1. Department of Occupational & Environmental Health and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an, 710032, China;
2. Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
* Xinqin Liu and Peng Su contributed equally to this paper.
Lead (Pb) is a well-known neurotoxicant and a risk factor for neurologic disorders. The blood brain barrier (BBB) plays an important role in the maintenance of optimal brain function. BBB is a target of Pb, and studies have shown that Pb induced barrier loss and decreased the expression of tight junction proteins, but the detailed mechanisms are not fully understood. Matrix metalloproteinases (MMPs) are important components of extracellular matrix proteasome and can affect the remodeling and degradation of tight junction (TJ). The role of MMP-2/9 in Pb-induced damage of BBB is not known. In our study, we used an in vitro BBB model by co-culturing human umbilical vascular endothelial cells (ECV304 cells) with rat glioma cells (C6 cells), and detected the expression of related TJ proteins and MMP-2/9. Our results showed that Pb increased the permeability of the in vitro BBB model, and stimulating C6 cells with Pb could decrease the protein level of ZO-1 (zonula occludens-1) and occludin in ECV304 cells. Pb could increase the mRNA and protein level of MMP-2/9 in C6 cells, and inhibition of MMP-2/9 by SB-3CT could partially alleviate Pb-induced down-regulation of TJ proteins in ECV304 cells and Pb-induced barrier damage in the in vitro BBB model. Our research established potential therapeutic targets for modulating and preserving optimal BBB function.
Keywords: Lead, blood brain barrier, matrix metalloproteinase, tight junction.