Niaspan对1型糖尿病大鼠脑缺血再灌注损伤的保护作用
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摘要
目的：研究1型糖尿病大鼠脑缺血再灌注损伤后脑血管的改变及其潜在的可能机制,探讨Niaspan对1型糖尿病大鼠脑缺血再灌注损伤的保护作用。
方法：首先使用链脲霉素诱导1型糖尿病大鼠模型,并在此基础上进行大脑中动脉缺血再灌注模型(T1DM-MCAo),同时也在健康大鼠上进行大脑中动脉缺血再灌注模型(WT-MCAo),造模成功后给予Niaspan药物干预1型糖尿病大鼠脑缺血再灌注模型,然后比较各组大鼠之间的神经功能缺损评分、血脑屏障通透性、微血管开放性及相关免疫染色指标检测,同时进行体外颈动脉细胞及大脑微血管内皮细胞培养,并比较药物干预对他们的影响。
结果：和WT-MCAo大鼠相比,T1DM-MCAo大鼠脑梗塞面积没有增加,但是脑出血的发生率和血脑屏障的通透性明显增加,同时血管的破坏也明显增加,微血管开放性明显降低,神经功能恢复明显变差。Niaspan治疗T1DM-MCAo大鼠可以明显提高微血管的开放性,降低血脑屏障的通透性,促进血管的重塑和成熟,促进脑梗塞后神经功能恢复。同时,我们也发现,和WT-MCAo大鼠相比,T1DM-MCAo大鼠缺血半暗带区Ang2的表达明显增加而Ang1的表达则降低,而Niaspan治疗可以明显提高T1DM-MCAo大鼠缺血半暗带区Ang1的表达并降低Ang2的表达。体外试验表明,和WT-MCAo大鼠相比,T1DM-MCAo起源的颈动脉细胞迁移能力明显降低,而Niacin和Ang1干预后可以明显提高T1DM-MCAo起源的颈动脉细胞迁移能力,中和Ang1后能够降低颈动脉细胞的迁移能力。类似的结果我们在大脑微血管内皮细胞集落形成试验中也观察到了。
结论：Niaspan能够促进TlDM-MCAo大鼠脑新生血管的重塑和成熟,改善脑梗塞后神经功能的恢复。Angl/Ang2信号通路在Niaspan诱导的脑保护作用中起一定作用。
Introduction:We investigated the changes and the molecular mechanisms of cerebral vascular damage and tested the therapeutic effects of Niaspan in type-1streptozotocin induced diabetic (T1DM) rats after stroke.
Methods:T1DM-rats were subjected to transient middle cerebral artery occlusion (MCAo) and treated without or with Niaspan. Non-streptozotocin rats (WT) were also subjected to MCAo. Functional outcome, blood-brain-barrier (BBB) leakage, microvascular patency, immunostaining and in vitro arterial explant cell culture were performed.
Results:Compared to WT-MCAo-rats, T1DM-MCAo-rats did not show an increase lesion volume, but exhibited significantly increased brain hemorrhage, BBB leakage and vascular damage as well as decreased microvascular patency and functional outcome after stroke. Niaspan treatment of stroke in T1DM-MCAo-rats significantly increased microvascular patency, attenuated BBB damage, promoted vascular remodeling and improved functional outcome after stroke. T1DM-MCAo-rats exhibited significantly increased Angiopoietin2(Ang2) expression, but decreased Angl expression in the ischemic brain compared to WT-MCAo-rats. Niaspan treatment attenuated Ang2, but increased Angl expression in the ischemic brain in T1DM-MCAo-rats. In vitro data show that arterial explant cell migration significantly decreased in arteries derived from T1DM-MCAo-rats compared to arteries from WT-MCAo-rats. Niacin and Angl treatment increased arterial explant cell migration in T1DM-artery. Anti-Angl significantly attenuated Niacin-induced arterial cell migration.
Conclusions:Niaspan treatment of stroke in T1DM-rats promotes vascular remodeling and improves functional outcome. The Angl/Ang2pathway may contribute to Niaspan induced brain plasticity. Niaspan warrants further investigation as a therapeutic agent for the treatment of stroke in diabetics.
方法：首先使用链脲霉素诱导1型糖尿病大鼠模型,并在此基础上进行大脑中动脉缺血再灌注模型(T1DM-MCAo),同时也在健康大鼠上进行大脑中动脉缺血再灌注模型(WT-MCAo),造模成功后给予Niaspan药物干预1型糖尿病大鼠脑缺血再灌注模型,然后比较各组大鼠之间的神经功能缺损评分、血脑屏障通透性、微血管开放性及相关免疫染色指标检测,同时进行体外颈动脉细胞及大脑微血管内皮细胞培养,并比较药物干预对他们的影响。
结果：和WT-MCAo大鼠相比,T1DM-MCAo大鼠脑梗塞面积没有增加,但是脑出血的发生率和血脑屏障的通透性明显增加,同时血管的破坏也明显增加,微血管开放性明显降低,神经功能恢复明显变差。Niaspan治疗T1DM-MCAo大鼠可以明显提高微血管的开放性,降低血脑屏障的通透性,促进血管的重塑和成熟,促进脑梗塞后神经功能恢复。同时,我们也发现,和WT-MCAo大鼠相比,T1DM-MCAo大鼠缺血半暗带区Ang2的表达明显增加而Ang1的表达则降低,而Niaspan治疗可以明显提高T1DM-MCAo大鼠缺血半暗带区Ang1的表达并降低Ang2的表达。体外试验表明,和WT-MCAo大鼠相比,T1DM-MCAo起源的颈动脉细胞迁移能力明显降低,而Niacin和Ang1干预后可以明显提高T1DM-MCAo起源的颈动脉细胞迁移能力,中和Ang1后能够降低颈动脉细胞的迁移能力。类似的结果我们在大脑微血管内皮细胞集落形成试验中也观察到了。
结论：Niaspan能够促进TlDM-MCAo大鼠脑新生血管的重塑和成熟,改善脑梗塞后神经功能的恢复。Angl/Ang2信号通路在Niaspan诱导的脑保护作用中起一定作用。
Introduction:We investigated the changes and the molecular mechanisms of cerebral vascular damage and tested the therapeutic effects of Niaspan in type-1streptozotocin induced diabetic (T1DM) rats after stroke.
Methods:T1DM-rats were subjected to transient middle cerebral artery occlusion (MCAo) and treated without or with Niaspan. Non-streptozotocin rats (WT) were also subjected to MCAo. Functional outcome, blood-brain-barrier (BBB) leakage, microvascular patency, immunostaining and in vitro arterial explant cell culture were performed.
Results:Compared to WT-MCAo-rats, T1DM-MCAo-rats did not show an increase lesion volume, but exhibited significantly increased brain hemorrhage, BBB leakage and vascular damage as well as decreased microvascular patency and functional outcome after stroke. Niaspan treatment of stroke in T1DM-MCAo-rats significantly increased microvascular patency, attenuated BBB damage, promoted vascular remodeling and improved functional outcome after stroke. T1DM-MCAo-rats exhibited significantly increased Angiopoietin2(Ang2) expression, but decreased Angl expression in the ischemic brain compared to WT-MCAo-rats. Niaspan treatment attenuated Ang2, but increased Angl expression in the ischemic brain in T1DM-MCAo-rats. In vitro data show that arterial explant cell migration significantly decreased in arteries derived from T1DM-MCAo-rats compared to arteries from WT-MCAo-rats. Niacin and Angl treatment increased arterial explant cell migration in T1DM-artery. Anti-Angl significantly attenuated Niacin-induced arterial cell migration.
Conclusions:Niaspan treatment of stroke in T1DM-rats promotes vascular remodeling and improves functional outcome. The Angl/Ang2pathway may contribute to Niaspan induced brain plasticity. Niaspan warrants further investigation as a therapeutic agent for the treatment of stroke in diabetics.
引文
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30. Pfister, F., et al., Pericyte migration:a novel mechanism of pericyte loss in experimental diabetic retinopathy. Diabetes,2008.57(9):p.2495-502.
31. Iurlaro, M., et al., Rat aorta-derived mural precursor cells express the Tie2 receptor and respond directly to stimulation by angiopoietins. J Cell Sci,2003.116(Pt 17):p.3635-43.
32. Suri, C., et al., Increased vascularization in mice overexpressing angiopoietin-1. Science,1998.282(5388):p.468-71.
33. Metheny-Barlow, L.J., et al., Direct chemotactic action of angiopoietin-1 on mesenchymal cells in the presence of VEGF. Microvasc Res,2004.68(3):p.221-30.
34. Chen, J.X. and A. Stinnett, Ang-1 gene therapy inhibits hypoxia-inducible factor-1 alpha (HIF-1alpha)-prolyl-4-hydroxylase-2, stabilizes HIF-1 alpha expression, and normalizes immature vasculature in db/db mice. Diabetes,2008.57(12):p. 3335-43.
1. Bomont, L. and E.T. MacKenzie, Neuroprotection after focal cerebral ischaemia in hyperglycaemic and diabetic rats. Neurosci Lett,1995.197(1):p. 53-6.
2. Liang, W., et al., Reductions in mRNA of the neuroprotective agent, neuroserpin, after cerebral ischemia/reperfusion in diabetic rats. Brain Res, 2004.1015(1-2):p.175-80.
3. Rizk, N.N., et al., Insulin like growth factor-1 (IGF-1) decreases ischemia-reperfusion induced apoptosis and necrosis in diabetic rats. Endocrine,2007.31(1):p.66-71.
4. Li, W., et al., Adaptive cerebral neovascularization in a model of type 2 diabetes:relevance to focal cerebral ischemia. Diabetes.59(1):p.228-35.
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11. Chen, J., et al., Niaspan increases angiogenesis and improves functional recovery after stroke. Ann Neurol,2007.62:p.49-58.
12. Like, A. A. and A. A. Rossini, Streptozotocin-induced pancreatic insulitis:new model of diabetes mellitus. Science,1976.193(4251):p.415-7.
13. Wu, K.K. and Y. Huan, Streptozotocin-induced diabetic models in mice and rats. Curr. Protoc. Pharmacol.,2008.40:p.5.47.1-5.47.14.
14. Chen, J., et al., Therapeutic benefit of intravenous administration of bone marrow stromal cells after cerebral ischemia in rats. Stroke,2001.32(4):p. 1005-11.
15. Zhang, Z.G., et al., Angiopoietin-1 reduces cerebral blood vessel leakage and ischemic lesion volume after focal cerebral embolic ischemia in mice. Neuroscience,2002.113(3):p.683-7.
16. Swanson, R.A., et al., A semiautomated method for measuring brain infarct volume. J Cereb Blood Flow Metab,1990.10(2):p.290-3.
17. Chen, J., et al., Intravenous administration of human bone marrow stromal cells induces angiogenesis in the ischemic boundary zone after stroke in rats. Circ Res,2003.92(6):p.692-9.
18. Calza, L., et al., Nerve growth factor control of neuronal expression of angiogenetic and vasoactive factors.Proc Natl Acad Sci U S A,2001.98(7):p. 4160-5.
19. Ho, T.K., et al., Increased angiogenic response but deficient arteriolization and abnormal microvessel ultrastructure in critical leg ischaemia. Br J Surg,2006. 93(11):p.1368-76.
20. Zhang, L., et al., Adjuvant treatment with a glycoprotein Ⅱb/Ⅲa receptor inhibitor increases the therapeutic window for low-dose tissue plasminogen activator administration in a rat model of embolic stroke. Circulation,2003. 107(22):p.2837-43.
21. Hori, S., et al., Apericyte-derived angiopoietin-1 multimeric complex induces occludin gene expression in brain capillary endothelial cells through Tie-2 activation in vitro. J Neurochem,2004.89(2):p.503-13.
22. Nishigaya, K., et al., Impairment and restoration of the endothelial blood-brain barrier in the rat cerebral infarction model assessed by expression of endothelial barrier antigen immunoreactivity. Acta Neuropathol,2000.99(3):p. 231-7.
23. Riesen, F.K., B. Rothen-Rutishauser, and H. Wunderli-Allenspach, A ZO1-GFP fusion protein to study the dynamics of tight junctions in living cells. Histochem Cell Biol,2002.117(4):p.307-15.
24. Armulik, A., et al., Pericytes regulate the blood-brain barrier. Nature,2010. 468(7323):p.557-61.
25. Hoffman, W.H., et al., Cerebral vasoreactivity in children and adolescents with type 1 diabetes mellitus. Endocr Res,2004.30(3):p.315-25.
26. Arora, S., et al., Cutaneous microcirculation in the neuropathic diabetic foot improves significantly but not completely after successful lower extremity revascularization. J Vasc Surg,2002.35(3):p.501-5.
27. Ben-nun, J., V.A. Alder, and I.J. Constable, Retinal microvascular patency in the diabetic rat. Int Ophthalmol,2004.25(4):p.187-92.
28. Armulik, A., A. Abramsson, and C. Betsholtz, Endothelial/pericyte interactions. Circ Res,2005.97(6):p.512-23.
29. Heil, M., et al., Arteriogenesis versus angiogenesis:similarities and differences. J Cell Mol Med,2006.10(1):p.45-55.
30. Hershey, J.C., et al., Revascularization in the rabbit hindlimb:dissociation between capillary sprouting and arteriogenesis. Cardiovasc Res,2001.49(3):p. 618-25.
31. Pfister, F., et al., Pericyte migration:a novel mechanism of pericyte loss in experimental diabetic retinopathy. Diabetes,2008.57(9):p.2495-502.
32. Iurlaro, M., et al., Rat aorta-derived mural precursor cells express the Tie2 receptor and respond directly to stimulation by angiopoietins. J Cell Sci,2003. 116(Pt 17):p.3635-43.
33. Suri, C., et al., Increased vascularization in mice overexpressing angiopoietin-1. Science,1998.282(5388):p.468-71.
34. Metheny-Barlow, L.J., et al., Direct chemotactic action of angiopoietin-1 on mesenchymal cells in the presence of VEGF. Microvasc Res,2004.68(3):p. 221-30.
35. Chen, J.X. and A. Stinnett, Ang-1 gene therapy inhibits hypoxia-inducible factor-1alpha (HIF-lalpha)-prolyl-4-hydroxylase-2, stabilizes HIF-1alpha expression, and normalizes immature vasculature in db/db mice. Diabetes, 2008.57(12):p.3335-43.
1. Bomont, L. and E.T. MacKenzie, Neuroprotection after focal cerebral ischaemia in hyperglycaemic and diabetic rats. Neurosci Lett,1995.197(1):p.53-6.
2. Liang, W., et al., Reductions in mRNA of the neuroprotective agent, neuroserpin, after cerebral ischemia/reperfusion in diabetic rats. Brain Res,2004.1015(1-2):p. 175-80.
3. Rizk, N.N., et al., Insulin like growth factor-1 (IGF-1) decreases ischemia-reperfusion induced apoptosis and necrosis in diabetic rats. Endocrine,2007. 31(1):p.66-71.
4. Li, W., et al., Adaptive cerebral neovascularization in a model of type 2 diabetes: relevance to focal cerebral ischemia. Diabetes.59(1):p.228-35.
5. Elam, M.B., et al., Effect of niacin on lipid and lipoprotein levels and glycemic control in patients with diabetes and peripheral arterial disease:the ADMIT study:A randomized trial. Arterial Disease Multiple Intervention Trial. JAMA,2000.284(10): p.1263-70.
6. Like, A.A. and A.A. Rossini, Streptozotocin-induced pancreatic insulitis:new model of diabetes mellitus. Science,1976.193(4251):p.415-7.
7. Wu, K.K. and Y. Huan, Streptozotocin-induced diabetic models in mice and rats. Curr. Protoc. Pharmacol.,2008.40:p.5.47.1-5.47.14.
8. Chen, J., et al., Therapeutic benefit of intravenous administration of bone marrow stromal cells after cerebral ischemia in rats. Stroke,2001.32(4):p.1005-11.
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12. Pfister, F., et al., Pericyte migration:a novel mechanism of pericyte loss in experimental diabetic retinopathy. Diabetes,2008.57(9):p.2495-502.
13. Iurlaro, M., et al., Rat aorta-derived mural precursor cells express the Tie2 receptor and respond directly to stimulation by angiopoietins. J Cell Sci,2003.116(Pt 17):p.3635-43.
14. Suri, C., et al., Increased vascularization in mice overexpressing angiopoietin-1. Science,1998.282(5388):p.468-71.
15. Metheny-Barlow, L.J., et al., Direct chemotactic action of angiopoietin-1 on mesenchymal cells in the presence of VEGF. Microvasc Res,2004.68(3):p.221-30.
16. Zhang, Z.G, et al., Angiopoietin-1 reduces cerebral blood vessel leakage and ischemic lesion volume after focal cerebral embolic ischemia in mice. Neuroscience, 2002.113(3):p.683-7.
17. Chen, J.X. and A. Stinnett, Ang-1 gene therapy inhibits hypoxia-inducible factor-1alpha (HIF-1alpha)-prolyl-4-hydroxylase-2, stabilizes HIF-1alpha expression, and normalizes immature vasculature in db/db mice. Diabetes,2008.57(12):p. 3335-43.
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