The accumulation of amyloid-β peptide (Aβ) in the brain is a critical hallmark of Alzheimer's disease. This high cerebral Aβ concentration may be partly caused by impaired clearance of Aβ across the blood-brain barrier (BBB). The low-density lipoprotein receptor-related protein-1 (LRP-1) and the ATP-binding cassette (ABC) protein ABCB1 (P-glycoprotein) are involved in the efflux of Aβ across the BBB. We hypothesized that other ABC proteins, such as members of the G subfamily, are also involved in the BBB clearance of Aβ. We therefore investigated the roles of ABCG2 (BCRP) and ABCG4 in the efflux of [3H] Aβ1-40 from HEK293 cells stably transfected with human ABCG2 or mouse abcg4. We showed that ABCG2 and Abcg4 mediate the cellular efflux of [3H] Aβ1-40. In addition, probucol fully inhibited the efflux of [3H] Aβ1-40 from HEK293-abcg4 cells. Using the in situ brain perfusion technique, we showed that GF120918 (dual inhibitor of Abcb1 and Abcg2) strongly enhanced the uptake (Clup, μl/g/s) of [3H] Aβ1-40 by the brains of Abcb1-deficient mice, but not by the brains of Abcb1/Abcg2-deficient mice, suggesting that Abcg2 is involved in the transport of Aβ at the mouse BBB. Perfusing the brains of Abcb1/Abcg2- and Abca1-deficient mice with [3H] Aβ1-40 plus probucol significantly increased the Clup of Aβ. This suggests that a probucol-sensitive transporter that is different from Abca1, Abcb1, and Abcg2 is involved in the brain efflux of Aβ. We suggest that this probucol-sensitive transporter is Abcg4. We conclude that Abcg4 acts in concert with Abcg2 to efflux Aβ from the brain across the BBB.
The blood-brain barrier restricts the passage of substances into the brain. Neuropeptides, such as enkephalins, cannot be delivered into the brain when given systemically because of this barrier. Therefore, there is a need to develop efficient transport systems to deliver these drugs to the brain. Recently, we have demonstrated that conjugation of doxorubicin or penicillin to peptide vectors significantly enhances their brain uptake. In this study, we have conjugated the enkephalin analog dalargin with two different peptide vectors, SynB1 and SynB3, to improve its brain delivery and its pharmacological effect. We show by in situ brain perfusion that vectorization markedly enhances the brain uptake of dalargin. We also show using the hot-plate model that this enhancement in brain uptake results in a significant improvement in the observed antinociceptive effect of dalargin. These results support the usefulness of peptide-mediated strategies for improving the availability and efficacy of central nervous system drugs.Brain delivery is one of the major challenges for the neuropharmaceutical industry since increasing number of hydrophilic therapeutic agents, such as anticancer drugs, antibiotics, and antiviral drugs are unable to cross the blood-brain barrier (BBB). The BBB represents a complex endothelial interface in vertebrates that separates the blood compartment from the extracellular fluid compartment of the brain parenchyma. The capillaries in the brain parenchyma possess a high electrical resistance due to tight junctions between the endothelial cells and also lack pores. Thus, the brain capillary endothelium behaves like a continuous lipid bilayer, and diffusion through this BBB layer is largely dependent on the lipid solubility of the drug. Because peptides are hydrophilic, biologically unstable, and large molecules, it is difficult for them to penetrate the BBB. Even though their brain uptake is not so high, some peptides and proteins are delivered into the brain by carrier-mediated transport, receptor-mediated transport, or adsorptive-mediated transport mechanisms. One of the problems associated with the inability of many peptides and proteins to accumulate in the brain in therapeutically meaningful amounts is the efflux transport systems. For example, it has been shown that the selective ␦-opioid receptors against [D-Pen 2 ,D-Pen 5 ]-enkephalin (DPDPE) has a poor BBB permeability that is explained in part by P-glycoprotein (P-gp)-mediated efflux, and DPDPE is also a substrate of the rat organic anion transporting polypeptide 2 (OATP2) and human OATP-A (Kakyo et al., 1999;Gao et al., 2000).To overcome the limited access of drugs to the brain, various strategies have been applied to direct central nervous system (CNS) drugs into the brain . Most of these methods are invasive, such as surgical implantation of an intraventricular catheter followed by drug infusion into the ventricular compartment, transient opening of the tight junctions by the intracarotid infusion of a hypertonic solution (Chamberl...
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