【作者】 叶新春；

【导师】 刘新峰； Jieli Chen； 刘宝瑞；

【作者基本信息】 南京大学 ， 内科学， 2011， 博士

【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。更多还原

【Abstract】 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.更多还原