褪黑素与西拉普利干预高血压大鼠基底前脑和海马细胞凋亡及学习记忆的比较研究
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摘要
目的探讨褪黑素及西拉普利对肾性高血压模型大鼠学习记忆障碍及基底前脑(Meynert基核、斜角带核垂直支)和海马两个亚区(CA1、CA3)细胞凋亡以及凋亡相关基因Bax与Bcl-2蛋白表达的影响模式。
方法将成年健康雄性SD大鼠随机分为四个组:假手术组、高血压组、褪黑素组和西拉普利组,在建立肾性高血压模型及进行相应处理方式后,定期测量大鼠的血压、用Morris水迷宫测定大鼠的学习记忆能力、免疫组织化学检验方法观察Bax及Bcl-2阳性细胞数的变化、TUNEL原位分子杂交技术检测发生凋亡的趋势。
结果高血压组大鼠与假手术组大鼠相比较,基底前脑及海马各亚区TUNEL阳性细胞数和Bax阳性细胞数显著上升,而Bcl-2/Bax比值明显下降,学习记忆能力也明显下降(p<0.05)。西拉普利组大鼠较高血压组大鼠的血压明显下降(p<0.05),Bax阳性细胞数明显减少,Bcl-2/Bax比值上升,TUNEL阳性细胞数减少,学习记忆能力得以明显提高(p<0.05);褪黑素组大鼠与高血压组大鼠比较血压稍下降(p>0.05),与西拉普利组大鼠的血压值比较明显升高(p<0.05),褪黑素组大鼠与高血压组比较Bax阳性细胞数无明显减少(p>0.05),Bcl-2的阳性细胞数显著增加(p<0.05), Bcl-2/Bax明显升高,TUNEL阳性细胞数也明显减少(p<0.05),并且学习记忆能力也有明显改善(p<0.05)。
结论应用西拉普利治疗可调整肾性高血压模型大鼠血压至正常水平,阻止Meynert基底核、斜角带核垂直支及海马CA1、CA3区抗凋亡基因Bcl-2蛋白质和凋亡基因Bax表达水平比例失常而引发的细胞凋亡过度,改善学习记忆能力;褪黑素干预后,血压下降不明显,但是能调节Bax和Bcl-2蛋白表达,纠正细胞凋亡过度,改善学习记忆障碍。提示联合应用西拉普利与褪黑素可能是早期防治高血压及其脑并发症的一种具有潜力的药物配伍干预方案。
Objective:To investigate the effects of melatonin and cilazapril on the change in memory, Bax/Bcl-2 protein and cellular apoptosis in basal forebrain(nucleus basalis of Meynert ; vertical limb of diagonal band of Broca,vDB)and hippocampal subdivisions(CA1、CA3)of renal hypertensive rats.
Methods: Healthy adult Sprague-Dawley rats were randomly divided into following four groups with ten rats in each group: sham, renovascular hypertensive plus vehicle treatment, renovaseular hypertensive plus melatonin treatment, renovaseular hypertensive plus cilazapril treatment. After the renal hypertension model was established, the four group rats received corresponding treatments, and blood pressure was measured accordingly. Learning and memory were detected in Morris water maze. Bcl-2/Bax protein or apoptotic cells in the above brain areas were examined by immunohistochemistoy or by TUNEL technique.
Results: The number of Bax immunoreactive (Bax-IR)cells and apoptotic cells in basal forebrain and hippocampal subdivisions increased significantly (p<0.05),but the ratio of Bcl-2/ Bax and the ability of learning and memory significantly decreased in renovascular hypertensive group rats, compared with those of sham operation group (p<0.05). Comparing with those of renovascular hypertensive plus vehicle treatment, the blood pressure and the number of Bax-IR cells and apoptotic cells significantly decreased (p<0.05), the ratio of Bcl-2/ Bax and the ability of learning and memory also significantly increased (p<0.05) in renovaseular hypertensive plus cilazapril treatment. Compared with those of renovascular hypertensive plus vechicle treatments rats, the blood pressure decreased slightly in melatonin-treated group, but was significantly higher than that of renovascular hypertensive plus vichicle or cilazapril treatment rats (p<0.05), the number of Bax-IR cells of metatonin group was not significantly different from that of renovascular hypertensive group(p>0.05). However, the number of Bcl-2-IR cells and the ratio of Bcl-2/ Bax in cilazapril-treated group significantly increased, while the number of apoptotic cells was significantly decreased, but the ability of learning and memory of the cilazapril group increased (p<0.05).
Conclusions:The blood pressure may be adjusted to normal level,and the imbalance of the ratio of Bcl-2/ Bax is corrected by cilazapril, which leads to lowering the number of apoptosis cells, improving the impaired ability of learning and memory. Blood pressure slightly is affected, and the protein expression of Bax and Bcl-2, is regulated by melatonin,which results in proventing excessive apoptosis, and retifying impaired of learning and memory of hypertensive rats.
方法将成年健康雄性SD大鼠随机分为四个组:假手术组、高血压组、褪黑素组和西拉普利组,在建立肾性高血压模型及进行相应处理方式后,定期测量大鼠的血压、用Morris水迷宫测定大鼠的学习记忆能力、免疫组织化学检验方法观察Bax及Bcl-2阳性细胞数的变化、TUNEL原位分子杂交技术检测发生凋亡的趋势。
结果高血压组大鼠与假手术组大鼠相比较,基底前脑及海马各亚区TUNEL阳性细胞数和Bax阳性细胞数显著上升,而Bcl-2/Bax比值明显下降,学习记忆能力也明显下降(p<0.05)。西拉普利组大鼠较高血压组大鼠的血压明显下降(p<0.05),Bax阳性细胞数明显减少,Bcl-2/Bax比值上升,TUNEL阳性细胞数减少,学习记忆能力得以明显提高(p<0.05);褪黑素组大鼠与高血压组大鼠比较血压稍下降(p>0.05),与西拉普利组大鼠的血压值比较明显升高(p<0.05),褪黑素组大鼠与高血压组比较Bax阳性细胞数无明显减少(p>0.05),Bcl-2的阳性细胞数显著增加(p<0.05), Bcl-2/Bax明显升高,TUNEL阳性细胞数也明显减少(p<0.05),并且学习记忆能力也有明显改善(p<0.05)。
结论应用西拉普利治疗可调整肾性高血压模型大鼠血压至正常水平,阻止Meynert基底核、斜角带核垂直支及海马CA1、CA3区抗凋亡基因Bcl-2蛋白质和凋亡基因Bax表达水平比例失常而引发的细胞凋亡过度,改善学习记忆能力;褪黑素干预后,血压下降不明显,但是能调节Bax和Bcl-2蛋白表达,纠正细胞凋亡过度,改善学习记忆障碍。提示联合应用西拉普利与褪黑素可能是早期防治高血压及其脑并发症的一种具有潜力的药物配伍干预方案。
Objective:To investigate the effects of melatonin and cilazapril on the change in memory, Bax/Bcl-2 protein and cellular apoptosis in basal forebrain(nucleus basalis of Meynert ; vertical limb of diagonal band of Broca,vDB)and hippocampal subdivisions(CA1、CA3)of renal hypertensive rats.
Methods: Healthy adult Sprague-Dawley rats were randomly divided into following four groups with ten rats in each group: sham, renovascular hypertensive plus vehicle treatment, renovaseular hypertensive plus melatonin treatment, renovaseular hypertensive plus cilazapril treatment. After the renal hypertension model was established, the four group rats received corresponding treatments, and blood pressure was measured accordingly. Learning and memory were detected in Morris water maze. Bcl-2/Bax protein or apoptotic cells in the above brain areas were examined by immunohistochemistoy or by TUNEL technique.
Results: The number of Bax immunoreactive (Bax-IR)cells and apoptotic cells in basal forebrain and hippocampal subdivisions increased significantly (p<0.05),but the ratio of Bcl-2/ Bax and the ability of learning and memory significantly decreased in renovascular hypertensive group rats, compared with those of sham operation group (p<0.05). Comparing with those of renovascular hypertensive plus vehicle treatment, the blood pressure and the number of Bax-IR cells and apoptotic cells significantly decreased (p<0.05), the ratio of Bcl-2/ Bax and the ability of learning and memory also significantly increased (p<0.05) in renovaseular hypertensive plus cilazapril treatment. Compared with those of renovascular hypertensive plus vechicle treatments rats, the blood pressure decreased slightly in melatonin-treated group, but was significantly higher than that of renovascular hypertensive plus vichicle or cilazapril treatment rats (p<0.05), the number of Bax-IR cells of metatonin group was not significantly different from that of renovascular hypertensive group(p>0.05). However, the number of Bcl-2-IR cells and the ratio of Bcl-2/ Bax in cilazapril-treated group significantly increased, while the number of apoptotic cells was significantly decreased, but the ability of learning and memory of the cilazapril group increased (p<0.05).
Conclusions:The blood pressure may be adjusted to normal level,and the imbalance of the ratio of Bcl-2/ Bax is corrected by cilazapril, which leads to lowering the number of apoptosis cells, improving the impaired ability of learning and memory. Blood pressure slightly is affected, and the protein expression of Bax and Bcl-2, is regulated by melatonin,which results in proventing excessive apoptosis, and retifying impaired of learning and memory of hypertensive rats.
引文
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[27] Touyz RM, Chen X, Tabet F, et al. Expression of a functionally active gp91phox-containing neutrophil-type NAD(P)H oxidase in smooth muscle cells from human resistance arteries: regulation by angiotensin II. Circ Res, 2002, 90(2):1205–1213.
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[29] Callera GE, Tostes RC, Yogi A, et al. Endothelin-1-induced oxidative stress in DOCA-salt hypertension involves NADPH-oxidase-independent mechanisms [J].Clin Sci(Lond), 2006, 110(2): 243-253.
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[33]Simic DV, Mimic-Oka J, Pljesa-Ercegovac M, et al. Byproducts of oxidative protein damage and antioxidantenzyme activities in plasma ofpatientswith different degrees of essential hypertension. JHum Hypertens, 2006, 20(2): 149-155.
[34]Zhang GX, Kimura S,Nishiyama A, et al. ROS during the acute phase ofAngⅡh ypertension participates in cardiovascularMAPK activation butnotvasoconstriction. Hypertension, 2004, 43(1): 117-124.
[35]Elmarakby AA, Loomis ED, Pollock JS, et al. NADPH oxidase inhibition attenuates oxidative stress butnothypertension produced by chronic ET-1.Hypertension, 2005, 45(2): 283-287.
[36]Banday AA, Lokhandwala MF. Oxidative stress-induced renal angiotensinAT1 receptorupregulation causes increased stimulation of sodium transporters and hypertension.Am J Physiol Renal Physiol, 2008, 295(3):F698-F706.
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[38]Zalba G, San JoséG, Moreno MU, et al. NADPH oxidase-mediated oxidative stress: genetic studies of the p22 (phox) gene in hypertension. Antioxid Redox Signal, 2005, 7(9-10): 1327-1336.
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[47] Touyz RM, Schiffrin EL. Increased generation of superoxide by angiotensin II in smooth muscle cells from resistance arteries of hypertensive patients: role of phospholipase D-dependent NAD(P)H oxidase-sensitive pathways. J Hypertens, 2001, 19(4):1245–1254.
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