Blood-brain barrier dysfunction induced by silica NPs in vitro and in vivo: Involvement of oxidative stress and Rho-kinase/JNK signaling pathways.

Silica nanoparticles (SiO2 -NPs) has been extensively exploited in biomedical fields and mostly designed to enter the circulatory system, however, few studies focused on the potential adverse effects of SiO2 -NPs exposure on the blood-brain barrier (BBB) that serves as a critical barrier between the central nervous system (CNS) and the peripheral circulation. This study attempts to provide an understanding of whether and how SiO2 -NPs disrupts the BBB in vitro and in vivo. Through a human BBB model, we found that SiO2 -NPs could induce tight junction loss and cytoskeleton arrangement, and increase inflammatory response and the release of vascular endothelial growth factor (VEGF) of brain microvessel endothelial cells (BMECs), which further activates astrocytes to amplify the generation of VEGF and increase the aquaporin-4 expression, and thus causing BBB disruption through a complex immunoregulatory loop between BMECs and astrocytes under SiO2 -NPs exposure. Additionally, our data show that inhibition of reactive oxygen species (ROS) and Rho-kinase (ROCK) could effectively protect the SiO2 -NPs-induced BBB dysfunction. In vivo studies further confirmed that SiO2 -NPs could cause the BBB paracellular opening, oxidative stress and astrocyte activation in brains of Sprague-Dawley (SD) rats. These findings demonstrate that SiO2 -NPs could disturb BBB structure and function and induce BBB inflammation, and suggest that these effects may occur through ROS and ROCK-mediated pathways, which not only improve neurotoxicity evaluation for SiO2 -NPs but also provide useful information in development of SiO2 -NPs in neuro-therapeutics and nanodiagnostics.