Transport of oxytocin to the brain after peripheral administration by membrane-bound or soluble forms of receptors for advanced glycation end-products.
Munesue SI; Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan.
Liang M; Department of Basic Research on Social Recognition and Memory, Research Centre for Child Mental Development, Kanazawa University, Kanazawa, Japan.
Harashima A; Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan.
Zhong J; Department of Basic Research on Social Recognition and Memory, Research Centre for Child Mental Development, Kanazawa University, Kanazawa, Japan.
Furuhara K; Department of Basic Research on Social Recognition and Memory, Research Centre for Child Mental Development, Kanazawa University, Kanazawa, Japan.
Boitsova EB; Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan.; Laboratory for Social Brain Studies, Research Institute of Molecular Medicine and Pathobiochemistry, Department of Biochemistry, Krasnoyarsk State Medical University named after Prof. V. F. Voino-Yasentsky, Krasnoyarsk, Russia.
Cherepanov SM; Department of Basic Research on Social Recognition and Memory, Research Centre for Child Mental Development, Kanazawa University, Kanazawa, Japan.
Gerasimenko M; Department of Basic Research on Social Recognition and Memory, Research Centre for Child Mental Development, Kanazawa University, Kanazawa, Japan.
Yuhi T; Department of Basic Research on Social Recognition and Memory, Research Centre for Child Mental Development, Kanazawa University, Kanazawa, Japan.
Yamamoto Y; Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan.
Higashida H; Department of Basic Research on Social Recognition and Memory, Research Centre for Child Mental Development, Kanazawa University, Kanazawa, Japan.; Laboratory for Social Brain Studies, Research Institute of Molecular Medicine and Pathobiochemistry, Department of Biochemistry, Krasnoyarsk State Medical University named after Prof. V. F. Voino-Yasentsky, Krasnoyarsk, Russia.
Journal of neuroendocrinology [J Neuroendocrinol] 2021 Mar; Vol. 33 (3), pp. e12963.
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Publication: <2010->: Malden, MA : Wiley & Sons
Original Publication: Eynsham, Oxon, UK : Oxford University Press, c1989-
Castel M, Gainer H, Dellmann HD. Neuronal secretory systems. Int Rev Cytol. 1984;88:303-459.
Russell JA. Fifty years of advances in neuroendocrinology. Brain Neurosci Adv. 2018;2:2398212818812014.
Jin D, Liu H-X, Hirai H, et al. CD38 is critical for social behaviour by regulating oxytocin secretion. Nature. 2007;446:41-45.
Leng G, Pineda R, Sabatier N, Ludwig M. 60 Years of Neuroendocrinology: the posterior pituitary, from Geoffrey Harris to our present understanding. J Endocrinol. 2015;226:T173-185.
Higashida H. Somato-axodendritic release of oxytocin into the brain due to calcium amplification is essential for social memory. J Physiol Sci. 2016;66:275-282.
Brown CH, Ludwig M, Tasker JG, Stern JE. Somato-dendritic vasopressin and oxytocin secretion in endocrine and autonomic regulation. J Neuroendocrinol. 2020;32:e12856.
Ferguson JN, Young LJ, Hearn EF, Matzuk MM, Insel TR, Winslow JT. Social amnesia in mice lacking the oxytocin gene. Nat Genet. 2000;25:284-288.
Rilling JK, Young LJ. The biology of mammalian parenting and its effect on offspring social development. Science. 2014;345:771-776.
Bridges RS. Neuroendocrine regulation of maternal behavior. Front Neuroendocrinol. 2015;36:178-196.
Feldman R, Monakhov M, Pratt M, Ebstein RP. Oxytocin pathway genes: evolutionary ancient system impacting on human affiliation, sociality, and psychopathology. Biol Psychiatry. 2016;79:174-184.
Carter CS. The oxytocin-vasopressin pathway in the context of love and fear. Front Endocrinol (Lausanne). 2017;8:356.
Yoshihara C, Numan M, Kuroda KO. Oxytocin and parental behaviors. Curr Top Behav Neurosci. 2018;35:119-153.
Guastella AJ, Mitchell PB, Mathews F. Oxytocin enhances the encoding of positive social memories in humans. Biol Psychiatry. 2008;64:256-258.
Bartz JA, Zaki J, Bolger N, Ochsner KN. Social effects of oxytocin in humans: context and person matter. Trends Cogn Sci. 2011;15:301-309.
Brambilla M, Manenti R, de Girolamo G, Adenzato M, Bocchio-Chiavetto L, Cotelli M. Effects of intranasal oxytocin on long-term memory in healthy humans: a systematic review. Drug Dev Res. 2016;77:479-488.
Tillman R, Gordon I, Naples A, et al. Oxytocin enhances the neural efficiency of social perception. Front Hum Neurosci. 2019;13:71.
Tolomeo S, Chiao B, Lei Z, Chew SH, Ebstein RP. A novel role of CD38 and oxytocin as tandem molecular moderators of human social behavior. Neurosci Biobehav Rev. 2020;115:251-272.
Anagnostou E, Soorya L, Chaplin W, et al. Intranasal oxytocin versus placebo in the treatment of adults with autism spectrum disorders: a randomized controlled trial. Mol Autism. 2012;3:16.
Modi ME, Young LJ. The oxytocin system in drug discovery for autism: animal models and novel therapeutic strategies. Horm Behav. 2012;61:340-350.
Dadds MR, MacDonald E, Cauchi A, et al. Nasal oxytocin for social deficits in childhood autism: a randomized controlled trial. Autism Dev Disord. 2014;44:521-531.
Parker KJ, Garner JP, Libove RA, et al. Plasma oxytocin concentrations and OXTR polymorphisms predict social impairments in children with and without autism spectrum disorder. Proc. Natl. Acad. Sci. USA. 2014;111:12258-12263.
Parker KJ, Oztan O, Libove RA, et al. Intranasal oxytocin treatment for social deficits and biomarkers of response in children with autism. Proc Natl Acad Sci USA. 2017;114:8119-8124.
Munesue T, Nakamura H, Kikuchi M, et al. Oxytocin for male subjects with autism spectrum disorder and comorbid intellectual disabilities: a randomized pilot study. Front Psychiatry. 2017;7:2.
Kosaka H, Okamoto Y, Munesue T, et al. Oxytocin efficacy is modulated by dosage and oxytocin receptor genotype in young adults with high-functioning autism: a 24-week randomized clinical trial. Transl Psychiatry. 2016;6:e872.
Yamasue H, Okada T, Munesue T, et al. Effect of intranasal oxytocin on the core social symptoms of autism spectrum disorder: a randomized clinical trial. Mol Psych. 2020;25:1849-1858.
Cai Q, Feng L, Yap KZ. Systematic review and meta-analysis of reported adverse events of long-term intranasal oxytocin treatment for autism spectrum disorder. Psychiatry Clin Neurosci. 2018;72:140-151.
Higashida H, Munesue T, Kosaka H, Yamasue H, Yokoyama S, Kikuchi M. Social interaction improved by oxytocin in the subclass of autism with comorbid intellectual disabilities. Diseases. 2019;7:24.
Owada K, Okada T, Munesue T, et al. Quantitative facial expression analysis revealed the efficacy and time course of oxytocin in autism. Brain. 2019;142:2127-2136.
Alaerts K, Bernaerts S, Prinsen J, Dillen C, Steyaert J, Wenderoth N. Oxytocin induces long-lasting adaptations within amygdala circuitry in autism: a treatment-mechanism study with randomized placebo-controlled design. Neuropsychopharmacology. 2020;45:1141-1149.
Bernaerts S, Boets B, Bosmans G, Steyaert J, Alaerts K. Behavioral effects of multiple-dose oxytocin treatment in autism: a randomized, placebo-controlled trial with long-term follow-up. Mol Autism. 2020;11:6.
Yee JR, Kenkel WM, Frijling JL, et al. Oxytocin promotes functional coupling between paraventricular nucleus and both sympathetic and parasympathetic cardioregulatory nuclei. Horm Behav. 2016;80:82-91.
Jurek B, Neumann ID. The oxytocin receptor: from intracellular signaling to behavior. Physiol Rev. 2018;98:1805-1908.
Lee MR, Jayant RD. Penetration of the blood-brain barrier by peripheral neuropeptides: new approaches to enhancing transport and endogenous expression. Cell Tissue Res. 2019;375:287-293.
Neumann ID, Landgraf R. Balance of brain oxytocin andvasopressin: implications for anxiety, depression, and social behaviors. Trends in Neurosci. 2012;35:649-659.
Neumann ID, Maloumby R, Beiderbeck DI, Lukas M, Landgraf R. Increased brain and plasma oxytocin after nasal and peripheral administration in rats and mice. Psychoneuroendocrinology. 2013;38:1985-1993.
Feldman R. The neurobiology of human attachments. Trends Cogn Sci. 2017;21:80-99.
Tanaka A, Furubayashi T, Arai M, et al. Delivery of oxytocin to the brain for the treatment of autism spectrum disorder by nasal application. Mol Pharm. 2018;15:1105-1111.
Higashida H, Furuhara K, Yamauchi A-M, et al. Intestinal transepithelial permeability of oxytocin into the blood is dependent on the receptor for advanced glycation end products in mice. Sci Rep. 2017;7:7883.
Yamamoto Y, Liang M, Munesue S, et al. Vascular RAGE transports oxytocin into the brain to elicit its maternal bonding behaviour in mice. Commun Biol. 2019;2:76.
Yamamoto Y, Higashida H. RAGE regulates oxytocin transport into the brain. Commun Biol. 2020;3:70.
Kamide T, Kitao Y, Takeichi T, et al. RAGE mediates vascular injury and inflammation after global cerebral ischemia. Neurochem Int. 2012;60:220-228.
Shimizu YU, Harashima AI, Munesue S, et al. Neuroprotective effects of endogenous secretory receptor for advanced glycation end-products in brain ischemia. Aging Dis. 2020;11:547-558.
Yamamoto Y, Kato I, Doi T, et al. Development and prevention of advanced diabetic nephropathy in RAGE-overexpressing mice. J Clin Invest. 2001;108:261-268.
Yonekura H, Yamamoto Y, Sakurai S, et al. Novel splice variants of the receptor for advanced glycation end-products expressed in human vascular endothelial cells and pericytes, and their putative roles in diabetes-induced vascular injury. Biochem J. 2003;370:1097-1109.
Cheng C, Tsuneyama K, Kominami R, et al. Expression profiling of endogenous secretory receptor for advanced glycation end products in human organs. Mod Pathol. 2005;18:1385-1396.
Koyama H, Shoji T, Yokoyama H, et al. Plasma level of endogenous secretory RAGE is associated with components of the metabolic syndrome and atherosclerosis. Arterioscler Thromb Vasc Biol. 2005;25:2587-2593.
Harashima AI, Yamamoto Y, Cheng C, et al. Identification of mouse orthologue of endogenous secretory receptor for advanced glycation end-products: structure, function and expression. Biochem J. 2006;396:109-115.
Hudson BI, Carter AM, Harja E, et al. Identification, classification, and expression of RAGE gene splice variants. FASEB J. 2008;22:1572-1580.
Kalea AZ, Schmidt AM, Hudson BI. Alternative splicing of RAGE: roles in biology and disease. Front Biosci (Landmark Ed). 2011;16:2756-2770.
Koch M, Chitayat S, Dattilo BM, et al. Structural basis for ligand recognition and activation of RAGE. Structure. 2010;18:1342-1352.
Fritz G, Fritz G. RAGE: a single receptor fits multiple ligands. Trends Biochem Sci. 2011;36:625-632.
Yamamoto Y, Yamamoto H. RAGE-mediated inflammation, type 2 diabetes, and diabetic vascular complication. Front Endocrinol (Lausanne). 2013;4:105.
Prasad K. Low levels of serum soluble receptors for advanced glycation end products, biomarkers for disease state: myth or reality. Int J Angiol. 2014;23:11-16.
Braley A, Kwak T, Jules J, Harja E, Landgraf R, Hudson BI. Regulation of receptor for advanced glycation end products (RAGE) ectodomain shedding and its role in cell function. J Biol Chem. 2016;291:12057-12073.
Antonelli A, Di Maggio S, Rejman J, et al. The shedding-derived soluble receptor for advanced glycation endproducts sustains inflammation during acute Pseudomonas aeruginosa lung infection. Biochim Biophys Acta Gen Subj. 2017;1861:354-364.
Kwak T, Drews-Elger K, Ergonul A, et al. Targeting of RAGE-ligand signaling impairs breast cancer cell invasion and metastasis. Oncogene. 2017;36:1559-1572.
Martins DA, Mazibuko N, Zelaya F, et al. Effects of route of administration on oxytocin-induced changes in regional cerebral blood flow in humans. Nat Commun. 2020;11:1160.
Lee MR, Shnitko TA, Blue SW, et al. Labeled oxytocin administered via the intranasal route reaches the brain in rhesus macaques. Nat Commun. 2020;11:2783.
Higashida H, Hashii M, Tanaka Y, et al. CD38, CD157, and RAGE as molecular determinants for social behavior. Cells. 2019;9:62.
Zheng J-J, Li S-J, Zhang X-D, et al. Oxytocin mediates early experience- dependent cross-modal plasticity in the sensory cortices. Nat. Neurosci. 2014;17:391.
Fuxe K, Borroto-Escuela DO, Romero-Fernandez W, et al. On the role of volume transmission and receptor-receptor interactions in social behaviour: focus on central catecholamine and oxytocin neurons. Brain Res. 2012;1476:119-131.
Brewer JB, Zhao Z, Desmond JE, Glover GH, Gabrieli JD. Making memories: brain activity that predicts how well visual experience will be remembered. Science. 1998;281:1185-1187.
Leonard JA, Mackey AP, Finn AS, Gabrieli JD. Differential effects of socioeconomic status on working and procedural memory systems. Front Hum Neurosci. 2015;9:554.
Kummer KK, Mitrić M, Kalpachidou T, Kress M. The medial prefrontal cortex as a central hub for mental comorbidities associated with chronic pain. Int J Mol Sci. 2020;21:3440.
Quintana DS, Westlye LT, Alnaes D, et al. Low-dose intranasal oxytocin delivered with Breath Powered device modulates pupil diameter and amygdala activity: a randomized controlled pupillometry and fMRI study. Neuropsychopharmacology. 2018;44:306-313.
Myint K-M, Yamamoto Y, Doi T, et al. RAGE control of diabetic nephropathy in a mouse model: effects of RAGE gene disruption and administration of low-molecular weight heparin. Diabetes. 2006;55:2510-2522.
Yamamoto Y, Harashima AI, Saito H, et al. Septic shock is associated with receptor for advanced glycation end products ligation of LPS. J Immunol. 2011;186:3248-3257.
Sugihara T, Munesue S, Yamamoto Y, et al. Endogenous secretory receptor for advanced glycation end-products inhibits amyloid-β1-42 uptake into mouse brain. J Alzheimers Dis. 2012;28:709-720.
Zhong J, Amina S, Liang M, et al. Cyclic ADP-ribose and heat regulate oxytocin release via CD38 and TRPM2 in the hypothalamus during social or psychological stress in mice. Front Neurosci. 2016;10:304.
Lim NK, Moestrup V, Zhang X, Wang WA, Møller A, Huang FD. An improved method for collection of cerebrospinal fluid from anesthetized mice. J Vis Exp. 2018;133:56774.
Šakić B. Cerebrospinal fluid collection in laboratory mice: Literature review and modified cisternal puncture method. J Neurosci Methods. 2019;311:402-407.
Nakagawa S, Deli MA, Nakao S, et al. Pericytes from brain microvessels strengthen the barrier integrity in primary cultures of rat brain endothelial cells. Cell Mol Neurobiol. 2007;27:687-694.
Nakagawa S, Ohara H, Niwa M, Yamagata K, Nabika T. Defective function of the blood-brain barrier in a stroke-prone spontaneously hypertensive rat: evaluation in an in vitro cell culture model. Cell Mol Neurobiol. 2020;40:113-121.
MacLean EL, Gesquiere LR, Gee N, Levy K, Martin WL, Carter CS. Validation of salivary oxytocin and vasopressin as biomarkers in domestic dogs. J Neurosci Methods. 2018;293:67-76.
Yuhi T, Kyuta H, Mori H-A, et al. Salivary oxytocin concentration changes during a group drumming intervention for maltreated school children. Brain Sci. 2017;7:152.
Neuwelt EA, Bauer B, Fahlke C, et al. Engaging neuroscience to advance translational research in brain barrier biology. Nat Rev Neurosci. 2011;12:169-182.
McConnell HL, Kersch CN, Woltjer RL, Neuwelt EA. The translational significance of the neurovascular unit. J Biol Chem. 2017;292:762-770.
Grinevich V, Knobloch-Bollmann HS, Eliava M, Busnelli M, Chini B. Assembling the puzzle: pathways of oxytocin signaling in the brain. Biol Psychiatry. 2016;79:155-164.
Otero-García M, Agustín-Pavón C, Lanuza E, et al. Distribution of oxytocin and co-localization with arginine vasopressin in the brain of mice. Brain Struct Funct. 2016;221:3445-3473.
DiBenedictis BT, Nussbaum ER, Cheung HK, et al. Quantitative mapping reveals age and sex differences in vasopressin, but not oxytocin, immunoreactivity in the rat social behavior neural network. J Comp Neurol. 2017;525:2549-2570.
Godefroy D, Dominici C, Hardin-Pouzet H, et al. Three-dimensional distribution of tyrosine hydroxylase, vasopressin and oxytocin neurones in the transparent postnatal mouse brain. J Neuroendocrinol. 2017;29:12.
Smith CJW, DiBenedictis BT, Veenema AH. Comparing vasopressin and oxytocin fiber and receptor density patterns in the social behavior neural network: Implications for cross-system signaling. Front Neuroendocrinol. 2019;53:100737.
Althammer F, Jirikowski G, Grinevich V. The oxytocin system of mice and men-similarities and discrepancies of oxytocinergic modulation in rodents and primates. Peptides. 2018;109:1-8.
Grinevich V, Jirikowski GF. Towards new frontiers in neuroendocrinology: a tribute to Peter H. Seeburg. Cell Tissue Res. 2019;375:1-2.
Koyama H, Tanaka S, Monden M, et al. Comparison of effects of pioglitazone and glimepiride on plasma soluble RAGE and RAGE expression in peripheral mononuclear cells in type 2 diabetes: randomized controlled trial (PioRAGE). Atherosclerosis. 2014;234:329-334.
Fishman SL, Sonmez H, Basman C, et al. The role of advanced glycation end-products in the development of coronary artery disease in patients with and without diabetes mellitus: a review. Mol Med. 2018;24:59.
Bongarzone S, Savickas V, Luzi F, et al. Targeting the Receptor for Advanced Glycation Endproducts (RAGE): a medicinal chemistry perspective. J Med Chem. 2017;60:7213-7232.
Mackic JB, Stins M, McComb JG, et al. Human blood-brain barrier receptors for Alzheimer's amyloid-beta 1-40. Asymmetrical binding, endocytosis, and transcytosis at the apical side of brain microvascular endothelial cell monolayer. J Clin Invest. 1998;102:734-743.
Deane R, Du Yan S, Submamaryan RK, et al. RAGE mediates amyloid-beta peptide transport across the blood-brain barrier and accumulation in brain. Nat Med. 2003;9:907-913.
Cuevas E, Rosas-Hernandez H, Burks SM, et al. Amyloid Beta 25-35 induces blood-brain barrier disruption in vitro. Metab Brain Dis. 2019;34:1365-1374.
Leung SS, Forbes JM, Leung BDJ, et al. Receptor for Advanced Glycation End Products (RAGE) in type 1 diabetes pathogenesis. Curr Diab Rep. 2016;16:100.
Park EY, Seo MJ, Park JH, et al. Effects of specific genes activating RAGE on polycystic kidney disease. Am J Nephrol. 2010;32:169-178.
Yatime L, Andersen GR. Structural insights into the oligomerization mode of the human receptor for advanced glycation end-products. FEBS J. 2013;280:6556-6568.
Contributed Indexing :
Keywords: blood-brain barrier; brain transport; esRAGE; mRAGE; oxytocin
Entry Date(s) :
Date Created: 20210318 Latest Revision: 20210318
Update Code :
Oxytocin (OT) is a neuropeptide hormone. Single and repetitive administration of OT increases social interaction and maternal behaviour in humans and mammals. Recently, it was found that the receptor for advanced glycation end-products (RAGE) is an OT-binding protein and plays a critical role in the uptake of OT to the brain after peripheral OT administration. Here, we address some unanswered questions on RAGE-dependent OT transport. First, we found that, after intranasal OT administration, the OT concentration increased in the extracellular space of the medial prefrontal cortex (mPFC) of wild-type male mice, as measured by push-pull microperfusion. No increase of OT in the mPFC was observed in RAGE knockout male mice. Second, in a reconstituted in vitro blood-brain barrier system, inclusion of the soluble form of RAGE (endogenous secretory RAGE [esRAGE]), an alternative splicing variant, in the luminal (blood) side had no effect on the transport of OT to the abluminal (brain) chamber. Third, OT concentrations in the cerebrospinal fluid after i.p. OT injection were slightly higher in male mice overexpressing esRAGE (esRAGE transgenic) compared to those in wild-type male mice, although this did not reach statistical significance. Although more extensive confirmation is necessary because of the small number of experiments in the present study, the reported data support the hypothesis that RAGE may be involved in the transport of OT to the mPFC from the circulation. These results suggest that the soluble form of RAGE in the plasma does not function as a decoy in vitro.
(© 2021 British Society for Neuroendocrinology.)