Article

Center Role of the Oxytocin-Secreting System in Neuroendocrine-Immune Network Revisited

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Abstract

The hypothalamic neuroendocrine system has extensive and bidirectional interactions with immune system. In parallel with the hypothalamic-pituitary-adrenal axis, the oxytocin-secreting system composed of hypothalamic oxytocin neurons and their associated neural tissues has also emerged as a major part of the neuroendocrine center that regulates immunologic activities of living organisms. This oxytocin neuron-immune network can synthesize and release many cytokines and oxytocin while being the target of both oxytocin and cytokines by the mediation of corresponding receptors. Pathogens and cytokines along with the humoral and neural activities induced by them provide afferent input onto oxytocin neurons while oxytocin, cytokines and autonomic nervous systems convey efferent signals from the oxytocin-secreting system to the immune system. Serving as an integrative organelle, the oxytocin-secreting system coordinates all neural, humoral and immunologic signals to change immunologic activities through releasing oxytocin into the brain and blood to minimize pathological injury and secure the functional stability of our body. Oxytocin exerts these effects through strengthening surface barriers and maintaining immunologic homeostasis involving both humoral immunity and cellular immunity. In this review, we revisit the novel concept: the oxytocin-secreting system is the center structure in the oxytocin neuron-immune network.

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... Another approach for OXT protection is its influencing the secretion of many cytokines [50,51]. For example, OXT infusion dosedependently increases plasma ANP concentration as much as 4-fold after 20 min. ...
... The OXT-secreting system is considered as the higher neuroendocrine regulation center of the immune system [50,51] and key protective factor of CV system. Interruption of this system by COVID-19 partially accounts for the CV complications while reviving the OXT-secreting system or supplying OXT becomes a feasible strategy of inhibiting the pathogenesis of CV manifestations in COVID-19. ...
... OXT can reduce the expression of panicrelated behaviors (e.g. fear and escape) by acting on the medial amygdala and the dorsal periaqueductal gray as previously reviewed [51]. OXT is positively associated with diminished stress among securely attached participants and can attenuate perception of stress due to adverse life events in old age [128]. ...
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... Other molecules, such as interleukin-6, that affect lipid metabolism (Yudkin, 2003) are associated with increased level of C-reactive protein production, which changes inversely to serum OT levels (Qian et al., 2014). OT was also identified as an agent that suppresses the production of inflammatory cytokines (Wang, 2016), including smooth muscle and vascular endothelial cells . Moreover, OT could down-regulate neutrophil chemotactic molecules and myocardial neutrophil infiltration, and prevent myocardial injury by reducing inflammatory reaction and reactive oxygen species (ROS) produced by neutrophils (Al-Amran and Shahkolahi, 2013). ...
... Moreover, OT could down-regulate neutrophil chemotactic molecules and myocardial neutrophil infiltration, and prevent myocardial injury by reducing inflammatory reaction and reactive oxygen species (ROS) produced by neutrophils (Al-Amran and Shahkolahi, 2013). Thus, along with the general immunological regulatory functions (Wang P. et al., 2015;Wang, 2016), OT could be a potentially preventative agent in those at high-risk for atherosclerosis development and further limit the progression in those with existing disease. ...
... Lastly, disorder of the immune system in the pathogenesis of hypertension has been firmly established by a large number of investigations (Rodriguez-Iturbe et al., 2017); hence, OT could also reduce hypertension through its immune homeostatic functions (Wang P. et al., 2015;Wang, 2016). Thus, OT can exert anti-hypertensive effects through multiple approaches. ...
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... epends on immune homeostasis. Peripartum stress can disrupt maternal behavior (Bystrova et al., 2009;Dumas et al., 2013;Liu et al., 2019) in association with maternal inflammation (Gustafsson et al., 2018). OT regulates development of the thymus and bone marrow, and participates in immune surveillance, defense and homeostasis (P. Wang et al., 2015;Y. F. Wang, 2016). For example, OT significantly reduced lipopolysaccharide-induced release of interleukin (IL)-1b, and IL-6 and acute lung injury in mice, which can be blocked by pretreatment with OTR antagonist . While these facts support a pivotal role of activating OT neurons in maternal behavior and immunological activities, how OT modulates materna ...
... Mechanistically, CD-evoked abnormal OT secretion can disrupt the immunological defense functions of OT (P. Wang et al., 2015;Y. F. Wang, 2016). This is supported by the findings that OTR deficiency mice are more susceptible to inflammatory reactions compared with the wild mice (Tang et al., 2019) and that blocking OTR reduces endotoxin-evoked IL-1b release . It is consistent with that disruption of maternal behavior is associated with reproductive injury (i.e. perinea lacerati ...
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Oxytocin (OT), a neuropeptide produced in the supraoptic (SON) and paraventricular (PVN) nuclei, is not only essential for lactation and maternal behavior but also for normal immunological activity. However, mechanisms underlying OT regulation of maternal behavior and its association with immunity around parturition, particularly under mental and physical stress, remain unclear. Here, we observed effects of OT on maternal behavior in association with immunological activity in rats after cesarean delivery (CD), a model of reproductive stress. CD significantly reduced maternal interests to the pups throughout postpartum day 1-8. On postpartum day 5, CD decreased plasma OT levels and thymic index but increased vasopressin, interleukin (IL)-1β, IL-6 and IL-10 levels. CD had no significant effect on plasma adrenocorticotropic hormone and corticosterone levels. In the hypothalamus, CD decreased corticotropin-releasing hormone contents in the PVN but increased OT contents in the PVN and SON and OT release from hypothalamic implants. CD also increased c-Fos expression, particularly in the cytoplasm of OT neurons. Lastly, CD depolarized resting membrane potential and increased spike width while increasing the variability of the firing rate of OT neurons in brain slices. Thus, CD can increase hypothalamic OT contents and release but reduce pituitary release of OT into the blood, which is associated with depressive-like maternal behavior, increased inflammatory cytokine release and decreased relative weight of the thymus.
... On the basis of photos and videos, the individuals (adults and immatures) were considered as bearing external signs of pathology when they showed at least one of the following external signs: abnormal swelling on trunk, limbs, and/or neck, probably related to Taenia serialis infection, as it has been found in other gelada populations (Ohsawa and Dunbar 1984;Nguyen et al. 2015;Schneider-Crease et al. 2017); and alopecia, defined as hair loss either diffuse or patchy, in areas where the loss could not be caused by infant clinging (Fig. 1). The external signs of pathologies were considered for males and two categories of females (lactating and non-lactating) due to the effect that lactation can have on the immune system (Wang 2016). Depending on the group they belonged to, individuals were assigned to either frequent or infrequent crop user groups. ...
... A diagnosis could not be performed on biological samples; therefore none of these possibilities can be ruled out. The fact that the external signs of pathology were significantly more frequent in non-lactating adult females than in lactating females (Fig. 2b) might be related to the immunological properties of oxytocin, produced during lactation to regulate milk production (Wang 2016). On the contrary, testosterone in males can weaken the immune system, potentially explaining the more frequent signs of pathology in adult males than adult females (Roberts et al. 2004;Weisman et al. 2014;Muller 2017). ...
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Human–primate interfaces are expanding and, despite recent studies on primates from peri-urban environments, little research exists on the impact of agriculture and/or pasture areas on primate social behavior and health. We assessed how crop/pasture areas potentially alter social behavior and health of wild geladas ( Theropithecus gelada ) frequenting the unprotected area of Kundi (Ethiopia). We predicted that compared to pasture areas, crop areas (i) would be more challenging for geladas (prediction 1) and (ii) would have a greater impact on both aggressive and affiliative behavior, by reducing grooming time and enhancing competition (prediction 2). During January–May 2019 and December 2019–February 2020, we collected data (via scan, focal animal sampling, and video analyses) on direct human disturbance, external signs of pathologies and social behavior of 140 individuals from 14 one-male units and two all-male units. Animals experienced the highest level of human disturbance in crop areas (in line with prediction 1). Individuals from the groups preferentially frequenting crop areas showed the highest prevalence of external signs of pathologies consistent with chemical and biological contamination (alopecia/abnormally swollen parts). We collected 48 fecal samples. Samples from frequent crop users contained the highest rates of parasitic elements/gram (egg/larva/oocyst/cyst) from Entamoeba histolytica/dispar , a parasite common in human settlements of the Amhara region. In crop areas, subjects spent less time grooming but engaged in lower rates of intense aggression (in partial agreement with prediction 2). We speculate that the reduction in social behavior may be a tactic adopted by geladas to minimize the likelihood of detection and maximize food intake while foraging in crops.
... Oxytocin can suppress hyperlipidemia and hyperglycemia (123) that underlie obesity, atherosclerosis, diabetes and their associated diseases, such as hypertension, coronary artery disease and ischemic stroke (129). Oxytocin has immune-regulating functions (96,102) and thus makes the body ready to fight against viral infection. Oxytocin has anxiolytic and anti-stress functions (130,131), which, together with the anti-atherosclerosis effect, exerts anti-hypertension effect. ...
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... Noticeably, OXT suppression of CRC migration through the FAPα-CCL-2 signaling is dominant over the migration-promoting effect of TGF-β signaling as proved by our migration study. This finding is consistent with the antiinflammatory effect of OXT and its possible function in curbing the migration of CAC cells, as previously studied (Wang, 2016). Thus, our study highlights the therapeutic value of suppression of CRC migration, at least for CAC. ...
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Oxytocin (OXT) and its receptor (OXTR) are present in the gastrointestinal system and are involved in gastrointestinal tumorigenesis. However, the effect of OXTR signaling on the development of colorectal cancer (CRC) and its underlying mechanisms remain unexplored. To address these issues, we first examined the expressions of OXT, OXTR, and several cancer-associated proteins using colon “tissue chips” from a spectrum of malignant progression of the colon, which included normal colon tissue, chronic colitis, colorectal adenoma, and colorectal adenocarcinoma (CAC). The results showed that the expressions of OXT and OXTR decreased gradually with the malignant progression of the disease. Stimulation of CAC tissues with OXT increased OXTR expression while down-regulated FAPα and CCL-2 protein expressions in a concentration- and time-dependent manner. Moreover, cell invasion experiment showed that OXT treatment reduced the invasion ability of colon cancer cells and blocking OXTR with atosiban blocked OXT-reduced invasion ability of human colon cancer cell lines Ls174T and SW480. The results indicate that OXT has the potential to inhibit CRC development via down-regulating the immunosuppressive proteins FAPα and CCL-2. When the OXTR signaling is weakened, colon tissues may transform to CRC. These findings also highlight the possibility of applying OXT to inhibit CRC development directly.
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Background. In addition to the well known role played on lactation and parturition, Oxytocin (OT) and OT receptor (OTR) are involved in many other aspects such as the control of maternal and social behavior, the regulation of the growth of the neocortex, the maintenance of blood supply to the cortex, the stimulation of limbic olfactory area to mother-infant recognition bond, and the modulation of the autonomic nervous system via vagal pathway. Moreover, OT and OTR show anti-inflammatory, anti-oxidant, anti-pain, antidiabetic, anti-dyslipidemic and anti-atherogenic effects. Objective. The aim of this narrative review is to summarize the main data coming from the literature dealing with the role of OT and OTR in physiology and pathologic conditions focusing on the most relevant aspects. Methods. Appropriate keywords and MeSH terms were identified and searched in Pubmed. Finally, references of original articles and reviews were examined. Results. We report the most significant and updated data about the role played by OT and OTR in physiology and in different clinical context. Conclusion. Emerging evidence indicates the involvement of OT system in several pathophysiological mechanisms influencing brain anatomy, cognition, language, sense of safety and trust and maternal behavior, with a possible use of exogenous administered OT in the treatment of specific neuro-psychiatric conditions. Furthermore, it modulates pancreatic β-cell responsiveness and lipid metabolism leading to possible therapeutic use in diabetic and dyslipidemic patients and for limiting and even reversing atherosclerotic lesions.
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Oxytocin (OXT) is a hypothalamic neuropeptide composed of nine amino acids. The functions of OXT cover a variety of social and nonsocial activity/behaviors. Therapeutic effects of OXT on aberrant social behaviors are attracting more attention, such as social memory, attachment, sexual behavior, maternal behavior, aggression, pair bonding, and trust. The nonsocial behaviors/functions of brain OXT have also received renewed attention, which covers brain development, reproduction, sex, endocrine, immune regulation, learning and memory, pain perception, energy balance, and almost all the functions of peripheral organ systems. Coordinating with brain OXT, locally produced OXT also involves the central and peripheral actions of OXT. Disorders in OXT secretion and functions can cause a series of aberrant social behaviors, such as depression, autism, and schizophrenia as well as disturbance of nonsocial behaviors/functions, such as anorexia, obesity, lactation failure, osteoporosis, diabetes, and carcinogenesis. As more and more OXT functions are identified, it is essential to provide a general view of OXT functions in order to explore the therapeutic potentials of OXT. In this review, we will focus on roles of hypothalamic OXT on central and peripheral nonsocial functions.
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The aim of this review is to provide a comprehensive examination of the current literature describing the neural-immune interactions, with emphasis on the most recent findings of the effects of neurohormones on immune system. Particularly, the role of hypothalamic hormones such as Thyrotropin-releasing hormone (TRH), Corticotropin-releasing hormone (CRH) and Gonadotropin-releasing hormone (GnRH). In the past few years, interest has been raised in extrapituitary actions of these neurohormones due to their receptors have been found in many non-pituitary tissues. Also, the receptors are present in immune cells, suggesting an autocrine or paracrine role within the immune system. In general, these neurohormones have been reported to exert immunomodulatory effects on cell proliferation, immune mediators release and cell function. The implications of these findings in understanding the network of hypothalamic neuropeptides and immune system are discussed.
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Oxytocin stimulates the cardiomyogenesis of embryonic stem cells and adult cardiac stem cells. We previously reported that oxytocin has a promigratory effect on umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs). In this study, UCB-MSCs were cultured with oxytocin and examined for their therapeutic effect in an infarcted heart. UCB-MSCs were pretreated with 100 nM oxytocin and cardiac markers were assessed by immunofluorescence staining. Next, oxytocin-supplemented USC-MSCs (OT-USCs) were cocultured with hypoxia/reoxygenated neonatal rat cardiomyocytes and cardiac markers and dye transfer were then examined. For the in vivo study, ischemia/reperfusion was induced in rats, and phosphate-buffered saline (group 1), 1-day OT-USCs (group 2), or 7-day OT-USCs (group 3) were injected into the infarcted myocardium. Two weeks after injection, histological changes and cardiac function were examined. UCB-MSCs expressed connexin 43 (Cnx43), cardiac troponin I (cTnI), and α-sarcomeric actin (α-SA) after oxytocin supplementation and coculture with cardiomyocytes. Functional gap junction formation was greater in group 3 than in groups 1 and 2. Cardiac fibrosis and macrophage infiltration were lower in group 3 than in group 2. Restoration of Cnx43 expression was greater in group 3 than in group 2. Cnx43- and cTnI-positive OT-USCs in the peri-infarct zone were observed in group 2 and more frequently in group 3. The ejection fraction (EF) was increased in groups 2 and 3 in 2 weeks. The improved EF was sustained for 4 weeks only in group 3. Our findings suggest that the supplementation of UCB-MSCs with oxytocin can contribute to the cardiogenic potential for cardiac repair.
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While an increasing amount of evidence demonstrates the homeostatic functions of the cardiac oxytocin (OT) system, less is known about the role of this hormone in the injured heart. The current study examined the effect of OT infusion on cell apoptosis, expression of proliferating cell nuclear antigen (PCNA) and inflammation in the acute and subacute phases of myocardial infarction (MI). Prior MI male Sprague-Dawley rats were infused subcutaneously with OT 25 or 125 ng/(kg h) for 3 or 7 days. Saline-treated MI and sham-operated rats served as controls. Echocardiography and analysis of cardiac sections were used to disclose OT actions. Left ventricular fractional shortening, estimated to be 46.0 +/- 1.8% in sham controls, declined to 21.1 +/- 3.3% in vehicle-treated MI rats and was improved to 34.2 +/- 2.1 and to 30.9 +/- 2.5% after treatment with OT 25 and 125 ng/(kg h), respectively. OT infusion resulted in: (1) increase of cells expressing PCNA in the infarct zone, diminished cell apoptosis and fibrotic deposits in the remote myocardium; (2) suppression of inflammation by reduction of neutrophils, macrophages and T lymphocytes; (3) depression of the expression of proinflammatory cytokines tumor necrosis factor-alpha and interleukin-6 with promotion of transforming growth factor-beta. OT treatment reduced expression of atrial and brain natriuretic peptides in the infarcted ventricle, as well as the concentration of both peptides in the circulation. These results indicate that continuous OT delivery reduces inflammation and apoptosis in infarcted and remote myocardium, thus improving function in the injured heart.
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Interleukin (IL)-1beta is present throughout the magnocellular neuroendocrine system and co-depletes with oxytocin and vasopressin from the neural lobe during salt-loading. To examine whether IL-1beta is released from the dendrites/soma of magnocellular neurones during osmotic stimulation, microdialysis adjacent to the supraoptic nucleus (SON) in conscious rats was combined with immunocapillary electrophoresis and laser-induced fluorescence detection to quantify cytokine in 5-min dialysates collected before (0-180 min; basal), and after (180-240 min), hypertonic saline injected s.c. (1.5 m NaCl). Osmotic release of IL-1beta was compared after inhibiting local voltage-gated channels for Na+ (tetrodotoxin) and Ca2+ (cadmium and nickel) or by reducing intracellular Ca2+ stores (thapsigargin). Immunohistochemistry combined with microdialysis was used to localise cytokine sources (IL-1beta+) and microglia (OX-42+). Under conditions of microdialysis, the basal release of IL-1beta+ in the SON area was measurable and stable (pg/ml; mean +/- SEM) from 0-60 min (2.2 +/- 0.06), 60-120 min (2.32 +/- 0.05) and 120-180 min (2.33 +/- 0.06), likely originating locally from activated microglia (OX42+; IL-1beta+; ameboid, hypertrophied) and magnocellular neurones expressing IL-1beta. In response to osmotic stimulation, IL-1beta increased progressively in dialysates of the SON area by a mechanism dependent on intracellular Ca2+ stores sensitive to thapsigargin and, similar to dendritic secretion of oxytocin and vasopressin, required local voltage-gated Na+ and Ca2+ channels for activation by osmoregulatory pathways from the forebrain. During osmotic stimulation, neurally dependent release of IL-1beta in the SON area likely upregulates osmosensitive cation currents on magnocellular neurones (observed in vitro by others), to facilitate dendritic release of neurohypophysial hormones.
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Receptor sites for the neurohypophyseal peptides arginine vasopressin (AVP) and oxytocin (OT) have been identified and characterized in some tissues involved in immune function in the rat. Novel radioiodinated ligands for the detection of neurohypophyseal hormone receptors, with a high specific radioactivity and affinity, enabled the selective detection of OT receptors in the thymus and vasopressin (VP) receptors in the spleen. OT receptors were detected in thymic membrane preparations and on thymocytes, which had a ligand selectivity similar to that of uterine OT receptors. AVP receptors of the V1 pressor type were present in a splenic membrane preparation. Specific AVP-binding sites, probably of the V1 type, were also present on splenic lymphocytes. Binding sites for AVP and OT could not be detected on mononuclear cells in peripheral blood of the rat. This study demonstrates that the use of the newly developed radioiodinated AVP and OT receptor ligands, with high specific radioactivity and affinity, enables the selective characterization of receptor sites for the neurohypophyseal hormones, even in the thymus, where previously no binding sites could be detected.
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Effect of oxytocin on the respiratory tract epithelium of rats infected with Escherichia coli following the prolonged emotional-painful stress, was studied using the methods of histochemistry, immunocytochemistry, light and electron microscopy. It was found, that prolonged stress caused the exertion of protective-adaptive capacities of the epithelium, while the administration of an antigen resulted in the failure of adaptational mechanisms. Oxytocin was found to participate in the formation of the response of the epithelial secretory cells to stressful influences by activating their protective functions. It stimulated and supported the protein-synthetic (CC16 protein production by Clara cells) and mucin-producing (goblet cells) functions of secretory cells, thus stabilizing the protective epithelial mechanisms under the conditions of intense functioning.
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Interactions between the nervous system and immune system have been studied extensively. However, the mechanisms underlying the neural regulation of immune activity, particularly the neuroendocrine regulation of immunologic functions, remain elusive. In this review, we provide a comprehensive examination of current evidence on interactions between the immune system and hypothalamic oxytocin-secreting system. We highlight the fact that oxytocin may have significant effects in the body, beyond its classical functions in lactation and parturition. Similar to the hypothalamo-pituitary-adrenal axis, the oxytocin-secreting system closely interacts with classical immune system, integrating both neurochemical and immunologic signals in the central nervous system and in turn affects immunologic defense, homeostasis, and surveillance. Lastly, this review explores therapeutic potentials of oxytocin in treating immunologic disorders.
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Normal hypothalamic-pituitary-adrenal (HPA) axis activity leading to rhythmic and episodic release of adrenal glucocorticoids (GCs) is essential for body homeostasis and survival during stress. Acting through specific intracellular receptors in the brain and periphery, GCs regulate behavior, metabolic, cardiovascular, immune, and neuroendocrine activities. In contrast to chronic elevated levels, circadian and acute stress-induced increases in GCs are necessary for hippocampal neuronal survival and memory acquisition and consolidation, by inhibiting apoptosis, facilitating the glutamatergic neurotransmission and formation of excitatory synapse and inducing immediate early genes and dendritic spines formation. In addition to its metabolic actions leading to increased energy availability, GCs have profound effects on feeding behavior, mainly through modulation of orexigenic and anorixegenic neuropeptides. Evidence is also emerging that in addition to the recognized immune suppressive actions of GCs by counteracting adrenergic pro-inflammatory actions, circadian elevations have priming effects in the immune system, potentiating acute defensive responses. In addition, negative feedback by GCs involves multiple mechanisms leading to limiting HPA axis activation and preventing deleterious effects of excessive glucocorticoid (GC) production. Adequate GC secretion to meet body demands is tightly regulated by a complex neural circuitry controlling hypothalamic corticotrophin releasing hormone (CRH) and vasopressin secretion, the main regulators of pituitary adrenocorticotrophic hormone (ACTH). Rapid feedback mechanisms, likely involving non-genomic actions of GCs, mediate immediate inhibition of hypothalamic CRH and ACTH secretion, while intermediate and delayed mechanisms mediated by genomic actions involve modulation of limbic circuitry and peripheral metabolic messengers. Consistent with their key adaptive roles, HPA axis components are evolutionarily conserved, being present in the earliest vertebrates. Understanding these basic mechanisms may lead to novel approaches for the development of diagnostic and therapeutic tools for disorders related to stress and alterations of GC secretion. This article is protected by copyright. All rights reserved.
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The hypothalamic supraoptic and paraventricular nucleus contain magnocellular neurosecretory cells (MNCs) that project to the posterior pituitary gland where they secrete either oxytocin or vasopressin (the anti-diuretic hormone) into the circulation. Oxytocin is important for delivery at birth and is essential for milk ejection during suckling. Vasopressin primarily promotes water reabsorption in the kidney to maintain body fluid balance, but also increases vasoconstriction. The profile of oxytocin and vasopressin secretion is principally determined by the pattern of action potentials initiated at the cell bodies. While it has long been known that the activity of MNCs depends upon afferent inputs that relay information on reproductive, osmotic and cardiovascular status, it has recently become clear that activity depends critically on local regulation by glial cells, as well as intrinsic regulation by the MNCs themselves. Here, we provide an overview of recent advances in our understanding of how intrinsic and local extrinsic mechanisms integrate with afferent inputs to generate appropriate physiological regulation of oxytocin and vasopressin MNC activity. This article is protected by copyright. All rights reserved.
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Background: Oxytocin (OXY) is a well-known nonapeptide that functions in reproduction. It is also known as an antioxidant in several organs. However, little is about its role in the protection of tissue against ischemia/reperfusion injury in skeletal muscle. The aim of this study was to evaluate the protective and therapeutic antioxidant effect of oxytocin in skeletal muscle during ischemia/reperfusion (I/R) injury. Methods: Rats were divided into 4 groups. Hindlimb ischemia was achieved by clamping the common femoral artery in 3 of the groups, but not a control group. OXY was injected before ischemia in the preoperative (preop) I/R + OXY group and after the onset of ischemia in the postoperative (postop) I/R + OXY group. Saline solution was injected in the I/R group. Limbs were rendered ischemic for 90 min. At the end of 90-min reperfusion period, skeletal muscle tissue samples were taken from the ischemic muscle for evaluation at light and transmission electron microscopic levels. Biochemical analysis was done for malonedialdehyde and glutathione levels. Caspase immunohistochemistry was applied for apoptosis. Results: The light- and electron-microscopic scores of the OXY-treated groups were significantly lower than in the I/R group. The degree of tissue damage was ameliorated in the OXY-treated groups. The number of apoptotic cells was decreased in the OXY-treated groups compared with the I/R group. In OXY-treated groups, the malonedialdehyde level was lower than in the I/R group. Glutathione levels were found to be increased in the OXY-treated groups compared with the I/R group. Conclusions: Oxytocin has a protective effect against I/R injury in skeletal muscle and may reduce the incidence of compartment syndrome.
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Aging and aging related illnesses such as cancer have been associated with inflammatory changes. Cancer-related behavioral comorbidities such as fatigue, sleep disturbances, depression have also been associated with inflammation, hypothalamic-pituitary-adrenal (HPA) axis dysregulation and other neuroendocrine changes. From a clinical perspective, cancer-related fatigue demonstrates striking similarities with the cytokine-induced sickness phenomenon in animal models. Thyrotopin-releasing hormone (TRH) plays a homeostatic role in its interaction with several biological systems, including a critical role in its interactions with the immune system. Considerable evidence supports a pivotal role for TRH in the inflammatory processes with specific relevance to the "cytokine-induced sickness behavior" paradigm. Additionally, TRH exerts arousing and analeptic effects in instances of behavioral depression. In a small proof-of-concept study conducted by our group, we investigated TRH administration as a treatment fatigue in cancer survivors in comparison with saline administration using a double-blind, crossover design. We also evaluated impact of TRH/saline administration on the inflammatory markers in these patients. TRH administration was associated with significant improvement (p < 0.05) in fatigue levels as measured by the Visual Analog Scale-Energy (VAS-E), was associated with significant (p < 0.05) improvement in sleep disturbances and improved quality of life. Notably, TRH administration was associated with decrease in C-reactive protein (CRP) levels, a marker of inflammation. This decrease in CRP level with TRH administration was associated with improvement in energy levels as measured by the VAS-E. The present review supports potential utility of TRH-based therapeutics in medical and psychiatric disorders with underlying inflammatory processes.
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In virgin rats, systemic administration of interleukin (IL)-1β (i.e. to mimic infection), increases oxytocin secretion and the firing rate of oxytocin neurones in the supraoptic nucleus (SON). However, in late pregnancy, stimulated oxytocin secretion is inhibited by an endogenous opioid mechanism, preserving the expanded neurohypophysial oxytocin stores for parturition and minimising the risk of preterm labour. Central levels of the neuroactive metabolite of progesterone, allopregnanolone, increase during pregnancy and allopregnanolone acting on GABA(A) receptors on oxytocin neurones enhances inhibitory transmission. In the present study, we tested whether allopregnanolone induces opioid inhibition of the oxytocin system in response to IL-1β in late pregnancy. Inhibition of 5α-reductase (an allopregnanolone-synthesising enzyme) with finasteride potentiated IL-1β-evoked oxytocin secretion in late pregnant rats, whereas allopregnanolone reduced the oxytocin response in virgin rats. IL-1β increased the number of magnocellular neurones in the SON and paraventricular nucleus (PVN) expressing Fos (an indicator of neuronal activation) in virgin but not pregnant rats. In immunoreactive oxytocin neurones in the SON and PVN, finasteride increased IL-1β-induced Fos expression in pregnant rats. Conversely, allopregnanolone reduced the number of magnocellular oxytocin neurones activated by IL-1β in virgin rats. Treatment with naloxone (an opioid antagonist) greatly enhanced the oxytocin response to IL-1β in pregnancy, and finasteride did not enhance this effect, indicating that allopregnanolone and the endogenous opioid mechanisms do not act independently. Indeed, allopregnanolone induced opioid inhibition over oxytocin responses to IL-1β in virgin rats. Thus, in late pregnancy, allopregnanolone induces opioid inhibition over magnocellular oxytocin neurones and hence on oxytocin secretion in response to immune challenge. This mechanism will minimise the risk of preterm labour and prevent the depletion of neurohypophysial oxytocin stores, which are required for parturition.
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The inflammatory response provides a powerful means for the body to fight an infection. The neuroendocrine system plays an important role in controlling the magnitude and duration of this response and maintaining homeostasis in the inflamed state. Glucocorticoids released following activation of the hypothalamic-pituitary-adrenal axis limit the synthesis of pro-inflammatory molecules, whereas the neurohypophysial hormones vasopressin and oxytocin act both within the brain and in the periphery to maintain cardiovascular and metabolic homeostasis and to limit the rise in body temperature.
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To study in vitro and in vivo effect of oxytocin and ciprofloxacin combination on formation of biofilms by agents of surgical infections. Microorganisms of different species isolated by conventional methods from patients with purulent soft tissue infections were used in experiments. Ciprofloxacin manufactured by "Dr. Reddys" (India) and oxytocin manufactured by "Gedeon Richter" (Hungary) were used. For in vitro experiments one-half of minimal inhibitory concentrations of drugs were used. Oxytocin-placebo ("Gedeon Richter", Hungary) was used for control tests. Formation of biofilms was assessed using method proposed by G. O'Toole (2000). For in vivo experiments septic wounds in 1st phase of wound process were modeled according to method proposed by E.M. Danilova (1992). Wounds were infected with Staphylococcus aureus strain 104, which has strong ability to form biofilms. Efficacy of treatment was assessed on signs of inflammatory process and microscopy of touch smears for detection of bacterial biofilms. In experiments in vivo addition of oxytocin to nutrient medium resulted in suppression of biofilm formation by studied microorganisms. Obtained data were confirmed by in vivo experiments which demonstrated higher efficacy of local application of ciprofloxacin and oxytocin combination for treatment of septic wounds compared to separate use of ciprofloxacin or oxytocin. Studies performed in vitro and in vivo showed efficacy of oxytocin and ciprofloxacin combination, which is determined not only by enhancement of antimicrobial effect of the drug against pathogen but also by suppression of biofilm formation in the wound during infection.
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Glucocorticoids secreted in response to stress activation of the hypothalamic-pituitary-adrenal axis feed back onto the hypothalamus to rapidly suppress neuroendocrine activation, including oxytocin and vasopressin secretion. Here we provide a brief review focused on our recent findings of a rapid glucocorticoid-induced opposing regulation of glutamate and gamma-aminobutyric acid (GABA) inputs to magnocellular neurons via the release of distinct retrograde messengers. The stress hormone corticosterone and its synthetic analogue dexamethasone elicit the rapid retrograde release of endocannabinoids by activating a novel membrane-associated, G protein-coupled receptor in parvocellular and magnocellular neuroendocrine cells of the hypothalamic paraventricular and supraoptic nuclei. Glucocorticoids also cause the rapid retrograde release of an unknown messenger that facilitates presynaptic GABA release onto magnocellular neuroendocrine cells. These finding suggest that there is a strict synapse-specific segregation of the opposing actions of the two retrogradely released messengers. Thus, the combined actions of glucocorticoids cause a rapid synaptic inhibition of the magnocellular neurons and would be expected, therefore, to mediate a rapid feedback inhibition of the secretion of oxytocin and vasopressin during stress activation of the hypothalamic-pituitary-adrenal axis.
Article
Elevated perceptions of psychosocial stress and stressful life events are linked to faster disease progression in individuals living with HIV and these associations may be stronger for women from ethnic minority populations. Levels of neurohormones such as oxytocin (OT), cortisol, and norepinephrine (NE) have been shown to influence the effects of psychosocial stress in different populations. Understanding how intrinsic neuroendocrine substances moderate the effects of stressors in minority women living with HIV (WLWH) may pave the way for interventions to improve disease management. We examined circulating levels of plasma OT as a moderator of the effects of stress on disease status (viral load, CD4+ cell count) in 71 low-income ethnic minority WLWH. At low levels of OT, there was an inverse association between stress and CD4+ cell counts. Counter-intuitively, at high levels of OT there was a positive association between stress and CD4+ cell counts. This pattern was unrelated to women's viral load. Other neuroendocrine hormones known to down-regulate the immune system (cortisol, norepinephrine) did not mediate the effects of OT and stress on immune status. OT may have stress buffering effects on some immune parameters and possibly health status in low income ethnic minority WLWH reporting elevated stress.
Article
Associations of breast cancer with diseases of the thyroid have been repeatedly reported, but the mechanism underlying this association remains to be elucidated. It has been reported that oxytocin (OXT) attenuates the thyroid-stimulating hormone (TSH) release in response to thyrotrophin-releasing hormone (TRH) and decreased plasma levels of TSH as well as the thyroid hormones by an effect mediated by the central nervous system. Oxytocinase (IRAP) is the regulatory proteolytic enzyme reported to hydrolyze OXT. Changes in IRAP activity have been reported in both human breast cancer and N-methyl-nitrosourea (NMU)-induced rat mammary tumours. Here, we measure IRAP activity fluorometrically using cystyl-β-naphthylamide as the substrate, in the hypothalamus-pituitary-thyroid axis together with the circulating levels of OXT, and its relationship with circulating levels of TSH and free thyroxine (fT4), as markers of thyroid function in control rats and rats with breast cancer induced by NMU. We found decreased thyroid function in rats with breast cancer induced by NMU, supported by the existence of lower serum circulating levels of both TSH and fT4 than their corresponding controls. Concomitantly, we found a decrease of hypothalamic IRAP activity and an increase in circulating levels of OXT. We propose that breast cancer increases OXT pituitary release by decreasing its hypothalamic catabolism through IRAP activity, probably due to the alteration of the estrogenic endocrine status. Thus, high circulating levels of OXT decreased TSH release from the pituitary, and therefore, of thyroid hormones from the thyroid, supporting the association between breast cancer and thyroid function disruption.
Article
Immune challenges can lead to marked behavioral changes, including fatigue, reduced social interest, anorexia, and somnolence, but the precise neuronal mechanisms that underlie sickness behavior remain elusive. Part of the neurocircuitry influencing behavior associated with illness likely includes viscerosensory nuclei located in the caudal brainstem, based on findings that inactivation of the dorsal vagal complex (DVC) can prevent social withdrawal. These brainstem nuclei contribute multiple neuronal projections that target different components of autonomic and stress-related neurocircuitry. In particular, catecholaminergic neurons in the ventrolateral medulla (VLM) and DVC target the hypothalamus and drive neuroendocrine responses to immune challenge, but their particular role in sickness behavior is not known. To test whether this catecholamine pathway also mediates sickness behavior, we compared effects of DVC inactivation with targeted lesion of the catecholamine pathway on exploratory behavior, which provides an index of motivation and fatigue, and associated patterns of brain activation assessed by immunohistochemical detection of c-Fos protein. LPS treatment dramatically reduced exploratory behavior, and produced a pattern of increased c-Fos expression in brain regions associated with stress and autonomic adjustments paraventricular hypothalamus (PVN), bed nucleus of the stria terminalis (BST), central amygdala (CEA), whereas activation was reduced in regions involved in exploratory behavior (hippocampus, dorsal striatum, ventral tuberomammillary nucleus, and ventral tegmental area). Both DVC inactivation and catecholamine lesion prevented reductions in exploratory behavior and completely blocked the inhibitory LPS effects on c-Fos expression in the behavior-associated regions. In contrast, LPS-induced activation in the CEA and BST was inhibited by DVC inactivation but not by catecholamine lesion. The findings support the idea that parallel pathways from immune-sensory caudal brainstem sources target distinct populations of forebrain neurons that likely mediate different aspects of sickness. The caudal medullary catecholaminergic projections to the hypothalamus may significantly contribute to brain mechanisms that induce behavioral "fatigue" in the context of physiological stressors.
Article
Recent studies show that oxytocin has various effects on cellular behaviors. Oxytocin is reported to stimulate cardiomyogenesis of embryonic stem cells and endothelial cell proliferation. Mesenchymal stem cells (MSCs) are widely used for cardiac repair, and we elucidated the effect of oxytocin on umbilical cord derived-MSCs (UCB-MSCs). UCB-MSCs were pretreated with oxytocin (100 nM) and washed with saline prior to experiments. To evaluate their angiogenic potential and migration activity, tube formation assay and Boyden chamber assay were performed. For in vivo study, ischemia-reperfusion was induced in rats, and UCB-MSCs with or without oxytocin pretreatment were injected into the infarcted myocardium to evaluate the engraftment of injected cells. Histological and hemodynamic studies were performed. Oxytocin-treated UCB-MSCs showed a decrease in tube formation but a drastic increase in transwell migration activity. The transcription level of matrix metalloproteinase (MMP)-2 was increased in oxytocin-treated UCB-MSCs. Knock-down of MMP-2 by use of siRNA restored the tube formation, while reducing transmigration activity. In rats injected with oxytocin-treated UCB-MSCs, cardiac fibrosis and CD68 infiltration in the peri-infarct zone were reduced, whereas cell engraftment and connexin43 expression were greater than in rats injected with untreated UCB-MSCs. By contrast, angiogenesis did not differ significantly between the two groups. Cardiac contractility was higher in the group injected with oxytocin-treated UCB-MSCs than in the group injected with phosphate-buffered saline alone. Collectively, oxytocin is an effective priming reagent for stem cells for application to damaged heart tissue.
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Thermal injury may cause distant organ inflammation and multiorgan failure. Oxytocin (OT), a nonapeptide, modulates the immune and inflammatory processes. To investigate the effects of oxytocin on burn-induced tissue injury, Sprague-Dawley rats were subjected to a partial thickness burn. Immediately after burn, half of the burned rats were placed single in the cages, while others were caged in groups. All the rats then were treated with either OT (5 microg/kg, s.c) or saline twice daily for 5 d. The control rats had no burn injury and received no treatments. On day 5, the rats were decapitated, tissue and serum samples were obtained to score the severity of damage and to assay TNF-alpha levels. Burn trauma resulted in oxidative ileal damage, as evidenced by increased apoptotic rate, increased neutrophil recruitment, and enhanced lipid peroxidation. OT treatment depressed the TNF-alpha level and alleviated dermal degeneration, while attenuating ileal damage. Although a higher degree of skin damage was observed in the animals kept isolated following burn injury, keeping the rats in groups did not affect the level of TNF-alpha or the severity of dermal or ileal injury, but abolished the burn-induced elevations in ileal lipid peroxidation and myeloperoxidase activity. Moreover, OT treatment reduced the ileal apoptosis when applied to rats housed in groups, while the treatment did not alter apoptotic ratio in the isolated rats. Oxytocin can be considered as a potential agent in treating burn-induced distant organ injury.
Article
Interleukin (IL)-6 is a pro-inflammatory cytokine that also affects metabolic function because IL-6 depleted (IL-6(-/-)) mice develop late-onset obesity. IL-6 appears to act in the central nervous system, presumably in the hypothalamus, to increase energy expenditure that appears to involve stimulation of the sympathetic nervous system. In the present study, we explored possible central mechanisms for the effects exerted by IL-6 on body fat. Therefore, we measured the effects of IL-6 depletion in IL-6(-/-) mice on expression of key hypothalamic peptide genes involved in energy balance by the real time polymerase chain reaction. Additionally, co-localisation between such peptides and IL-6 receptor alpha was investigated by immunohistochemistry. IL-6 deficiency decreased the expression of several peptides found in the paraventricular nucleus (PVN), which is a nucleus that has been attributed an adipostatic function. For example, corticotrophin-releasing hormone (CRH), which is reported to stimulate the sympathetic nervous system, was decreased by 40% in older IL-6(-/-) mice. Oxytocin, which is reported to prevent obesity, was also decreased in older IL-6(-/-) animals, as was arginine vasopressin (AVP). The IL-6 receptor alpha was abundantly expressed in the PVN, but also in the supraoptic nucleus, and was shown to be co-expressed to a high extent with CRH, AVP, oxytocin and thyrotrophin-releasing hormone. These data indicate that depletion of endogenous IL-6, a body fat suppressing cytokine, is associated with the decreased expression of CRH and oxytocin (i.e. energy balance regulating peptides) as well as AVP in the PVN. Because IL-6 receptor alpha is co-expressed with CRH, oxytocin and AVP, IL-6 could stimulate the expression of these peptides directly.
Article
Arginine vasopressin (AVP) and corticotrophin-releasing hormone (CRH) in the parvocellular neurosecretory cells of the paraventricular nucleus (PVN) play a major role in activating the hypothalamic-pituitary-adrenal axis, which is the main neuroendocrine response against the many kinds of stress. We examined the effects of chronic inflammatory/nociceptive stress on the expression of the AVP-enhanced green fluorescent protein (eGFP) fusion gene in the hypothalamus, using the adjuvant arthritis (AA) model. To induce AA, the AVP-eGFP rats were intracutaneously injected heat-killed Mycobacterium butyricum (1 mg/rat) in paraffin liquid at the base of their tails. We measured AVP, oxytocin and corticosterone levels in plasma and changes in eGFP and CRH mRNA in the hypothalamus during the time course of AA development. Then, we examined eGFP fluorescence in the PVN, the supraoptic nucleus (SON), median eminence (ME) and posterior pituitary gland (PP) when AA was established. The plasma concentrations of AVP, oxytocin and corticosterone were significantly increased on days 15 and 22 in AA rats, without affecting the plasma osmolality and sodium. Although CRH mRNA levels in the PVN were significantly decreased, eGFP mRNA levels in the PVN and the SON were significantly increased on days 15 and 22 in AA rats. The eGFP fluorescence in the SON, the PVN, internal and external layers of the ME and PP was apparently increased in AA compared to control rats. These results suggest that the increases in the concentrations of ACTH and corticosterone in AA rats are induced by hypothalamic AVP, based on data from AVP-eGFP transgenic rats.
Article
Oxytocin is synthesized and released in the heart and vasculature, tissues that also express oxytocin receptors. Although it has been established this intrinsic cardiovascular oxytocin system is important in normal homeostatic cardiac and vascular regulation, a role for this system in cardiovascular pathophysiology has not been investigated. The current study examined the influence of oxytocin on mechanisms in atherogenesis, oxidative stress, and inflammation in cultured human vascular cells, THP-1 monocytes, and macrophages. Oxytocin receptor protein and mRNA expression, NADPH-dependent superoxide activity, and interleukin-6 secretion were measured. Results demonstrated oxytocin receptor protein and mRNA in THP-1 monocytes and macrophages. Incubation of cells at physiological levels of oxytocin significantly decreased basal and stimulated NADPH-dependent superoxide activity in vascular cells, monocytes, and macrophages by 24-48%. Oxytocin also attenuated interleukin-6 secretion from stimulated THP-1 macrophages and endothelial cells by 56 and 26%, respectively. These findings suggest that oxytocin attenuates vascular oxidative stress and inflammation, two important pathophysiological processes in atherosclerosis. The fact that oxytocin receptors are found in monocytes and macrophages, and oxytocin decreases both superoxide production and release of a proinflammatory cytokine from these cells, suggests a potentially larger role for oxytocin in the attenuation of disease.
Article
The thymic repertoire of neuroendocrine 'self' antigens has been previously described on the basis of the intrathymic expression of neurohypophysial (NHP)- and tachykinin-related peptide signals and receptors. According to that model, the cryptocrine signalling between thymic epithelial/nurse cells and thymocytes through NHP-related signals and receptors constitutes one accessory pathway in the process of T-cell differentiation and/or activation. A pharmacological manipulation of that novel type of cell-to-cell signalling was tested by the investigation of the immunomodulatory properties of novel cyclic hexapeptide oxytocin (OT) antagonists (MSD Research Laboratories). These compounds were found to significantly inhibit the productions of cytokines (mainly IL-1 beta and IL-6) elicited by anti-CD3 treatment of human whole blood cell cultures. Cytokine productions were more significantly reduced by OT antagonists in whole blood cell cultures derived from female volunteers than in those obtained from male donors, suggesting an influence of the gonadal steroid environment on the expression of NHP peptide receptors by immune cells. These observations support the concept of novel immunomodulating approaches through immune-specific neuropeptide antagonists, as well as the pharmacological value of such strategies in selective immunotherapy.
Article
The nucleus tractus solitarius/dorsal motor nucleus of the vagus nerve (NTS/DMV) area was perfused by the push-pull perfusion technique in anesthetized rats, and perfusates were assayed for arginine vasopressin (AVP) and oxytocin (OXT) immunoreactivity. As compared with controls, electrical stimulation of the ipsilateral paraventricular nucleus (PVN) resulted in increased amounts of both AVP (approximately 5-fold) and OXT (approximately 10-fold, P less than 0.05 each) in the perfusates. During the poststimulation perfusion period, peptide concentrations were found to return to control levels. Elevation of circulating AVP and OXT by an osmotic stimulus did not result in increases of AVP and OXT in NTS/DMV perfusates. These data suggest that AVP and OXT are released from NTS/DMV area fiber terminals during electrical stimulation of descending PVN neurons. Furthermore, they are consistent with the view that both peptides are involved as neurotransmitters in autonomic regulation.
Article
We have reported previously that autoantibodies in sera from patients with multiple sclerosis (MS) were reactive with rat brain, including pituitary, and with swine pituitary in areas thought to contain peptides of the somatotropin family and/or vasopressin/oxytocin. We have now tested the same patient sera for their specificity to antigenic determinants which are common to animal and human peptides. Localization of the binding sites of the MS sera was demonstrated in rat pituitaries and brains using the double immunofluorescence staining method, employing anti-bovine somatotropin (STH), anti-ovine prolactin (PRL), anti-neurophysin I and II, anti-somatostatin, and anti-vasopressin as reference antibodies. In the pituitary, the positive MS sera reacted specifically with cells which were also reactive with anti-bSTH. In the brain, positivity of MS sera was mainly localized in structures reactive with anti-neurophysin I and II and anti-vasopressin. Absorption experiments, immunocytochemical model assays, and radioimmunoassays, however, did not show specific binding of the MS sera to any of the above-mentioned peptides. Therefore, while these data present additional evidence on the localization of the immunocytochemical reaction sites of the MS autoantibodies, they do not enable us to identify the specificity of these antibodies.
Article
The subarachnoid space of the spinal cord was perfused in vivo in urethane-anesthetized rats and perfusates were assayed for arginine-vasopressin (AVP) and oxytocin immunoreactivity. In control perfusates, oxytocin concentrations were 3 times those of AVP. Electrical stimulation of the paraventricular nucleus (PVN) of the hypothalamus, but not of other hypothalamic areas, yielded increased amounts of immunoassayable peptides in the spinal cord perfusates. Intravenous infusion of AVP did not elevate AVP concentrations in the cord perfusates. These data suggest that electrical stimulation of PVN neurons caused release of AVP and oxytocin from spinal cord terminals and support the concept that these peptides are neurotransmitters in the cord.
Article
The investigations were carried out on male Wistar rats. 12 h after birth newborn rats were subjected to thymectomy, and subsequently observed for the period of 8 weeks. The studies of the rat hypothalamus revealed that supraoptic nuclei (NSO) contained numerous cells which dyed dark. The cells were deprived of nuclei, or else they were shrunk. Similar cells were encountered in the medial eminence (EM). Measurements of cellular nuclei within NSO and NPV demonstrated that their size diminished following thymectomy what after t-test calculations yielded a statistically significant value.
Article
Thymic epithelial and nurse cells (TEC/TNC) synthesize an oxytocin (OT)-like peptide in association with a neurophysin (NP)-related protein in a way similar to in the hypothalamo-neurohypophysial (NHP) system. The central T-cell tolerance of the NHP neuroendocrine functions have been proposed to be mediated through these thymic NHP-related peptides due to their close homology with the NHP neurohormones OT and vasopressin (VP). In order to investigate their putative presentation by proteins of the major histocompatibility complex (MHC), human thymic membranes were purified and passed through an immunoaffinity column using mAb B9.12 directed to the monomorphic determinant of human MHC class I proteins. This methodology provided the following observations: (1) a NP-like protein is translocated in human thymic membranes and is retained by B9.12 on the column; (2) the MW of this NP-like material (50-55 kD) is quite different from the MW of hypothalamic NP proteins (10 kD), and (3) this thymic NP-like protein could be identified on Western blots with mAb B9.12. The precise extent of this relationship between the thymic NP-like protein and the Ig/MHC superfamily is actually investigated through the characterization of the genetic mechanisms responsible for the thymic expression of NHP-related peptides. Given the physiological importance of OT and of its binding to NP for transport along the axonal processes of the NHP tract, we postulate that, somewhat analogously, the thymic NP-/MHC class I-related protein could be involved in the presentation of the OT-like peptide to immature T-cells.