Olanzapine Reversed Brain Gene Expression Changes Induced by Phencyclidine Treatment in Non-Human Primates.
Olanzapine Reversed Brain Gene Expression Changes Induced by Phencyclidine Treatment in Non-Human Primates.
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奥氮平逆转了非人类灵长类动物中苯环己哌啶治疗引起的脑基因表达变化。
DOI：
10.1159/000430786
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Vawter,MarquisP
中科院分区：
文献类型：
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作者：
Martin,MaureenV;Mirnics,Karoly;Nisenbaum,LauraK;Vawter,MarquisP
NMDA受体拮抗剂苯环利定（PCP）在正常对照中产生精神分裂症样症状。研究了PCP对非人灵长类动物大脑基因表达的影响，并与奥氮平治疗引起的变化进行了比较。PCP和抗精神病药物的实验研究对理解精神分裂症的病理生理和治疗有直接的意义。前额叶皮层基因表达的全基因组变化显示，与对照相比，PCP治疗组有146个转录本发生了变化。失调基因在与神经和遗传疾病有关的已确定类别中富集，包括精神病学基因组学联盟108个位点的精神分裂症基因，以及经pcp治疗的灵长类动物的细胞死亡。典型通路分析揭示了包括突触长期增强和钙信号在内的几个组的显着过度代表。与PCP共给药的奥氮平使146个PCP诱导的探针组表达变化中的34%正常化，并且鉴定了一个由17个奥氮平正常化基因组成的网络，这些基因在以RGS4、SYN1和AKT为节点的精神分裂症候选基因中丰富。本研究结果支持在非人类灵长类动物中使用PCP作为精神分裂症的谷氨酸能模型，并表明奥氮平可以逆转PCP诱导的大量表达差异。这项研究的结果可能为鉴定与精神分裂症治疗相关的药物遗传学和生物标志物研究的潜在候选者提供信息。
The NMDA receptor antagonist phencyclidine (PCP) creates schizophrenia-like symptoms in normal controls. The effect of PCP on non-human primate brain gene expression was examined and compared to changes induced by olanzapine treatment. Experimental studies of PCP and antipsychotic drugs have direct relevance to understanding the pathophysiology and treatment of schizophrenia. Genome-wide changes in prefrontal cortex gene expression revealed alterations of 146 transcripts in the PCP treatment group compared to vehicle controls. Dysregulated genes were enriched in identified classes implicated in neurological and genetic disorders, including schizophrenia genes from the Psychiatric Genomics Consortium 108 loci as well as cell death in PCP-treated primates. Canonical pathway analysis revealed a significant overrepresentation of several groups including synaptic long-term potentiation and calcium signaling. Olanzapine coadministered with PCP normalized 34% of the 146 PCP-induced probe set expression changes, and a network of 17 olanzapine-normalized genes was identified enriched in schizophrenia candidate genes containing RGS4, SYN1 and AKT as nodes. The results of this study support the use of PCP administration in non-human primates as a glutamatergic model of schizophrenia and suggest that a large number of PCP-induced expression differences can be reversed by olanzapine. The results of this study may be informative for identification of potential candidates for pharmacogenetics and biomarker research related to the treatment of schizophrenia.