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阻断NMDA受体可增强皮质酮对海马脑源性神经营养因子表达的抑制：cAMP反应元件结合蛋白的作用

冯昊, 陆利民, 黄莺, 朱依纯, 姚泰

复旦大学上海医学院生理学与病理生理学系.上海 200032

摘要

高浓度的皮质酮可引起海马形态与功能的损伤，其中脑源性神经营养因子(brain--derived neurotrophic factor, BDNF)表达的改变在海马形态与功能损伤中扮演重要角色。该实验的目的是观察单次皮下注射皮质酮后海马内BDNF mRNA、前体蛋白及成熟型蛋白表达的改变，并观察{sl N}--甲基--{sl D}--天冬氨酸({sl N}--methyl--{sl D}--aspartate NMDA)受体阻滞剂MK801对皮质酮作用的影响。实验结果显示，单次皮下注射皮质酮2 mg/kg，3 h后海马内BDNF mRNA、前体蛋白及成熟型蛋白的表达均降低；MK801 (0.1 mg/kg)对皮质酮的这一作用有增强效果。单独给予皮质酮或注射MK801 30 min后再给予皮质酮，均能明显降低海马中cAMP反应元件结合蛋白 (cAMP response element binding protein，CREB)的磷酸化水平，MK801与皮质酮联用时CREB的磷酸化水平降低更为显著(与单独给予皮质酮相比，{sl P}<0.05)。实验结果提示，CREB磷酸化水平降低可能是皮质酮引起海马BDNF表达减少的重要中间环节，阻断NMDA受体可加强皮质酮降低BDNF表达的效应。

关键词： 皮质酮; 海马; 脑源性神经营养因子; NMDA受体; MK801; cAMP反应元件结合蛋白

Blockade of NMDA receptor enhances corticosterone-induced downregulation of brain-derived neurotrophic factor gene expression in the rat hippocampus through cAMP response element binding protein pathway

Feng Hao, Lu Limin, Huang Ying, Zhu Yichun, Yao Tai

Department of Physiology and pathophysiology, Shanghai Medical College, Fudan University.Shanghai 200032

Abstract

High concentration of corticosterone leads to morphological and functional impairments in hippocampus, ranging from a reversible atrophy of pyramidal CA3 apical dendrites to the impairment of long-term potentiation (LTP) and hippocampus-dependent learning and memory. Glutamate and N-methyl-D-aspartate (NMDA) receptor play an important role in this effect. Because of the importance of brain-derived neurotrophic factor (BDNF) in the functions of the hippocampal neurons, alteration of the expression of BDNF is thought to be involved in the corticosterone effect on the hippocampus. To determine whether change in BDNF in the hippocampus is involved in the corticosterone effect, we injected corticosterone (2 mg/kg, s.c.) to Sprague-Dawley rats and measured the mRNA, proBDNF and mature BDNF protein levels in the hippocampus. We also measured the phosphorylation level of the transcription factor cAMP response element binding protein (CREB). Furthermore, we intraperitoneally injected NMDA receptor antagonist MK801 (0.1 mg/kg) 30 min before corticosterone administration to investigate whether and how MK801 affected the regulation of BDNF gene expression by corticosterone. Our results showed that 3 h after single s.c. injection of corticsterone, the expression of BDNF mRNA, proBDNF and mature BDNF protein decreased significantly (P<0.01). MK801 promoted the downregulation of BDNF gene expression in the rat hippocampus by corticosterone. We also found that either applying corticosterone or co-applying corticosterone with MK801 downregulated the phosphoration level of CREB, the latter (corticosterone plus MK801) being more effective (P<0.05). Taken together, our results indicate that corticosterone downregulates BDNF gene expression in the rat hippocampus through CREB pathway and that blockade of NMDA receptor enhances this effect of corticosterone in reducing BDNF expression.

Key words: Corticosterone;Hippocampus;Brain-derived neurotrophic factor;NMDA receptor;MK801;cAMP response element binding protein

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引用本文：

冯昊, 陆利民, 黄莺, 朱依纯, 姚泰. 阻断NMDA受体可增强皮质酮对海马脑源性神经营养因子表达的抑制：cAMP反应元件结合蛋白的作用[J]. 生理学报 2005; 57 (5): .

Feng Hao, Lu Limin, Huang Ying, Zhu Yichun, Yao Tai. Blockade of NMDA receptor enhances corticosterone-induced downregulation of brain-derived neurotrophic factor gene expression in the rat hippocampus through cAMP response element binding protein pathway . Acta Physiol Sin 2005; 57 (5): (in Chinese with English abstract).