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  • This resembles a vicious cycle since BBB disruption and infl

    2021-09-02

    This resembles a vicious cycle since BBB disruption and inflammation are thought to be caused by epilepsy, but other contributing factors are also known to be their cause, such as peripheral infection, autoimmunity, estriol synthesis trauma and stroke that also underlie epilepsy [18]. Additional triggers that stimulate neuroinflammation and BBB disruption comprise high blood pressure, low blood pH, hypoxia and certain chemotherapy regimens [19,20]. Brain inflammation caused by these triggering events results in neuronal hyperexcitability that leads to the development of epilepsy and the generation of seizures [18]. Angiogenesis has also been reported as a relevant consequence of BBB damage [21]. Endothelial cells from the neurovascular unit express two main types of transporters responsible for moving compounds into and out of the CNS: solute carrier (SLC) transporters and ABC transporters [14]. The SLC transporters comprise a vast group of proteins mainly responsible for the influx of nutrients, ions and metabolites that are required for the appropriate function of the CNS. It encompasses a group of membrane transport proteins with over 400 members, including SLC2A1 [glucose transporter 1 (GLUT1)] [22]. Interestingly, GLUT1 deficiency is a genetic syndrome responsible for juvenile onset of epilepsy, causing great comorbidity in epileptic patients [23]. On the other hand, the majority of efflux transporters expressed in BBB belong to the ABC superfamily, and are essentially responsible for keeping xenobiotics and toxins out of the CNS, protecting the sensitive balance of the neuronal network [24]. However, when regarding central-acting drugs, ABC transporters often limit their access to the target site [25]. Efflux transporters present a major obstacle to drug penetration into the CNS, being a fundamental key point throughout drug discovery and development programs of new drugs. From the different types of transporters expressed in the BBB cells, including ion channels, solute transporters, aquaporins and ABC transporters, the last ones are currently ascribed as the most clinically relevant and responsible for drug efflux, particularly when concerning DRE [26]. For this reason, this superfamily will be described in-depth in the following section.
    Efflux transporters from the ABC family The ABC superfamily includes several transporter proteins mainly responsible for exporting substrates using the catalytic energy of ATP. In humans, as in all eukaryotic systems, this superfamily actively effluxes compounds, extruding toxins and drugs out of cells [27]. They have a broad variety of substrates, not only small substances such as ions and molecules, but also larger highly organised structures like peptides, lipids, polysaccharides [28]. In humans, there are 48 ABC transporters classified in 7 different subfamilies, from A to G, regarding their genetic and amino acid structure [26]. The most widely studied and significant for their drug efflux potential are the ABCB, ABCC and ABCG subfamilies. Among them, the ABCB1 transporter, encoded by the ABCB1 gene and also known as P-glycoprotein, has been the most studied efflux transporter, followed by ABCCs, known as multidrug resistance-associated proteins and ABCG2, also named breast cancer resistance protein [29]. Constitutively, ABC transporters have a variable number of nucleotide-binding domains (NBDs) and transmembrane domains (TMDs), generally being two of each in order to be functional [30]. The NBDs contain singular motifs (Walker A and Walker B), common in all ABC proteins, and the TMDs contain between 6 and 12 membrane spanning α-helices, responsible for substrate specificity [31]. However, there are some exceptions, namely the ABCG subfamily, as it comprises only one TMD and one NBD, requiring homo- or heterodimerization to attain adequate functionality [30]. ABCB1, the most extensively studied efflux transporter of its family, is composed by 1280 amino acids and encoded by the ABCB1 gene on the 7q21.1 human chromosomal region [29]. ABCB1 is acknowledged by its polyspecificity that results from the large and variable binding pocket of its structure, transporting a remarkable number of substrates [32]. The broad number of ABCB1 substrates includes several classes of pharmaceutical compounds such as anticancer drugs, immunosuppressive agents, corticoids, analgesics, antiviral drugs, calcium channel blockers, antidepressants, antibiotics and AEDs [29]. ABCB1 is mainly expressed in the apical membrane of cells of organs responsible for absorption, distribution, metabolism and excretion [33]. Its main sites of expression include the small intestine, liver, kidney, and blood tissue barriers such as the BBB and the blood cerebral spinal fluid barrier (BCSFB) [33]. In the small intestine, colon and liver, it works as first-pass elimination process for orally administered drugs, critically affecting their bioavailability [34]. On the other hand, its induction/inhibition seems to be a major player in drug-drug interactions [33]. In the kidneys, it works as an excretion mechanism because of its location in the apical membrane of epithelial cells of proximal tubes [35].