Altar C Anthony, Hunt Rachel A, Jurata Linda W, Webster Maree J, Derby Eric, Gallagher Paul, Lemire Andrew, Brockman Jeffrey, Laeng Pascal
Psychiatric Genomics, Inc., Gaithersburg, Maryland, USA.
Biol Psychiatry. 2008 Dec 15;64(12):1077-87. doi: 10.1016/j.biopsych.2008.08.031. Epub 2008 Oct 30.
Genes associated with energy metabolism are decreased in schizophrenia brain and human and rodent diabetic skeletal muscle. These and other similarities between diabetes and schizophrenia suggest that an insulin signaling deficit may underlie schizophrenia. We determined with human SH-SY5Y neuroblastoma and astrocyte cell lines whether insulin or other molecules could modulate genes opposite to their change reported in schizophrenia brain.
Both cell lines were treated with insulin, insulin-like growth factor (IGF)-1, IGF-2, or brain-derived neurotrophic factor (BDNF). Genes whose expression was found with microarrays to be changed by insulin in a reciprocal manner to their change in schizophrenia were used in a 16-gene miniarray to identify small molecules that might mimic insulin.
Insulin phosphorylated its receptor in the neuroblastoma cells but not in astrocytes and, like IGF-1, increased ERK1/2 and Akt phosphorylation. Insulin and IGF-1 increased the expression of genes decreased in schizophrenia, including those involved in mitochondrial functions, glucose and energy metabolism, hydrogen ion transport, and synaptic function. These gene effects were confirmed and shown to be dose related with the 16-gene miniarrays. Most of 1940 pharmacologically unique compounds failed to alter gene expression, with the exception of muscarinic agonists, which mimicked insulin and IGF-1, and which were blocked by the muscarinic antagonists atropine and telenzepine.
Stimulation of muscarinic and insulin/IGF-1 receptors alter genes associated with metabolic and synaptic functions in a manner reciprocal to their changes in schizophrenia. Pharmacologic activation of these receptors may normalize genomic alterations in schizophrenia and better address root causes of this disease.
与能量代谢相关的基因在精神分裂症患者大脑以及人类和啮齿动物的糖尿病骨骼肌中表达降低。糖尿病与精神分裂症之间的这些以及其他相似之处表明，胰岛素信号缺陷可能是精神分裂症的潜在病因。我们利用人SH-SY5Y神经母细胞瘤和星形胶质细胞系，研究胰岛素或其他分子是否能够调节与精神分裂症患者大脑中变化相反的基因。
两种细胞系均用胰岛素、胰岛素样生长因子（IGF）-1、IGF-2或脑源性神经营养因子（BDNF）进行处理。通过微阵列发现其表达因胰岛素而发生与精神分裂症中变化相反改变的基因，被用于一个16基因的微阵列中，以鉴定可能模拟胰岛素作用的小分子。
胰岛素在神经母细胞瘤细胞中使其受体磷酸化，但在星形胶质细胞中则不然，并且与IGF-1一样，可增加ERK1/2和Akt的磷酸化。胰岛素和IGF-1增加了精神分裂症中表达降低的基因的表达，包括那些参与线粒体功能、葡萄糖和能量代谢、氢离子转运以及突触功能的基因。这些基因效应通过16基因微阵列得到证实，并显示出与剂量相关。1940种具有药理学独特性的化合物中，大多数未能改变基因表达，但毒蕈碱激动剂除外，其可模拟胰岛素和IGF-1的作用，并且这种作用可被毒蕈碱拮抗剂阿托品和替仑西平阻断。
毒蕈碱和胰岛素/IGF-1受体的刺激以与精神分裂症中变化相反的方式改变与代谢和突触功能相关的基因。这些受体的药理学激活可能使精神分裂症中的基因组改变正常化，并更好地解决该疾病的根本原因。
