone is best among them;
5. Low, middle and high does of (?)-asarone could decrease the levels of total cholesterol and low density lipoprotein, and high does of (?)-asarone is best among them; Acorus tatarinowii schott could decrease the levels of triglyceride and low density lipoprotein; and high does of B-asarone decrease the levels of low density lipoprotein better than Acorus tatarinowii schott;
6. Low, middle and high does of (?)-asarone and nimodipine could improve AD rats' cerebral metabolism, and high does of B-asarone is best among them;
7. (?)-asarone could dissipate phlegm for resuscitation and grow in intelligence and treat AD;
8. High does of (?)-asarone could downregulate ET-1 mRNA expression in hippocampus of AD Rats, and maybe downregulate eNOS and APP mRNA expression, which elucidate the mechanisms of vascular protection of (?)-asarone on AD rats.
引文
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