RU486 (MIFEPRISTONE) AMELIORATES COGNITIVE DYSFUNCTION AND REVERSES THE DOWN-REGULATION OF ASTROCYTIC N-MYC DOWNSTREAM-REGULATED GENE 2 IN STREPTOZOTOCIN-INDUCED TYPE-1 DIABETIC RATS
RU486 (MIFEPRISTONE) AMELIORATES COGNITIVE DYSFUNCTION AND REVERSES THE DOWN-REGULATION OF ASTROCYTIC N-MYC DOWNSTREAM-REGULATED GENE 2 IN STREPTOZOTOCIN-INDUCED TYPE-1 DIABETIC RATS
复制标题
RU486（米非司酮）可改善链脲佐菌素诱导的 1 型糖尿病大鼠的认知功能障碍并逆转星形胶质细胞 N-myc 下游调节基因 2 的下调
DOI：
10.1016/j.neuroscience.2011.06.025
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发表时间：
2011-09-05
期刊：
影响因子：
3.3
通讯作者：
Li, Y. -Q.
中科院分区：
文献类型：
--
作者：
Zuo, Z. -F.;Wang, W.;Li, Y. -Q.
糖尿病认知功能障碍（diabetic cognitive dysfunction，DCD）是1型糖尿病最严重的并发症之一，常伴有糖皮质激素水平的慢性升高和海马星形胶质细胞的改变。然而，长期升高的糖皮质激素和海马星形胶质细胞激活在DCD中的作用仍有待阐明，目前尚不清楚星形胶质细胞N-myc下游调节基因2（NDRG 2，参与细胞分化和发育）是否参与了DCD。在本研究中，三个月后链脲佐菌素（STZ）诱导的1型糖尿病发病，大鼠在Morris水迷宫试验中表现出认知障碍，以及皮质酮水平升高。免疫组化、实时荧光定量PCR和Western blot检测显示，糖尿病大鼠海马神经胶质细胞酸性蛋白（GFAP）和NDRG 2表达下调。此外，RU 486阻断糖皮质激素受体（GR）9 d可改善糖尿病大鼠认知功能障碍，阻断GR 9 d可减轻糖尿病大鼠海马NDRG 2和GFAP的下调。这些结果表明糖皮质激素-GR系统是DCD的关键，星形胶质细胞反应性和NDRG 2参与了这些过程。因此，抑制海马中的GR激活可能是治疗DCD的新的治疗策略。(C)2011年IBRO。由爱思唯尔有限公司出版。保留所有权利。
Diabetic cognitive dysfunction (DCD), usually accompanied with chronically elevated glucocorticoids and hippocampal astrocytic alterations, is one of the most serious complications in patients with type-1 diabetes. However, the role for chronically elevated glucocorticoids and hippocampal astrocytic activations in DCD remains to be elucidated, and it is not clear whether astrocytic N-myc downstream-regulated gene 2 (NDRG2, involved in cell differentiation and development) participated in DCD. In the present study, three months after streptozotocin (STZ)-induced type-1 diabetes onset, rats showed cognitive impairments in Morris water maze test as well as elevated corticosterone level. Diabetic rats also presented down-regulation of glial fibrillary acidic protein (GFAP, a key indicator of astrocytic reactivity) and NDRG2 in hippocampus revealed by immunohistochemistry staining, real-time PCR and Western blot. Moreover, the diabetic cognitive impairments were ameliorated by 9-day glucocorticoids receptor (GR) blockade with RU486, and the down-regulation of hippocampal NDRG2 and GFAP in diabetic animals was also attenuated by 9-day GR blockade. These results suggest that glucocorticoids-GR system is crucial for DCD, and that astrocytic reactivity and NDRG2 are involved in these processes. Thus, inhibiting GR activation in the hippocampus may be a novel therapeutic strategy for treating DCD. (C) 2011 IBRO. Published by Elsevier Ltd. All rights reserved.