Oyamada Naofumi, Sone Masakatsu, Miyashita Kazutoshi, Park Kwijun, Taura Daisuke, Inuzuka Megumi, Sonoyama Takuhiro, Tsujimoto Hirokazu, Fukunaga Yasutomo, Tamura Naohisa, Itoh Hiroshi, Nakao Kazuwa
Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
Endocrinology. 2008 Aug;149(8):3764-77. doi: 10.1210/en.2007-1770. Epub 2008 Apr 24.
Mineralocorticoid receptors (MRs) are classically known to be expressed in the distal collecting duct of the kidney. Recently it was reported that MR is identified in the heart and vasculature. Although MR expression is also found in the brain, it is restricted to the hippocampus and cerebral cortex under normal condition, and the role played by MRs in brain remodeling after cerebral ischemia remains unclear. In the present study, we used the mouse 20-min middle cerebral artery occlusion model to examine the time course of MR expression and activity in the ischemic brain. We found that MR-positive cells remarkably increased in the ischemic striatum, in which MR expression is not observed under normal conditions, during the acute and, especially, subacute phases after stroke and that the majority of MR-expressing cells were astrocytes that migrated to the ischemic core. Treatment with the MR antagonist spironolactone markedly suppressed superoxide production within the infarct area during this period. Quantitative real-time RT-PCR revealed that spironolactone stimulated the expression of neuroprotective or angiogenic factors, such as basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), whereas immunohistochemical analysis showed astrocytes to be cells expressing bFGF and VEGF. Thereby the incidence of apoptosis was reduced. The up-regulated bFGF and VEGF expression also appeared to promote endogenous angiogenesis and blood flow within the infarct area and to increase the number of neuroblasts migrating toward the ischemic striatum. By these beneficial effects, the infarct volume was significantly reduced in spironolactone-treated mice. Spironolactone may thus provide therapeutic neuroprotective effects in the ischemic brain after stroke.
盐皮质激素受体（MRs）传统上被认为在肾脏远曲小管中表达。最近有报道称在心脏和血管中也发现了MR。尽管在大脑中也发现了MR的表达，但在正常情况下它仅限于海马体和大脑皮层，而MRs在脑缺血后脑重塑中所起的作用仍不清楚。在本研究中，我们使用小鼠大脑中动脉闭塞20分钟模型来研究缺血性脑中MR表达和活性的时间进程。我们发现，在中风后的急性期，尤其是亚急性期，缺血纹状体中MR阳性细胞显著增加，而在正常情况下该区域未观察到MR表达，并且大多数表达MR的细胞是迁移到缺血核心的星形胶质细胞。在此期间，用MR拮抗剂螺内酯治疗可显著抑制梗死区域内的超氧化物产生。定量实时RT-PCR显示，螺内酯刺激了神经保护或血管生成因子的表达，如碱性成纤维细胞生长因子（bFGF）和血管内皮生长因子（VEGF），而免疫组织化学分析表明星形胶质细胞是表达bFGF和VEGF的细胞。从而降低了细胞凋亡的发生率。上调的bFGF和VEGF表达似乎也促进了梗死区域内的内源性血管生成和血流，并增加了向缺血纹状体迁移的神经母细胞数量。通过这些有益作用，螺内酯治疗的小鼠梗死体积显著减小。因此，螺内酯可能为中风后缺血性脑提供治疗性神经保护作用。
