Effetti biologici dell'esposizione cronica al cadmio sulla barriera emato-encefalica

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. Thus, diet is the primary source of Cd exposure in humans. Other sources include smoking, occupational exposure and indoor spaces, particularly exposed to the metal. Once inside the bloodstream, Cd is capable of damaging the blood-brain barrier (BBB), a specialized system that shields the central nervous system (CNS) from toxic substances in the blood. This impairment allows a greater amount of the neurotoxic to enter the CNS leading to neurodegeneration. In fact, chronic exposure to Cd has been linked to numerous neurodegenerative disorders in adulthood, including Alzheimer’s and Parkinson’s disease. Although in vivo studies have established a Cd-dependent BBB dysfunction, the molecular mechanisms underlying the increased permeability of the barrier have not yet been fully elucidated. In this work, possible molecular pathways involved in the disassembly of tight junctions in a rat brain endothelium (RBE4) cell line have been outlined, as an in vitro model for the study of the BBB. This phenomenon coincided with the upregulation of GRP78 expression levels, a chaperone involved in the endoplasmic reticulum stress, and the activation of caspase-3. The cellular response to oxidative stress was also evaluated by the subcellular localization of Nrf2 and the consequent expression of SOD1, as part of a defense mechanism to counteract Cd-induced damage. On the other hand, the micronutrient Zinc (Zn), one of the most important microelements necessary for normal body functioning, was able to mitigate Cd harmful effects, partially preventing ZO-1 dislocation and altered cytoskeleton rearrangements. Based on the experimental data, Zn is able to interfere with the toxic action exerted by Cd, suggesting its diet integration as an effective strategy to hinder cellular oxidative stress, helping to maintain the barrier integrity. Cd neurotoxic effects on RBE4 cells were also evaluated in co-culture to determine whether these effects could be modulated in the presence of the other cell types that form the neurovascular unit, such as DI TNC1 astrocytes and RBVP pericytes. The results clearly showed that Cd influences mitochondrial activity and cell morphology even in co-culture conditions, but that the cytotoxic effects were dampened in the presence of astrocytes, but not pericytes. In addition, the support function of astrocytes highlighted their leading role in strengthening the tight junction structural complexes by the expression of adhesion molecules such as claudin-5.