Glial pathology in an animal model of depression: reversal of stress-induced cellular, metabolic and behavioral deficits by the glutamate-modulating drug riluzole.
Glial pathology in an animal model of depression: reversal of stress-induced cellular, metabolic and behavioral deficits by the glutamate-modulating drug riluzole.
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DOI：
10.1038/mp.2008.106
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发表时间：
2010-05
影响因子：
11
通讯作者：
中科院分区：
文献类型：
--
作者：
越来越多的证据表明，胶质细胞的病理和氨基酸神经递质系统的异常有助于病理生理，并可能是重性抑郁症的发病机制。本研究探讨了慢性不可预测应激（CUS）后大鼠前额叶皮层（PFC）神经胶质功能的变化。此外，我们分析了利鲁唑（一种食品和药物管理局批准的治疗肌萎缩侧索硬化症的药物，已知可调节谷氨酸释放和促进谷氨酸摄取）对神经胶质细胞诱导的神经胶质功能障碍和抑郁样行为的影响。我们提供了第一个实验证据表明，慢性应激损害皮质神经胶质功能。暴露于CUS和表现出行为缺陷的蔗糖偏好和主动回避的动物表现出显着降低13 C-乙酸代谢反映胶质细胞代谢，和胶质细胞相关蛋白（GFAP）mRNA表达的PFC。细胞，代谢和行为的改变CUS诱导的逆转和/或慢性治疗与谷氨酸调节药物利鲁唑阻断。利鲁唑对啮齿类动物中的药物诱导的快感缺失和无助感的有益作用证明了利鲁唑的抗抑郁作用。阿曲唑治疗还逆转了阿曲唑诱导的胶质细胞代谢和GFAP mRNA表达的减少。我们的结果与最近的开放标签临床试验一致，这些试验显示了该药物对情绪和焦虑症的影响。这项研究提供了进一步验证的假设，神经胶质功能障碍和破坏氨基酸神经传递有助于抑郁症的病理生理学和谷氨酸代谢，摄取和/或释放的调制代表抗抑郁药物开发的可行目标。
Growing evidence indicates that glia pathology and amino-acid neurotransmitter system abnormalities contribute to the pathophysiology and possibly the pathogenesis of major depressive disorder. This study investigates changes in glial function occurring in the rat prefrontal cortex (PFC) after chronic unpredictable stress (CUS), a rodent model of depression. Furthermore, we analyzed the effects of riluzole, a Food and Drug Administration-approved drug for the treatment of amyotrophic laterosclerosis, known to modulate glutamate release and facilate glutamate uptake, on CUS-induced glial dysfunction and depressive-like behaviors. We provide the first experimental evidence that chronic stress impairs cortical glial function. Animals exposed to CUS and showing behavioral deficits in sucrose preference and active avoidance exhibited significant decreases in 13C-acetate metabolism reflecting glial cell metabolism, and glial fibrillary associated protein (GFAP) mRNA expression in the PFC. The cellular, metabolic and behavioral alterations induced by CUS were reversed and/or blocked by chronic treatment with the glutamate-modulating drug riluzole. The beneficial effects of riluzole on CUS-induced anhedonia and helplessness demonstrate the antidepressant action of riluzole in rodents. Riluzole treatment also reversed CUS-induced reductions in glial metabolism and GFAP mRNA expression. Our results are consistent with recent open-label clinical trials showing the drug's effect in mood and anxiety disorders. This study provides further validation of hypothesis that glial dysfunction and disrupted amino-acid neurotransmission contribute to the pathophysiology of depression and that modulation of glutamate metabolism, uptake and/or release represent viable targets for antidepressant drug development.
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影响因子：
3.7
作者：
Moghaddam, B;Jackson, M
通讯作者：
Jackson, M
影响因子：
5.3
作者：
Lebon, V;Petersen, KF;Rothman, DL
通讯作者：
Rothman, DL
影响因子：
3.9
作者：
Hardingham GE
通讯作者：
Hardingham GE
DOI：
10.1016/j.molbrainres.2004.02.021
发表时间：
2004-05-19
期刊：
MOLECULAR BRAIN RESEARCH
影响因子：
--
作者：
Hughes, EG;Maguire, JL;Sutherland, ML
通讯作者：
Sutherland, ML
影响因子：
3.4
作者：
Newton, Samuel S.;Girgenti, Matthew J.;Duman, Ronald S.
通讯作者：
Duman, Ronald S.