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      Vascular RAGE transports oxytocin into the brain to elicit its maternal bonding behaviour in mice.

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          Abstract

          Oxytocin sets the stage for childbirth by initiating uterine contractions, lactation and maternal bonding behaviours. Mice lacking secreted oxcytocin (Oxt-/-, Cd38-/-) or its receptor (Oxtr-/-) fail to nurture. Normal maternal behaviour is restored by peripheral oxcytocin replacement in Oxt-/- and Cd38-/-, but not Oxtr-/- mice, implying that circulating oxcytocin crosses the blood-brain barrier. Exogenous oxcytocin also has behavioural effects in humans. However, circulating polypeptides are typically excluded from the brain. We show that oxcytocin is transported into the brain by receptor for advanced glycation end-products (RAGE) on brain capillary endothelial cells. The increases in oxcytocin in the brain which follow exogenous administration are lost in Ager-/- male mice lacking RAGE, and behaviours characteristic to abnormalities in oxcytocin signalling are recapitulated in Ager-/- mice, including deficits in maternal bonding and hyperactivity. Our findings show that RAGE-mediated transport is critical to the behavioural actions of oxcytocin associated with parenting and social bonding.

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          Structure and function of the blood-brain barrier.

          N. Abbott, Adjanie Patabendige, Diana Dolman … (2010)
          Neural signalling within the central nervous system (CNS) requires a highly controlled microenvironment. Cells at three key interfaces form barriers between the blood and the CNS: the blood-brain barrier (BBB), blood-CSF barrier and the arachnoid barrier. The BBB at the level of brain microvessel endothelium is the major site of blood-CNS exchange. The structure and function of the BBB is summarised, the physical barrier formed by the endothelial tight junctions, and the transport barrier resulting from membrane transporters and vesicular mechanisms. The roles of associated cells are outlined, especially the endfeet of astrocytic glial cells, and pericytes and microglia. The embryonic development of the BBB, and changes in pathology are described. The BBB is subject to short and long-term regulation, which may be disturbed in pathology. Any programme for drug discovery or delivery, to target or avoid the CNS, needs to consider the special features of the BBB.
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            RAGE mediates amyloid-beta peptide transport across the blood-brain barrier and accumulation in brain.

            Rashid Deane, Shi Du Yan, Ram Submamaryan … (2003)
            Amyloid-beta peptide (Abeta) interacts with the vasculature to influence Abeta levels in the brain and cerebral blood flow, providing a means of amplifying the Abeta-induced cellular stress underlying neuronal dysfunction and dementia. Systemic Abeta infusion and studies in genetically manipulated mice show that Abeta interaction with receptor for advanced glycation end products (RAGE)-bearing cells in the vessel wall results in transport of Abeta across the blood-brain barrier (BBB) and expression of proinflammatory cytokines and endothelin-1 (ET-1), the latter mediating Abeta-induced vasoconstriction. Inhibition of RAGE-ligand interaction suppresses accumulation of Abeta in brain parenchyma in a mouse transgenic model. These findings suggest that vascular RAGE is a target for inhibiting pathogenic consequences of Abeta-vascular interactions, including development of cerebral amyloidosis.
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              Drug transport across the blood-brain barrier.

              William Pardridge (2012)
              The blood-brain barrier (BBB) prevents the brain uptake of most pharmaceuticals. This property arises from the epithelial-like tight junctions within the brain capillary endothelium. The BBB is anatomically and functionally distinct from the blood-cerebrospinal fluid barrier at the choroid plexus. Certain small molecule drugs may cross the BBB via lipid-mediated free diffusion, providing the drug has a molecular weight <400 Da and forms <8 hydrogen bonds. These chemical properties are lacking in the majority of small molecule drugs, and all large molecule drugs. Nevertheless, drugs can be reengineered for BBB transport, based on the knowledge of the endogenous transport systems within the BBB. Small molecule drugs can be synthesized that access carrier-mediated transport (CMT) systems within the BBB. Large molecule drugs can be reengineered with molecular Trojan horse delivery systems to access receptor-mediated transport (RMT) systems within the BBB. Peptide and antisense radiopharmaceuticals are made brain-penetrating with the combined use of RMT-based delivery systems and avidin-biotin technology. Knowledge on the endogenous CMT and RMT systems expressed at the BBB enable new solutions to the problem of BBB drug transport.
              Article 0 comments Cited 341 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (iso-abbrev): Commun Biol
                Title: Communications biology
                Publisher: Springer Science and Business Media LLC
                ISSN (Electronic): 2399-3642
                ISSN (Print): 2399-3642
                Publication date (Electronic): 2019
                Volume: 2
                Affiliations
                [1 ] Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, 920-8640, Japan. yasuyama@med.kanazawa-u.ac.jp.
                [2 ] Department of Basic Research on Social Recognition and Memory, Research Centre for Child Mental Development, Kanazawa University, Kanazawa, 920-8640, Japan.
                [3 ] Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, 920-8640, Japan.
                [4 ] Medical Research Institute, Kanazawa Medical University and Medical Care Proteomics Biotechnology Co., Uchinada, Ishikawa, 920-0293, Japan.
                [5 ] Department of Neuroanatomy, Kanazawa University Graduate School of Medical Sciences, Kanazawa, 920-8640, Japan.
                [6 ] Department of Functional Anatomy, Kanazawa University Graduate School of Medical Sciences, Kanazawa, 920-8640, Japan.
                [7 ] Department of Neurosurgery, Kanazawa University Graduate School of Medical Sciences, Kanazawa, 920-8640, Japan.
                [8 ] Laboratory for Social Brain Studies, Research Institute of Molecular Medicine and Pathobiochemistry, and Department of Biochemistry, Krasnoyarsk State Medical University, Krasnoyarsk, Russia, 660022.
                [9 ] Division of Transgenic Animal Science, Kanazawa University Advanced Science Research Centre, Kanazawa, 920-8640, Japan.
                [10 ] Laboratory of Molecular Biology, Department of Molecular and Cell Biology, Graduate School of Agricultural Science, Tohoku University, Sendai, 981-8555, Japan.
                [11 ] Joslin Diabetes Centre & Harvard Medical School, Boston, MA, 02215, USA.
                [12 ] Komatsu University, Komatsu, 923-0921, Japan.
                [13 ] Department of Basic Research on Social Recognition and Memory, Research Centre for Child Mental Development, Kanazawa University, Kanazawa, 920-8640, Japan. haruhiro@med.kanazawa-u.ac.jp.
                [14 ] Laboratory for Social Brain Studies, Research Institute of Molecular Medicine and Pathobiochemistry, and Department of Biochemistry, Krasnoyarsk State Medical University, Krasnoyarsk, Russia, 660022. haruhiro@med.kanazawa-u.ac.jp.
                Article
                Publisher Item ID: 10.1038/s42003-019-0325-6
                DOI: 10.1038/s42003-019-0325-6
                PMC ID: 6389896
                PubMed ID: 30820471
                SO-VID: 35973359-01ff-476d-82ed-943525017b1e
                History

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