关键词: NMDAr hypofunction antipsychotics clozapine haloperidol organotypic culture schizophrenia

Mesh : Animals Humans Clozapine / pharmacology Haloperidol / pharmacology Excitatory Amino Acid Antagonists / pharmacology Dizocilpine Maleate / pharmacology Proteome / metabolism N-Methylaspartate Glutamic Acid / metabolism Receptors, N-Methyl-D-Aspartate / metabolism Proteomics Antipsychotic Agents / pharmacology Brain / metabolism

来  源:   DOI:10.1111/jnc.16059

Abstract:
Deciphering the molecular pathways associated with N-methyl-D-aspartate receptor (NMDAr) hypofunction and its interaction with antipsychotics is necessary to advance our understanding of the basis of schizophrenia, as well as our capacity to treat this disease. In this regard, the development of human brain-derived models that are amenable to studying the neurobiology of schizophrenia may contribute to filling the gaps left by the widely employed animal models. Here, we assessed the proteomic changes induced by the NMDA glutamate receptor antagonist MK-801 on human brain slice cultures obtained from adult donors submitted to respective neurosurgery. Initially, we demonstrated that MK-801 diminishes NMDA glutamate receptor signaling in human brain slices in culture. Next, using mass-spectrometry-based proteomics and systems biology in silico analyses, we found that MK-801 led to alterations in proteins related to several pathways previously associated with schizophrenia pathophysiology, including ephrin, opioid, melatonin, sirtuin signaling, interleukin 8, endocannabinoid, and synaptic vesicle cycle. We also evaluated the impact of both typical and atypical antipsychotics on MK-801-induced proteome changes. Interestingly, the atypical antipsychotic clozapine showed a more significant capacity to counteract the protein alterations induced by NMDAr hypofunction than haloperidol. Finally, using our dataset, we identified potential modulators of the MK-801-induced proteome changes, which may be considered promising targets to treat NMDAr hypofunction in schizophrenia. This dataset is publicly available and may be helpful in further studies aimed at evaluating the effects of MK-801 and antipsychotics in the human brain.
摘要:
破译与N-甲基-D-天冬氨酸受体(NMDAr)功能减退相关的分子途径及其与抗精神病药的相互作用对于促进我们对精神分裂症基础的理解是必要的。以及我们治疗这种疾病的能力。在这方面,开发适合于精神分裂症神经生物学研究的人脑衍生模型可能有助于填补广泛使用的动物模型留下的空白。这里,我们评估了NMDA谷氨酸受体拮抗剂MK-801在接受切除神经外科手术的成年供体的人脑切片培养物中诱导的蛋白质组变化。最初,我们证明MK-801减少培养的人脑切片中的NMDA谷氨酸受体信号传导。接下来,在计算机分析中使用基于质谱的蛋白质组学和系统生物学,我们发现MK-801导致与先前与精神分裂症病理生理学相关的几种途径相关的蛋白质发生改变,包括Ephrin,阿片类药物褪黑激素,sirtuin信号,白细胞介素8,内源性大麻素,和突触小泡周期。我们还评估了典型和非典型抗精神病药物对MK-801诱导的蛋白质组变化的影响。有趣的是,与氟哌啶醇相比,非典型抗精神病药氯氮平在对抗NMDAr功能减退引起的蛋白质改变方面表现出更显著的能力.最后,使用我们的数据集,我们确定了MK-801诱导的蛋白质组变化的潜在调节剂,这可能被认为是治疗精神分裂症NMDAr功能减退的有希望的目标。该数据集是公开可用的,可能有助于旨在评估MK-801和抗精神病药物在人脑中的作用的进一步研究。
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