Update on zinc protection against Cd-induced BBB impairment

Over the years, anthropogenic factors have led to cadmium (Cd) accumulation in the environment causing various health problems. Due to its highly soluble nature compared to other metals, Cd is easily absorbed by plants giving rise to bioaccumulation phenomena. So, the diet is the primary source of Cd exposure in humans. Other sources include smoking, occupational exposure and house dust. Once inside the bloodstream, Cd is able to impair the blood-brain barrier (BBB), a specialized system that shields the brain from toxic substances in the blood. This impairment allows a greater amount of toxicant to enter the central nervous system leading to neurodegeneration. In fact, chronic exposure to Cd has been linked to numerous neurodegenerative disorders in adulthood including Alzheimer’s and Parkinson’s diseases. Although studies in rodents have established a Cd-dependent BBB dysfunction, how Cd may alter the cell-cell junctions in the endothelium remains elusive. In our previous studies, we investigated the signaling pathway of Cd-induced tight junctions disassembly in a rat brain endothelial cell line (RBE4), as an in vitro model for the study of the BBB. This phenomenon was coincident with a significant ROS production, upregulation of GRP78 expression levels, a chaperone involved in endoplasmic reticulum stress, caspase-3 activation and BAX overexpression leading to apoptotic cell death pathways. Surprisingly, the micronutrient Zinc (Zn), one of the most important microelements necessary for normal body functioning, was able to mitigate Cd harmful effects. Moreover, morphological analysis following Zn co-treatment showed the role of Zn in preventing ZO-1 dislocation and altered cytoskeleton rearrangements induced by Cd.These results highlight the protective role of Zn against Cd-induced alteration in the BBB, suggesting Zn supplementation as an effective strategy to prevent cell oxidative stress.