Chetcuti Albert, Adams Linda J, Mitchell Philip B, Schofield Peter R
Schizophrenia Research Institute, Sydney, New South Wales, Australia.
Psychiatr Genet. 2008 Apr;18(2):64-72. doi: 10.1097/YPG.0b013e3282fb0051.
Even after five decades of use, the mood stabilizer lithium continues to be the mainstay of treatment for bipolar disorder in many countries. The mechanism of action for lithium, however, remains unclear.
In this study, microarray analysis was used to identify genes and cellular pathways that are altered in the mouse brain after treatment with lithium at human therapeutic concentrations. Mice received daily injections of lithium chloride for 7 consecutive days. Whole-brain total RNA was used as a template for microarray gene expression profiling.
This study has identified 19 transcripts that are differentially expressed by four-fold when compared with control untreated mice. The altered expression of these genes was validated by quantitative PCR analysis with five genes showing significant differential expression. Lithium was found to significantly decrease the expression of metallothionein 3 (MT3), ATPase, Na/K transporting, alpha1 polypeptide (ATP1A1), transcription elongation factor B (SIII)-polypeptide 2 (TCEB2), proteasome subunit beta type 5 (PSMB5), and guanine nucleotide binding protein beta1 (GNB1).
These genes are involved in a diverse range of biological functions, including maintaining metal ion homeostasis and chemical/electrical gradients across membranes, regulating RNA polymerase II, protein degradation, and G-protein-coupled signal transduction. These results indicate that lithium can regulate a large number of different cellular pathways in the brain. Understanding the molecular and cellular mechanisms by which lithium achieves its therapeutic action represents a valuable step in clarifying the pathophysiology of bipolar disorder.
即便经过了五十年的使用，心境稳定剂锂在许多国家仍是双相情感障碍治疗的主要药物。然而，锂的作用机制仍不清楚。
在本研究中，利用微阵列分析来识别在用人类治疗浓度的锂处理后的小鼠大脑中发生改变的基因和细胞通路。小鼠连续7天每日注射氯化锂。全脑总RNA用作微阵列基因表达谱分析的模板。
本研究识别出了19个转录本，与未处理的对照小鼠相比，其表达差异达四倍。通过定量PCR分析验证了这些基因的表达改变，其中五个基因显示出显著的差异表达。发现锂可显著降低金属硫蛋白3（MT3）、ATP酶、钠/钾转运α1多肽（ATP1A1）、转录延伸因子B（SIII）-多肽2（TCEB2）、蛋白酶体亚基β5型（PSMB5）和鸟嘌呤核苷酸结合蛋白β1（GNB1）的表达。
这些基因参与多种生物学功能，包括维持金属离子稳态以及跨膜的化学/电势梯度、调节RNA聚合酶II、蛋白质降解和G蛋白偶联信号转导。这些结果表明锂可调节大脑中大量不同的细胞通路。了解锂实现其治疗作用的分子和细胞机制是阐明双相情感障碍病理生理学的重要一步。
