Targeting glial physiology and glutamate cycling in the treatment of depression.
Targeting glial physiology and glutamate cycling in the treatment of depression.
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DOI：
10.1016/j.bcp.2009.04.008
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发表时间：
2009-09-01
影响因子：
5.8
通讯作者：
Sanacora, Gerard
中科院分区：
文献类型：
--
作者：
Valentine, Gerald W.;Sanacora, Gerard
关键词：
越来越多的证据表明，氨基酸神经传递功能障碍与抑郁症的病理生理学有关。因此，氨基酸神经传递的调节代表了抗抑郁药开发的新策略。虽然已知谷氨酸受体配体具有抗抑郁作用，但调节谷氨酸循环和代谢的机制也可能是可行的药物靶点。特别是，兴奋性氨基酸转运蛋白（EAAT），嵌入神经胶质细胞的过程构成了清除突触外谷氨酸的主要手段。因此，在临床前应激模型中观察到的神经胶质细胞数量减少，以及抑郁症患者的死后组织中观察到的神经胶质细胞数量减少，为谷氨酸稳态破坏在抑郁症病理生理学中的作用提供了有趣但间接的证据。这一假设的更直接的证据来自使用磁共振波谱（MRS）的研究，这是一种在不同实验条件下非侵入性测量谷氨酸和其他氨基酸体内浓度的技术。此外，当与13C标记的代谢前体的输注相结合时，MRS可以测量通过离散代谢途径的通量。这种方法最近表明，神经胶质氨基酸代谢减少慢性应激，提供了环境应激和EAAT活性降低的大脑中的氧化应激增加的条件下观察到的联系的效果。此外，利鲁唑（一种通过EAAT增强谷氨酸摄取的药物）的给药逆转了这种应激诱导的神经胶质代谢变化。由于利鲁唑在动物模型和人类受试者中均具有抗抑郁作用，因此它可能代表了一类新型抗抑郁药的原型，其主要作用机制是调节神经胶质生理学。
Accumulating evidence indicates that dysfunction in amino acid neurotransmission contributes to the pathophysiology of depression. Consequently, the modulation of amino acid neurotransmission represents a new strategy for antidepressant development. While glutamate receptor ligands are known to have antidepressant effects, mechanisms regulating glutamate cycling and metabolism may be viable drug targets as well. In particular, excitatory amino acid transporters (EAATs) that are embedded in glial processes constitute the primary means of clearing extrasynaptic glutamate. Therefore, the decreased glial number observed in preclinical stress models, and in postmortem tissue from depressed patients provides intriguing, yet indirect evidence for a role of disrupted glutamate homeostasis in the pathophysiology of depression. More direct evidence for this hypothesis comes from studies using magnetic resonance spectroscopy (MRS), a technique that non-invasively measures in vivo concentrations of glutamate and other amino acids under different experimental conditions. Furthermore, when combined with the infusion of 13C-labeled metabolic precursors, MRS can measure flux through discrete metabolic pathways. This approach has recently shown that glial amino acid metabolism is reduced by chronic stress, an effect that provides a link between environmental stress and the decreased EAAT activity observed under conditions of increased oxidative stress in the brain. Furthermore, administration of riluzole, a drug that enhances glutamate uptake through EAATs, reversed this stress-induced change in glial metabolism. Because riluzole has antidepressant effects in both animal models and human subjects, it may represent the prototype for a novel class of antidepressants with the modulation of glial physiology as a primary mechanism of action.
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影响因子：
3
作者：
Bleakman, D.;Alt, A.;Witkin, J. M.
通讯作者：
Witkin, J. M.
DOI：
10.1038/npp.2008.172
发表时间：
2009-01
期刊：
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
影响因子：
--
作者：
通讯作者：
--
影响因子：
6.3
作者：
Chowdhury, Golam M. I.;Banasr, Mounira;Sanacora, Gerard
通讯作者：
Sanacora, Gerard
影响因子：
4.2
作者：
Albo, F;Pieri, M;Zona, C
通讯作者：
Zona, C
影响因子：
10.6
作者：
Berman, RM;Cappiello, A;Krystal, JH
通讯作者：
Krystal, JH