Manji H K, Lenox R H
Section on Clinical Pharmacology, National Institute of Mental Health, Bethesda, Maryland 20892.
Synapse. 1994 Jan;16(1):11-28. doi: 10.1002/syn.890160103.
Lithium, a simple monovalent cation, represents one of psychiatry's most important treatments and is the most effective treatment for reducing both the frequency and severity of recurrent affective episodes. Despite extensive research, the underlying biologic basis for the therapeutic efficacy this drug remains unknown, and in recent years, research has focused on signal transduction pathways to explain lithium's efficacy in treating both poles of manic-depressive illness. Critical to attributions of therapeutic relevance to any observed biochemical effect, however, is the observation that the characteristic prophylactic action of lithium in stabilizing the profound mood cycling of bipolar disorder requires a lag period for onset and is not immediately reversed upon discontinuation of treatment. Biochemical changes requiring such prolonged administration of a drug suggest alterations at the genomic level but, until recently, little has been known about the transcriptional and posttranscriptional factors regulated by chronic drug treatment, although long-term changes in neuronal synaptic function are known to be dependent upon the selective regulation of gene expression. In this paper, we will present evidence to show that chronic lithium exerts significant transcriptional and posttranscriptional effects, and that these actions of lithium may be mediated via protein kinase C (PKC)-induced alterations in nuclear transcription regulatory factors responsible for modulating the expression of proteins involved in long-term neural plasticity and cellular response. Such target sites for chronic lithium may help unravel the processes by which a simple monovalent cation can produce a long-term stabilization of mood in individuals vulnerable to bipolar illness.
锂是一种简单的单价阳离子，是精神病学领域最重要的治疗药物之一，也是减少复发性情感发作频率和严重程度最有效的治疗方法。尽管进行了广泛的研究，但这种药物治疗效果的潜在生物学基础仍然未知。近年来，研究集中在信号转导途径，以解释锂在治疗躁郁症两极症状方面的疗效。然而，对于将任何观察到的生化效应归因于治疗相关性而言，关键在于观察到锂在稳定双相情感障碍严重情绪波动方面的特征性预防作用需要一段时间才能起效，并且在停药后不会立即逆转。需要长期服用药物才能产生的生化变化表明在基因组水平上发生了改变，但直到最近，对于慢性药物治疗所调节的转录和转录后因子仍知之甚少，尽管已知神经元突触功能的长期变化依赖于基因表达的选择性调节。在本文中，我们将提供证据表明，慢性锂会产生显著的转录和转录后效应，并且锂的这些作用可能是通过蛋白激酶C（PKC）诱导的核转录调节因子的改变来介导的，这些调节因子负责调节参与长期神经可塑性和细胞反应的蛋白质的表达。慢性锂的此类靶点可能有助于揭示一个简单的单价阳离子如何能使易患双相情感障碍的个体实现情绪长期稳定的过程。
