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

• DOI: 10.1016/j.neuroscience.2011.06.025
• Publication Date: 2011-06-25T23:12:38Z
• Authors: Z.-F. Zuo; W. Wang; L. Niu; Z.-Z. Kou; C. Zhu; W. Wang; X.-H. Zhao; D.-S. Luo; T. Zhang; F.-X. Zhang; X.-Z. Liu; S.-X. Wu; Y.-Q. Li
• Keywords: Male; 0303 health sciences; Down-Regulation; Nerve Tissue Proteins; Streptozocin; Diabetes Mellitus, Experimental; Rats; 3. Good health; Rats, Sprague-Dawley; Mifepristone; 03 medical and health sciences; Cognition; Diabetes Mellitus, Type 1; Astrocytes; Animals; Cognition Disorders; Corticosterone; Maze Learning

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.