Glycative Stress Research
Online edition : ISSN 2188-3610
Print edition : ISSN 2188-3602
Received : May 23, 2023
Accepted : August 15, 2023
Published online : September 30, 2023
doi:10.24659/gsr.10.3_89

Review article

Life Events and Oxytocin -Recent TopicsYu Oshima, Yasuhiko Yamamoto
Department of Biochemistry and Molecular Vascular Biology,
Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan

Abstract

Oxytocin is a peptide hormone secreted into the blood from the posterior pituitary gland. Oxytocin's biosynthesis, receptors,
and functions have been studied extensively, and in recent years, in addition to its typical roles in uterine contraction andejaculation, its influence on social behaviors and anti-inflammatory effects have attracted attention. For oxytocin to influencesocial behaviors, oxytocin in the blood must cross the blood-brain barrier. The receptor for advanced glycation end-products(RAGE) has been found to act as a transporter to transfer it into the brain. Elucidation of the molecular mechanism ofoxytocin's impact on social behaviors of affection and trust formation has the potential to help address recent problems, i.e.,
child abandonment and maltreatment. Oxytocin can be a hormone that plays an important role in life events.

KEY WORDS: oxytocin, social behaviors, inflammation, RAGE (receptor for advanced glycation end-products)

1. Oxytocin overview
In 1906, Henry H. Dale found that an extract of theposterior pituitary gland had uterine contraction effects,
leading to the discovery of the peptide hormone oxytocin(hereafter OT) 1). In 1953, Vincent de Vigneaud et al. in the
U.S. discovered a peptide consisting of nine amino acids,
where the first and sixth amino acids are cysteine (Cys) andform a cyclic structure by disulfide (S-S) bonding, and theseventh to ninth amino acids were found to be side-chained 2).
In 1954, he succeeded in the artificial synthesis of OT, forwhich Vincent de Vigneaud was awarded the Nobel Prizein Chemistry in 1955. The OT gene is located on humanchromosome 20 (2 for mouse) and consists of three exonsand two introns.
The arginine vasopressin (AVP) and OT genes arelocated at the same locus on the same chromosome, back-toback across about 10 kb, and OT is first synthesized fromthe OT gene as an inactive precursor protein (prohormone
containing neurophysin I, an OT carrier protein) (Fig. 1).
It is then hydrolyzed stepwise via a series of enzymes tosmaller fragments, one of which is neurophysin I; the final
hydrolytic enzyme that forms the primary structure of OT
is peptidylglycine α-amidating monooxygenase (PAM) 3).
PAM is a two-headed enzyme consisting of a PHM(peptidylglycine-hydroxylating monooxygenase) domain anda PAL (peptidylamidoglycolate lyase) domain. OT has the
biological activity by amidation of the C-terminus of glycine,which enables it to bind to the OT receptor 4). Besides OT,
the C-terminal amide structures required for the active
expression of about half of the biologically active peptides
are generated by the catalytic action of the enzyme PAM.
After secretion, OT is known to be degraded by oxytocinase
and leucyl/cystinyl aminopeptidase 5). Morphological studies
of peptides in the nervous system have a history of multistage progression.
In 1928, Ernst Scharrer discovered the presence ofrelatively large neurons at the base of the brain with longaxonal projections to the neurohypophysis and contact
with capillaries in fish, first suggesting that neurosecretory
neurons located in the hypothalamus may play an endocrinerole in cooperation with the pituitary gland 6).
Since then, numerous studies have put forth the conceptof neurosecretion; OT is synthesized within the large
neurosecretory neurons in the hypothalamic nucleus, mainly
paraventricular hypothalamic nucleus (PVN) and supraoptic
nucleus (SON), packaged as secretory granules in theendoplasmic reticulum, moving towards the axon terminalthat projects to the posterior pituitary while being processed,and consequently released by exocytosis into the blood in an

Correspondence to: Yasuhiko Yamamoto, MD, PhD.
Department of Biochemistry and Molecular Vascular Biology,
Kanazawa University Graduate School of Medical Sciences
13 -1 Takara-machi, Kanazawa 920-8640, Japan
TEL: +81-76-265-2181 FAX: +81-76-234-4217
e-mail: yasuyama@med.kanazawa-u.ac.jp
Co-author: Oshima Y, cantabile.6102@gmail.com

Glycative Stress Research 2023; 10 (3): 89-093(c) Society for Glycative Stress Research_ 89 _

Life Events and Oxytocin

Fig. 1. Schematic representation of the synthesis and actions of oxytocin.

AVP, arginine vasopressin; BBB, blood-brain barrier; CNS, central nervous system; OT, oxytocin; OTR, oxytocin receptor;
RAGE, receptor for advanced glycation end-products.

_ 90 _Glycative Stress Researchaction potential-dependent manner. OT is also secreted into
the brain from neuronal dendrites and neurosecretory cells.
The following items (1) to (5) are generally known for
the functions of OT.
(1) In the last trimester, OT has a uterine contraction effectfor delivery.
(2) OT has the promotion effect of lactation from mammary
glands during breastfeeding (ejaculation).
(3) OT influences social behaviors, especially "all humaninteractions based on trust" through the "social brain"region including the amygdala, and is involved in theformation of affection and trust.
There is a known study in which 194 healthy malestudents at the Swiss Institute of Technology were divided
into OT administration groups with nasal drops and placebo
administration groups, and neuroeconomic experiments
were conducted in both groups based on game theory 7- 8).
In the game, when subjects were divided into investors who
have money and trustees who manage money and receive
refunds with different profit rates, it was examined if the
OT-treated group would become attached to the otherparty and increase their trust and confidence. In the result,
there was a tendency to deposit nearly the entire amount ofmoney in investment in the OT-treated group. In addition,mothers who have experienced abuse were found to havelower blood OT concentrations than mothers who have notexperienced abuse 9). Moreover, in autistic patients, the blood
OT concentration was also found to be low 10). When a man
diagnosed with autism was given OT nasal spray (16 IU aday), he stared at the examiner's face, occasionally smiled,and answered correctly to simple questions. A case is also
reported to be able to answer multiple-choice questions 11).
(4) Possible effects of OT on sleep.
In clinical trials using OT, a certain level of effect wasobserved in patients with sleep apnea syndrome after nasal
OT administration (40 IU ) 12). When the blood OT level
was examined to be correlated with the quality of sleep,
the OT level was found to have a certain correlation withthe degree of sleep disturbance in patients with Human
Immunodeficiency Virus (HIV) infection and cancer
patients 13, 14). However, clinical application is still far away
and further investigation is required.
(5) Anti-inflammatory action of OT.
Anti-inflammatory effects of OT have been reported inanimal disease models and human patient studies, including
cardiovascular, gastrointestinal, endocrine, genitourinary,and brain diseases. Examples are as follows.
OT receptors are reported to express on numerous typesof immune cells, such as neutrophils, macrophages, andlymphocytes, and may play an important role in immunologicalsurveillance, defense, and homeostasis 15). OT was found to
decrease IL-6 release, increase prostacyclin release, andinhibit platelet aggregation 16). Additionally, by increasing
nitric oxide synthase (eNOS) activity in platelets andendothelial cells, OT may inhibit sepsis-induced contact
between neutrophils and endothelial cells and may play arole in maintaining microvascular patency in septic shock 17).
In macrophages, expression of the OT receptor geneincreased during inflammation. This was mediated by thetranscription factor nuclear factor-kappa B (NF-кB) 18, 19).
OT prevented macrophages from transforming into active

inflammatory cells by enhancing the expression of betaarrestin 2 (macrophage polarizing), a multifunctional scaffold
that regulates G protein-coupled receptors (GPCRs).
OT also stimulated phosphorylation (or activation) of
signal transducers and activator of transcription (STAT) 6 aswell as suppression of NF-кB signaling in lipopolysaccharide(LPS)-stimulated macrophages 20). As a result, the release oftumor necrosis factor (TNF)-α and other proinflammatory
cytokines from macrophages was inhibited by the binding of
OT to the OT receptor 21).
Furthermore, OT has been shown to upregulate theexpression of peroxisome proliferator-activated receptor- γ(PPAR-γ), a potent transcription factor that suppresses
inflammatory responses in macrophages 17, 22). This suggeststhat OT may act via PPAR- γ to modulate inflammation 21).
OT may also exert its anti-inflammatory effects by reducing
the expression of nicotinamide adenine dinucleotide phosphate(NADPH) oxidase and p38 mitogen-activated protein
kinase (MAPK) 23, 24). In addition, OT was involved in selftolerance by T cells; OT receptors were found on progenitor
T cells in the thymus, and binding to OT regulated
lymphocyte maturation, differentiation, and survival 25).
Once lymphocytes were exposed to antigen, OT stimulated
lymphocyte proliferation by increasing the expression of
IL-2R (CD25 chain) and the activation marker CD95 26). As
described above, the anti-inflammatory action of OT has
been understood thus far.

2. OT and RAGE (receptor for advanced
glycation end-products)
It has been the prevailing belief that OT released into
the blood does not cross the blood-brain barrier (BBB) due to
its molecular size and hydrophilic characteristics. However,
RAGE on the surface of cerebral vascular endothelial cells,
which constitute the BBB, has been shown to allow OT tocross the BBB and be transported from the blood side to thebrain side 27). In other words, RAGE was found to function asa transporter of OT that unidirectionally transports OT fromthe blood to the brain side. However, this function does not
require intracellular signaling of RAGE, and the binding of
OT to RAGE does not affect the binding of various RAGE
ligands to RAGE and their subsequent intracellular signaling(Fig. 2).
OT transferred into the brain in this way is thought
to play an important role in maternal behavior, nurturing
activities, and social behavior in the parent-child relationship28 -30). OT is thus known as an affection hormone. In general,
pregnant mice give birth to 6 to 10 offspring at a once,
and the offspring grows up after drinking their mother's
milk. However, when RAGE of the BBB in the mother was
deficient, OT actions to the brain seemed to disappear, andonly 10 % of the babies survived 28). Though no effects wereobserved in the mother’s milk production, this phenomenon
was caused by the dam’s lack of concern in parenting.
Vascular endothelial cells of the BBB consistently express
RAGE, which mediates the transfer of OT into the brain. The
binding site of OT on RAGE is different from that of otherligands including AGEs. OT bound to RAGE could passthrough the BBB and enter the brain to exert "affection" 30).

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Life Events and Oxytocin

Fig. 2. RAGE-dependent OT transport from the blood side to the brain side through BBB.

The binding of OT to RAGE does not induce RAGE intracellular signal transductions. BBB, blood-brain barrier;
OT, oxytocin; RAGE, receptor of advanced glycation end-products.

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It is very fundamental and physiological function in motherbaby bonding. This may provide clues to solving social
problems such as childcare abandonment and child abuse,
which are becoming increasingly serious in this era of
declining birthrates, and future developments are expected.
The following is a brief explanation of RAGE.
Glycosylation is a reaction that adds sugar chains toproteins or lipids and is an important post-translational
modification. Glycosylation is known as an enzyme-controlled
reaction. On the other hand, glycation, discovered by Maillard
in 1912, is a complex reaction involving dehydration,condensation, cross-linking, etc., which eventually resultsin irreversible and heterogeneous products called advanced
glycation end-products (AGEs). RAGE is a receptor for
AGEs. RAGE belongs to the immunoglobulin superfamilyof cell surface molecules and is composed of one V domain
and two C domains 31).
RAGE is expressed on a variety of cells, including vascularendothelial cells, neutrophils, monocytes/macrophages,
and neurons 32). Numerous other ligands for RAGE are now
known in addition to AGEs. RAGE is known to be involvedin various pathological conditions such as inflammatory
reactions in LPS-induced sepsis, the development of diabetic
kidney disease and glomerulosclerosis, cerebral ischemic
damages, Alzheimer's disease, and tumor progression 30).
On the other hand, RAGE has physiological roles inbiological protection in addition to its function in parenting.
Specifically, it has been reported that RAGE prevents the
spread of pneumococcal infection, reduces adaptive immune
responses in limb ischemia, ameliorates renal reperfusion
injury by endogenous soluble RAGE, regenerates lung tissue
through HMGB-1-dependent epithelial repair, and is involvedin the recognition of phosphatidylserine by apoptotic cells
during epherocytosis 30).
The fact that RAGE, which has such diverse roles invivo, functions as a transporter for passage of OT is of great
biological interest.

3. Current Topics and Future Possibilities
Our laboratory recently found that OT administration tomouse models of autoimmune diseases could improve their
symptoms by inhibiting the pathogenesis of autoimmune
diseases and inflammation. OT therapy may have clinicalapplications as a treatment for autoimmune diseases in the
future.

Conflict of Interest Declaration
None applicable to this paper.

Research Funding
Grant-in-Aid for Scientific Research (KAKENHI) from
JSPS (24590375, 25461335, 18K06889, 21H02695), Takeda
Foundation for Advancement of Science, Life Science
Research Grant, Kanazawa University Sakigake Project 2018
& 2020).

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