Chana Gursharan, Lucero Ginger, Salaria Shahid, Lozach Jean, Du Pinyi, Woelk Christopher, Everall Ian
Department of Psychiatry, University of California San Diego, La Jolla, CA 92093-0603, USA.
Schizophr Res. 2009 Sep;113(2-3):273-6. doi: 10.1016/j.schres.2009.05.015. Epub 2009 Jun 7.
Growing genetic evidence has implicated a role for neuregulin-1 (NRG-1) in schizophrenia pathogenesis as well as alterations in SNAP receptor (SNARE) proteins at both gene and protein levels in post-mortem investigations. In relation to a potential therapeutic mechanism for atypical antipsychotic medications, clozapine has been shown to increase both NRG-1 levels and synaptic markers in rodents. As evidence continues to mount for a potential restoration in connectivity by antipsychotic medications being a mode of efficacy we chose to examine the effects of the atypical antipsychotic clozapine and the typical antipsychotic haloperidol on NRG-1 and SNARE protein transcripts in human brain aggregates exposed to plasma levels chronically for a period of three weeks. At the end of this exposure period we performed quantitative real-time PCR to investigate the mRNA levels of NRG-1, VAMP-1 and SNAP-25. Overall we found that clozapine had the ability to upregulate NRG-1 (+3.58 fold change) and VAMP-1 (+1.92) while SNAP-25 remained unchanged. Changes for haloperidol exposed aggregates were below our cut-off of +1.5. Overall the results of our investigation lend further support to atypical antipsychotic medications having the potential to increase levels of neurotrophic and synaptic markers such as NRG-1 and VAMP-1, the former being a strong candidate susceptibility gene for schizophrenia. In the absence of frank neuronal loss in schizophrenia, restoration of neuronal and synaptic functions by atypical antipsychotics in the brains of schizophrenics maybe a key mechanism of therapeutic efficacy by re-establishing normal connectivity and functioning.
越来越多的遗传学证据表明，神经调节蛋白-1（NRG-1）在精神分裂症发病机制中发挥作用，并且在尸检研究中发现，SNAP受体（SNARE）蛋白在基因和蛋白水平上均有改变。关于非典型抗精神病药物的潜在治疗机制，已表明氯氮平可提高啮齿动物体内的NRG-1水平和突触标记物。由于越来越多的证据表明，抗精神病药物恢复连接性的潜在作用是一种疗效模式，我们选择研究非典型抗精神病药物氯氮平和典型抗精神病药物氟哌啶醇对人脑聚集体中NRG-1和SNARE蛋白转录本的影响，这些人脑聚集体在三周的时间里持续暴露于血浆水平。在这个暴露期结束时，我们进行了定量实时PCR，以研究NRG-1、VAMP-1和SNAP-25的mRNA水平。总体而言，我们发现氯氮平能够上调NRG-1（变化倍数为+3.58）和VAMP-1（+1.92），而SNAP-25保持不变。氟哌啶醇处理的聚集体的变化低于我们设定的+1.5的临界值。总体而言，我们的研究结果进一步支持了非典型抗精神病药物有可能提高神经营养和突触标记物的水平，如NRG-1和VAMP-1，前者是精神分裂症的一个强有力的候选易感基因。在精神分裂症患者不存在明显神经元丢失的情况下，非典型抗精神病药物在精神分裂症患者大脑中恢复神经元和突触功能可能是通过重新建立正常连接和功能来实现治疗效果的关键机制。
