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用于有机磷和神经化学毒性筛选的三维（3D）脑器官芯片系统。

Three-dimensional (3D) brain microphysiological system for organophosphates and neurochemical agent toxicity screening.

机构信息

FIT BEST Laboratory, Department of Chemical, Biological, and Bio Engineering, North Carolina Agricultural and Technical State University, Greensboro, North Carolina, United States of America.

Center for Drug Discovery, RTI International, Research Triangle Park, Durham, North Carolina, United States of America.

出版信息

PLoS One. 2019 Nov 8;14(11):e0224657. doi: 10.1371/journal.pone.0224657. eCollection 2019.

DOI:10.1371/journal.pone.0224657
PMID:31703066
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6839879/
Abstract

We investigated a potential use of a 3D tetraculture brain microphysiological system (BMPS) for neurotoxic chemical agent screening. This platform consists of neuronal tissue with extracellular matrix (ECM)-embedded neuroblastoma cells, microglia, and astrocytes, and vascular tissue with dynamic flow and membrane-free culture of the endothelial layer. We tested the broader applicability of this model, focusing on organophosphates (OPs) Malathion (MT), Parathion (PT), and Chlorpyrifos (CPF), and chemicals that interact with GABA and/or opioid receptor systems, including Muscimol (MUS), Dextromethorphan (DXM), and Ethanol (EtOH). We validated the BMPS platform by measuring the neurotoxic effects on barrier integrity, acetylcholinesterase (AChE) inhibition, viability, and residual OP concentration. The results show that OPs penetrated the model blood brain barrier (BBB) and inhibited AChE activity. DXM, MUS, and EtOH also penetrated the BBB and induced moderate toxicity. The results correlate well with available in vivo data. In addition, simulation results from an in silico physiologically-based pharmacokinetic/pharmacodynamic (PBPK/PD) model that we generated show good agreement with in vivo and in vitro data. In conclusion, this paper demonstrates the potential utility of a membrane-free tetraculture BMPS that can recapitulate brain complexity as a cost-effective alternative to animal models.

摘要

我们研究了一种使用三维四培养脑微生理系统 (BMPS) 进行神经毒性化学物质筛选的可能性。该平台由含有神经母细胞瘤细胞、小胶质细胞和星形胶质细胞的细胞外基质 (ECM) 嵌入神经元组织，以及具有动态流动和无膜培养内皮层的血管组织组成。我们测试了该模型更广泛的适用性，重点研究了有机磷 (OP) 马拉硫磷 (MT)、对硫磷 (PT) 和氯吡硫磷 (CPF)，以及与 GABA 和/或阿片受体系统相互作用的化学物质，包括 Muscimol (MUS)、Dextromethorphan (DXM) 和 Ethanol (EtOH)。我们通过测量对屏障完整性、乙酰胆碱酯酶 (AChE) 抑制、活力和残留 OP 浓度的神经毒性影响来验证 BMPS 平台。结果表明，OPs 穿透了模型血脑屏障 (BBB) 并抑制了 AChE 活性。DXM、MUS 和 EtOH 也穿透了 BBB 并引起中度毒性。结果与可用的体内数据很好地相关。此外，我们生成的基于生理的药物动力学/药效学 (PBPK/PD) 模型的计算机模拟结果与体内和体外数据非常吻合。总之，本文证明了无膜四培养 BMPS 的潜在用途，作为动物模型的经济有效的替代方法，可以再现大脑的复杂性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/04d8/6839879/11d132cca517/pone.0224657.g007.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/04d8/6839879/11d132cca517/pone.0224657.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/04d8/6839879/818f491ffefb/pone.0224657.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/04d8/6839879/b2131b0f9635/pone.0224657.g002.jpg
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