Sanford Children's Health Research Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
Mol Psychiatry. 2013 Mar;18(3):347-57. doi: 10.1038/mp.2011.186. Epub 2012 Jan 31.
Although effective in treating an array of neurological disorders, antipsychotics are associated with deleterious metabolic side effects. Through high-throughput screening, we previously identified phenothiazine antipsychotics as modulators of the human insulin promoter. Here, we extended our initial finding to structurally diverse typical and atypical antipsychotics. We then identified the transforming growth factor beta (TGFβ) pathway as being involved in the effect of antipsychotics on the insulin promoter, finding that antipsychotics activated SMAD3, a downstream effector of the TGFβ pathway, through a receptor distinct from the TGFβ receptor family and known neurotransmitter receptor targets of antipsychotics. Of note, antipsychotics that do not cause metabolic side effects did not activate SMAD3. In vivo relevance was demonstrated by reanalysis of gene expression data from human brains treated with antipsychotics, which showed altered expression of SMAD3 responsive genes. This work raises the possibility that antipsychotics could be designed that retain beneficial CNS activity while lacking deleterious metabolic side effects.
尽管抗精神病药在治疗一系列神经紊乱方面非常有效，但它们也与有害的代谢副作用有关。通过高通量筛选，我们之前发现吩噻嗪类抗精神病药是人类胰岛素启动子的调节剂。在这里，我们将最初的发现扩展到结构多样的典型和非典型抗精神病药。然后，我们确定转化生长因子β（TGFβ）途径参与了抗精神病药对胰岛素启动子的影响，发现抗精神病药通过不同于 TGFβ 受体家族的受体以及已知的抗精神病药的神经递质受体靶点激活 TGFβ 途径的下游效应子 SMAD3。值得注意的是，不会引起代谢副作用的抗精神病药不会激活 SMAD3。通过对用抗精神病药治疗的人脑的基因表达数据进行重新分析，证明了这种体内相关性，该分析显示 SMAD3 反应基因的表达发生了改变。这项工作提出了一种可能性，即可以设计出既能保留有益的中枢神经系统活性又没有有害代谢副作用的抗精神病药。
