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

Autoři: Lumei Liu aff001;  Youngmi Koo aff001;  Chukwuma Akwitti aff001;  Teal Russell aff001;  Elaine Gay aff002;  Daniel T. Laskowitz aff003;  Yeoheung Yun aff001
Působiště autorů: FIT BEST Laboratory, Department of Chemical, Biological, and Bio Engineering, North Carolina Agricultural and Technical State University, Greensboro, North Carolina, United States of America aff001;  Center for Drug Discovery, RTI International, Research Triangle Park, Durham, North Carolina, United States of America aff002;  Departments of Neurology, Anesthesiology, and Neurobiology, Brain Injury Translational Research Center, Duke University, Durham, North Carolina, United States of America aff003
Vyšlo v časopise: PLoS ONE 14(11)
Kategorie: Research Article
doi: 10.1371/journal.pone.0224657


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.

Klíčová slova:

Astrocytes – Blood – Esterases – Gamma-aminobutyric acid – Microglial cells – Neurons – Toxic agents – Toxicity


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