Effects of the potential lithium-mimetic, ebselen, on brain neurochemistry: a magnetic resonance spectroscopy study at 7 tesla.
Effects of the potential lithium-mimetic, ebselen, on brain neurochemistry: a magnetic resonance spectroscopy study at 7 tesla.
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DOI：
10.1007/s00213-015-4189-2
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发表时间：
2016-03
影响因子：
3.4
通讯作者：
Cowen PJ
中科院分区：
文献类型：
--
作者：
Masaki C;Sharpley AL;Godlewska BR;Berrington A;Hashimoto T;Singh N;Vasudevan SR;Emir UE;Churchill GC;Cowen PJ
锂是双相情感障碍的有效治疗方法，但安全性问题使其临床应用复杂化。抗氧化剂药物依布硒啉可能是一种可能的锂模拟物，基于其抑制肌醇单磷酸酶（IMP酶）的能力，这是一种与锂共享的作用。我们的主要目的是确定依布硒啉是否能降低人脑中肌醇的水平。我们还评估了依布硒啉对其他脑神经代谢物的影响，包括谷胱甘肽、谷氨酸、谷氨酰胺和谷氨酸+谷氨酰胺（Glx）。在双盲、随机顺序、交叉设计中，对20名健康志愿者进行了两次接受依布硒啉（3600 mg，24 h）或相同安慰剂的测试。在最后一剂依布硒啉/安慰剂后两小时，参与者在7特斯拉（T）下接受质子磁共振波谱（1H MRS），体素置于前扣带和枕叶皮质。使用未抑制的水信号作为参考计算神经代谢物水平，并针对体素中的个体脑脊液含量进行校正。依布硒啉对枕叶皮质的神经代谢物水平没有影响。在前扣带皮层中，依布硒啉降低了肌醇（p = 0.028，Cohen's d = 0.60）以及谷胱甘肽（p = 0.033，d = 0.58）、谷氨酰胺（p = 0.024，d = 0.62）、谷氨酸（p = 0.01，d = 0.73）和Glx（p = 0.001，d = 1.0）的浓度。该研究表明，依布硒啉在人脑中对IMPase产生功能性抑制。依布硒啉降低谷氨酸的作用与其抑制酶谷氨酰胺酶的报道能力一致。Ebselen可能有潜力作为双相情感障碍的重新用途治疗。
Lithium is an effective treatment for bipolar disorder, but safety issues complicate its clinical use. The antioxidant drug, ebselen, may be a possible lithium-mimetic based on its ability to inhibit inositol monophosphatase (IMPase), an action which it shares with lithium. Our primary aim was to determine whether ebselen lowered levels of inositol in the human brain. We also assessed the effect of ebselen on other brain neurometabolites, including glutathione, glutamate, glutamine, and glutamate + glutamine (Glx) Twenty healthy volunteers were tested on two occasions receiving either ebselen (3600 mg over 24 h) or identical placebo in a double-blind, random-order, crossover design. Two hours after the final dose of ebselen/placebo, participants underwent proton magnetic resonance spectroscopy (1H MRS) at 7 tesla (T) with voxels placed in the anterior cingulate and occipital cortex. Neurometabolite levels were calculated using an unsuppressed water signal as a reference and corrected for individual cerebrospinal fluid content in the voxel. Ebselen produced no effect on neurometabolite levels in the occipital cortex. In the anterior cingulate cortex, ebselen lowered concentrations of inositol (p = 0.028, Cohen’s d = 0.60) as well as those of glutathione (p = 0.033, d = 0.58), glutamine (p = 0.024, d = 0.62), glutamate (p = 0.01, d = 0.73), and Glx (p = 0.001, d = 1.0). The study suggests that ebselen produces a functional inhibition of IMPase in the human brain. The effect of ebselen to lower glutamate is consistent with its reported ability to inhibit the enzyme, glutaminase. Ebselen may have potential as a repurposed treatment for bipolar disorder.