Oxytocin Dynamics in the Body and Brain Regulated by the Receptor for Advanced Glycation End-Products, CD38, CD157, and Nicotinamide Riboside

Higashida, Haruhiro; Furuhara, Kazumi; Lopatina, Olga; Gerasimenko, Maria; Hori, Osamu; Hattori, Tsuyoshi; Hayashi, Yasuhiko; Cherepanov, Stanislav M.; Shabalova, Anna A.; Салмина, А. Б.; Minami, Kazunori; Yuhi, Teruko; Tsuji, Chiharu; Fu, PinYue; Liu, Zhongyu; Luo, Shuxin; Zhang, Anpei; Yokoyama, Shigeru; Shuto, Satoshi; Watanabe, Mizuki; Fujiwara, Koichi; Harashima, Ai; Yamamoto, Yasuhiko

doi:10.3389/fnins.2022.858070

Cited by 9 publications

(7 citation statements)

References 119 publications

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“…While initial studies in animal models concluded that the BBB is relatively impermeable to OXT ( Mens et al, 1983 ; Kendrick et al, 1986 ), recent studies have demonstrated that it can be transported into the brain by binding to the receptor for advanced glycation end products (RAGE) in BBB endothelial cells ( Yamamoto et al, 2019 ; Yamamoto and Higashida, 2020 ; Munesue et al, 2021 ), with in vitro studies also reporting the presence of this potential transport system in humans (see Higashida et al, 2022 ). Compared to wild-type controls, RAGE knock-out mice do not exhibit increased OXT in the brain following intranasal or subcutaneous administration ( Yamamoto et al, 2019 ; Munesue et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Oro-mucosal administration of oxytocin using medicated lollipops alters social attention, similar to intranasal and lingual routes: Implications for therapeutic use

Li²,

Zhuang³

et al. 2022

Front. Neurosci.

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A key functional effect of intranasal administration of the neuropeptide oxytocin is on top-down control of social attention. However, an oro-mucosal administration route may be better tolerated for chronic therapeutic use and evidence suggests that some functional effects of oxytocin can be mediated via peripheral routes. The current study investigated if oxytocin administered orally using medicated lollipops can both increase blood oxytocin concentrations and influence social attention and state anxiety. In a randomized, double-blind, clinical trial adult male participants received oral oxytocin (24IU) or placebo 30-min before completing a well-established anti-saccade paradigm which can assess treatment effects on both top-down and bottom-up attention. Oxytocin administration modulated top-down social attentional processing by increasing anti-saccade error rates on both social and non-social stimuli although it only increased response latencies for social cues. Anti-saccade errors were also positively associated with the proportionate increase in plasma oxytocin concentrations. A comparison analysis showed that oral oxytocin administration increased blood concentrations to a similar degree as given by lingual spray, although less than when given intranasally. Importantly, attentional and anxiolytic effects of oxytocin in the anti-saccade task were similar across intranasal, lingual, and oral administration routes. These findings demonstrate that oral administration of oxytocin, similar to via intranasal and lingual routes, can modulate top-down social attention and state anxiety and support its potential for therapeutic use. They also provide further evidence that functional effects of exogenously administered oxytocin can be mediated indirectly either by crossing the blood brain barrier or producing receptor mediated vagal stimulation, as opposed to via direct entry into the brain.

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Section: Introductionmentioning

confidence: 99%

Oro-mucosal administration of oxytocin using medicated lollipops alters social attention, similar to intranasal and lingual routes: Implications for therapeutic use

Li²,

Zhuang³

et al. 2022

Front. Neurosci.

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“…It has been reported that functional effects of both intranasal and subcutaneous OXT do not occur in RAGE knockout mice and increased brain concentrations of OXT are prevented [65][66][67]. In vitro studies have also reported the presence of this potential transport system in humans [68]. Another potential mechanism is that increased peripheral OXT concentrations act on its receptors in the heart and gastrointestinal system to promote vagally-mediated stimulation of the brain [23,69,70].…”

Section: Discussionmentioning

confidence: 99%

Sniffing oxytocin: Nose to brain or nose to blood?

et al. 2023

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In recent years ample studies have reported that intranasal administration of the neuropeptide oxytocin can facilitate social motivation and cognition in healthy and clinical populations. However, it is still unclear how effects are mediated since intranasally administered oxytocin can both directly enter the brain (nose to brain) and increase peripheral vascular concentrations (nose to blood). The relative functional contributions of these routes are not established and have received insufficient attention in the field. The current study used vasoconstrictor pretreatment to prevent intranasal oxytocin (24 IU) from increasing peripheral concentrations and measured effects on both resting-state neural (electroencephalography) and physiological responses (electrocardiogram, electrogastrogram and skin conductance). Results demonstrated that intranasal oxytocin alone produced robust and widespread increases of delta-beta cross-frequency coupling (CFC) from 30 min post-treatment but did not influence peripheral physiological measures. As predicted, vasoconstrictor pretreatment greatly reduced the normal increase in peripheral oxytocin concentrations and, importantly, abolished the majority of intranasal oxytocin effects on delta-beta CFC. Furthermore, time-dependent positive correlations were found between increases in plasma oxytocin concentrations and corresponding increases in delta-beta CFC following oxytocin treatment alone. Our findings suggest a critical role of peripheral vasculature-mediated routes on neural effects of exogenous oxytocin administration with important translational implications for its use as an intervention in psychiatric disorders.

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“…At such doses, oxytocin could also pass directly into the brain via the blood-brain barrier. In addition, afferent stimulation of sensory nerves by peripheral oxytocin could also promote central oxytocin release [ 128 , 129 ].…”

Section: Discussionmentioning

confidence: 99%

Maternal and newborn plasma oxytocin levels in response to maternal synthetic oxytocin administration during labour, birth and postpartum – a systematic review with implications for the function of the oxytocinergic system

Buckley

Uvnäs‐Moberg

Pajalić

et al. 2023

BMC Pregnancy Childbirth

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Background The reproductive hormone oxytocin facilitates labour, birth and postpartum adaptations for women and newborns. Synthetic oxytocin is commonly given to induce or augment labour and to decrease postpartum bleeding. Aim To systematically review studies measuring plasma oxytocin levels in women and newborns following maternal administration of synthetic oxytocin during labour, birth and/or postpartum and to consider possible impacts on endogenous oxytocin and related systems. Methods Systematic searches of PubMed, CINAHL, PsycInfo and Scopus databases followed PRISMA guidelines, including all peer-reviewed studies in languages understood by the authors. Thirty-five publications met inclusion criteria, including 1373 women and 148 newborns. Studies varied substantially in design and methodology, so classical meta-analysis was not possible. Therefore, results were categorized, analysed and summarised in text and tables. Results Infusions of synthetic oxytocin increased maternal plasma oxytocin levels dose-dependently; doubling the infusion rate approximately doubled oxytocin levels. Infusions below 10 milliunits per minute (mU/min) did not raise maternal oxytocin above the range observed in physiological labour. At high intrapartum infusion rates (up to 32 mU/min) maternal plasma oxytocin reached 2–3 times physiological levels. Postpartum synthetic oxytocin regimens used comparatively higher doses with shorter duration compared to labour, giving greater but transient maternal oxytocin elevations. Total postpartum dose was comparable to total intrapartum dose following vaginal birth, but post-caesarean dosages were higher. Newborn oxytocin levels were higher in the umbilical artery vs. umbilical vein, and both were higher than maternal plasma levels, implying substantial fetal oxytocin production in labour. Newborn oxytocin levels were not further elevated following maternal intrapartum synthetic oxytocin, suggesting that synthetic oxytocin at clinical doses does not cross from mother to fetus. Conclusions Synthetic oxytocin infusion during labour increased maternal plasma oxytocin levels 2–3-fold at the highest doses and was not associated with neonatal plasma oxytocin elevations. Therefore, direct effects from synthetic oxytocin transfer to maternal brain or fetus are unlikely. However, infusions of synthetic oxytocin in labour change uterine contraction patterns. This may influence uterine blood flow and maternal autonomic nervous system activity, potentially harming the fetus and increasing maternal pain and stress.

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Oxytocin Dynamics in the Body and Brain Regulated by the Receptor for Advanced Glycation End-Products, CD38, CD157, and Nicotinamide Riboside

Cited by 9 publications

References 119 publications

Oro-mucosal administration of oxytocin using medicated lollipops alters social attention, similar to intranasal and lingual routes: Implications for therapeutic use

Oro-mucosal administration of oxytocin using medicated lollipops alters social attention, similar to intranasal and lingual routes: Implications for therapeutic use

Sniffing oxytocin: Nose to brain or nose to blood?

Maternal and newborn plasma oxytocin levels in response to maternal synthetic oxytocin administration during labour, birth and postpartum – a systematic review with implications for the function of the oxytocinergic system

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