The blood brain barrier (BBB) is a specialized structure which is crucial for preserving and maintaining the highly controlled microenvironment of the central nervous system (CNS) for optimal neural functioning (Abbot, Rönnbäck, & Hansson, 2006). The endothelial cells of the brain’s capillaries, in combination with astrocytes and pericytes, form this neurovascular unit (NVU) that is, BBB (Abbot, Patabendige, Dolman, Yusof, & Begley, 2010). The BBB is responsible for maintaining ionic homeostasis of the brain, providing nutrients to the brain, preventing “cross talk” between peripheral and central nervous system neurotransmitters, and preventing entry of plasma macromolecules and neurotoxins. These functions are achieved through a combination of a physical, transport, and metabolic barrier (Abbot et al., 2006). The physical barrier is a complex structure of tight junctions (TJs) between the endothelial cells of the brain, characterized by distinct morphology and functional features. TJs are created by different trans-membrane proteins, including claudins, occludins, and junction adhesion molecules (JAMS) in association with actin through cytoplasmic proteins like zonula occludin (ZO)-1, 2, and 3 (Ballabh et al., 2004, Kadry et al., 2020). The TJs are responsible for reducing paracellular and intracellular diffusion and redirecting the molecular traffic to the transcellular pathway; across the endothelial cells (Anderson, Van, & Itallie, 2009). Whilst a wide range of lipid soluble molecules can passively diffuse through the BBB, the permeability of these molecules is dependent on their molecular weight and lipophilicity. Essential nutrients required by the brain cannot diffuse through, and so the transport systems in place, allow for their delivery. Selective and region-specific (luminal/abluminal surfaces of endothelial cells) expression of transporters on the BBB results in polarity of the endothelial cells in physiological conditions (Kadry et al., 2020). Some transporters are equally distributed across both luminal (blood facing) and abluminal (brain facing) membranes, whilst others have an asymmetric distribution. Orientation of transporters therefore results in preferential transport of substrates into or across the endothelium. Solute carrier transporters (SLC) are present at both the luminal and abluminal membranes, facilitating the transport of small polar solutes like glucose and amino acids as well as the elimination of waste products (Morris, Rodriguez-Cruz, & Felmlee, 2017). Small peptides can traverse the BBB by uptake/efflux transporters (Abbot et al., 2010), whereas receptor and adsorptive-mediated transcytosis are responsible for the transport of larger molecules. A combination of specific ion channels and transporters are responsible for the maintenance of ionic homeostasis, irrespective of fluctuating ion concentrations in the plasma. Luminal transporters allow entry of Na+, K+, and Cl– into the endothelium from the blood, abluminal sodium pumps then transport Na1+ into the brain and K+ out, thereby maintaining a higher concentration of Na+ and low concentration of K+ in the brain (Kadry et al., 2020). In addition, the transporter system plays a vital role in protecting the brain from neurotoxins. Within the BBB, ATP-binding cassette (ABC) transporters, including breast cancer resistance protein (BCRP), P-glycoprotein (P-gp), and several multidrug resistance related proteins (MRPs), function to prevent the entry of toxic compounds in the brain as demonstrated through in vitro and in vivo experiments where these transporters were responsible for the active (against concentration gradient) efflux of a wide range of compounds from endothelium into the blood (Mahringer & Fricker, 2016). The metabolic barrier also prevents the entry of potential neurotoxins as the endothelial cells possess a combination of cell surface and intracellular enzymes, including CYP 450 enzymes. These enzymes are responsible for metabolism of certain molecules in transit, thereby preventing the entrance of potentially harmful substances into the CNS (Kadry et al., 2020).

Therefore, the integrity and functionality of the BBB is of vital importance. However, this can become compromised under pathological conditions. Due to industrialization and socioeconomic trends, exposure to various toxic metals (Pb2+, Cd2+, As2+, Hg+, Al3+, etc) has increased during the past few decades (Iqbal & Ahmed, 2019). These metals enter the human body either via dietary intake, dermal contact, or inhalation (Xie et al., 2023). They can then get access to the BBB, compromising its integrity and functionality (Zheng, Aschner, & Ghersi-Egea, 2003) and in turn enter the CNS (Fig. 1), where they induce neurotoxicity (Zheng et al., 2003). There is ongoing research to determine the mechanisms involved in BBB impairment caused by heavy metals and to identify potential therapeutic targets. This chapter will discuss the intricate processes and mechanisms by which heavy metals transverse and disrupt the BBB and possible therapeutic options.