oxytocin and Brain-Injuries

The neonatal period is critical for brain development and determinant for long-term brain trajectory. Yet, this time concurs with a sensitivity and risk for numerous brain injuries following perinatal complications such as preterm birth. Brain injury in premature infants leads to a complex amalgam of primary destructive diseases and secondary maturational and trophic disturbances and, as a consequence, to long-term neurocognitive and behavioral problems. Neuroinflammation is an important common factor in these complications, which contributes to the adverse effects on brain development. Mediating this inflammatory response forms a key therapeutic target in protecting the vulnerable developing brain when complications arise. The neuropeptide oxytocin (OT) plays an important role in the perinatal period, and its importance for lactation and social bonding in early life are well-recognized. Yet, novel functions of OT for the developing brain are increasingly emerging. In particular, OT seems able to modulate glial activity in neuroinflammatory states, but the exact mechanisms underlying this connection are largely unknown. The current review provides an overview of the oxytocinergic system and its early life development across rodent and human. Moreover, we cover the most up-to-date understanding of the role of OT in neonatal brain development and the potential neuroprotective effects it holds when adverse neural events arise in association with neuroinflammation. A detailed assessment of the underlying mechanisms between OT treatment and astrocyte and microglia reactivity is given, as well as a focus on the amygdala, a brain region of crucial importance for socio-emotional behavior, particularly in infants born preterm.

Topics: Brain; Brain Injuries; Female; Humans; Infant; Infant, Newborn; Microglia; Oxytocin; Pregnancy; Premature Birth

Intracerebral hemorrhage (ICH) causes severe sensorimotor dysfunction and cognitive decline which are aggravated by secondary brain injury, yet there are no effective management to alleviate these outcomes. Pyroptosis is strongly related to neuroinflammation, which plays a crucial role in the pathophysiological processes of secondary brain injury after ICH. OXT (oxytocin), as a pleiotropic neuropeptide, has multiple functions including anti-inflammation and antioxidation. This study aims to investigate the role of OXT in improving ICH outcomes and the underlying mechanisms.. C57BL/6 mice were used to establish the ICH model by autologous blood injection. OXT was administered intranasally (0.2 μg/g) after ICH. Combing behavioral tests, Western blot, immunofluorescence staining, electron microscopy, and pharmacological approaches, we evaluated the effect of intranasal OXT application on neurological outcomes after ICH and explored the underlying mechanism.. Endogenous OXT level was decreased, whereas OXTR (oxytocin receptor) expression was increased after ICH. OXT treatment improved the short-term and long-term neurological functions and alleviated neuronal pyroptosis and neuroinflammation. In addition, OXT reduced excessive mitochondrial fission and mitochondrial-derived oxidative stress 3 days after ICH. OXT decreased the expression of pyroptotic and proinflammatory factors including NLRP3 (NOD-like receptor protein 3), ASC (apoptosis-associated speck-like protein containing a CARD), GSDMD (gasdermin D), caspase-1, IL (interleukin)-1β, and IL-18 and increased the expression of p-PKA (phospho-protein kinase A) and p-DRP1 (S637; DRP1 [dynamin-related protein 1] phosphorylation at Ser637). OXT-induced neuroprotective effects were blocked by either OXTR inhibitor or PKA inhibitor.. Intranasal application of OXT can ameliorate neurological deficits and alleviate neural pyroptosis, inflammation, and excessive mitochondrial fission via OXTR/p-PKA/DRP1 signaling pathway after ICH. Thus, OXT administration may be a potential therapeutic strategy to improve the prognosis of ICH.

Topics: Animals; Brain Injuries; Cerebral Hemorrhage; Mice; Mice, Inbred C57BL; Mitochondrial Dynamics; Neuroinflammatory Diseases; Oxytocin; Pyroptosis

Cranial radiation therapy (CRT) is an effective treatment for brain tumors; however, it also causes brain injuries. The pediatric brain is considered especially vulnerable compared to the adult brain; thus, brain injuries caused by CRT may severely affect their quality of life. In this study, we determined the neuroprotective effects of nasal oxytocin administration following cranial radiation in mice. We investigated the cognitive behavior of mice (novel object recognition test and novel object location test), phosphorylated histone H2AX (γ-H2AX) and K

Topics: Animals; Brain Injuries; Chlorides; Cognitive Dysfunction; Cranial Irradiation; DNA Damage; Hippocampus; Humans; Mice; Neuroprotective Agents; Oxytocin; Quality of Life; Symporters

Every year, 30 million infants worldwide are delivered after intra-uterine growth restriction (IUGR) and 15 million are born preterm. These two conditions are the leading causes of ante-/perinatal stress and brain injury responsible for neurocognitive and behavioral disorders affecting more than 9 million children each year. Most pharmacological candidates to prevent perinatal brain damage have failed to demonstrate substantial benefits. In contrast, environment enrichment based on developmental care, skin-to-skin contact and vocal/music exposure appear to exert positive effects on brain structure and function. However, mechanisms underlying these effects remain unknown. There is strong evidence that an adverse environment during pregnancy and the neonatal period can influence hormonal responses of the newborn with long-lasting neurobehavioral consequences in infancy and adulthood. In particular, excessive cortisol release in response to perinatal stress associated with prematurity or IUGR is recognized to induce brain-programming effects and neuroinflammation, a key predictor of subsequent neurological impairments. These deleterious effects are known to be balanced by oxytocin (OT), a neuropeptide released by the hypothalamus, which plays a role during the perinatal period and in social behavior. In addition, preclinical studies suggest that OT is able to regulate the central inflammatory response to injury in the adult brain. Using a rodent model of IUGR associated with developing white matter damage, we recently reported that carbetocin, a brain permeable OT receptor (OTR) agonist, induced a significant reduction of activated microglia, the primary immune cells of the brain. Moreover, this reduced microglia reactivity was associated with long-term neuroprotection. These findings make OT a promising candidate for neonatal neuroprotection through neuroinflammation regulation. However, the mechanisms linking endogenous OT and central inflammation response to injury have not yet been established. Further studies are needed to assess the protective role of OT in the developing brain through modulation of microglial activation, a key feature of brain injury observed in infants born preterm or growth-restricted. They are expected to have several impacts in the near future not only for improving knowledge of microglial cell physiology and reactivity during brain development, but also to design clinical trials testing interventions associated with endogenous OT. Ocytocine  : une nouvelle cible de neuroprotection ?. Chaque année, dans le monde, 30 millions de nouveau-nés naissent après un retard de croissance intra-utérin (RCIU) et 15 millions naissent prématurément. Ces deux conditions sont les principales causes de stress anté-/périnatal et de lésions cérébrales responsables de troubles neurocognitifs et comportementaux chez plus de 9 millions d’enfants chaque année. La plupart des stratégies pharmacologiques visant à prévenir les lésions cérébrales périnatales n’ont pas réussi à démontrer des bénéfices cliniques substantiels. En revanche, l’enrichissement de l’environnement basé sur les soins de développement, le contact peau à peau et l’exposition vocale/musicale semblent avoir des effets positifs sur la structure et la fonctionnalité du cerveau. Toutefois, les mécanismes qui sous-tendent ces effets restent inconnus. De nombreuses évidences montrent qu’un environnement défavorable pendant la grossesse et la période néonatale peut influencer les réponses hormonales du nouveau-né et avoir des conséquences neurocomportementales durables pendant la petite enfance et à l’âge adulte. L’ocytocine (OT), un neuropeptide libéré par l’hypothalamus, joue un rôle pendant la période périnatale dans l’attachement parents-enfant et dans le comportement social. En outre, des études précliniques suggèrent que l’OT est capable de réguler la réponse inflammatoire centrale aux lésions dans le cerveau adulte. Ces données font de l’OT un candidat prometteur pour la neuroprotection néonatale par la régulation de la neuro-inflammation.

Topics: Brain; Brain Injuries; Female; Humans; Neuroinflammatory Diseases; Neuroprotection; Oxytocin; Pregnancy

Prematurity and fetal growth restriction (FGR) are frequent conditions associated with adverse neurocognitive outcomes. We have previously identified early deregulation of genes controlling neuroinflammation as a putative mechanism linking FGR and abnormal trajectory of the developing brain. While the oxytocin system was also found to be impaired following adverse perinatal events, its role in the modulation of neuroinflammation in the developing brain is still unknown. We used a double-hit rat model of perinatal brain injury induced by gestational low protein diet (LPD) and potentiated by postnatal injections of subliminal doses of interleukin-1β (IL1β) and a zebrafish model of neuroinflammation. Effects of the treatment with carbetocin, a selective, long lasting, and brain diffusible oxytocin receptor agonist, have been assessed using a combination of histological, molecular, and functional tools in vivo and in vitro. In the double-hit model, white matter inflammation, deficient myelination, and behavioral deficits have been observed and the oxytocin system was impaired. Early postnatal supplementation with carbetocin alleviated microglial activation at both transcriptional and cellular levels and provided long-term neuroprotection. The central anti-inflammatory effects of carbetocin have been shown in vivo in rat pups and in a zebrafish model of early-life neuroinflammation and reproduced in vitro on stimulated sorted primary microglial cell cultures from rats subjected to LPD. Carbetocin treatment was associated with beneficial effects on myelination, long-term intrinsic brain connectivity and behavior. Targeting oxytocin signaling in the developing brain may be an effective approach to prevent neuroinflammation - induced brain damage of perinatal origin.

Topics: Animals; Animals, Genetically Modified; Animals, Newborn; Brain; Brain Injuries; Cells, Cultured; Computational Biology; Diet, Protein-Restricted; Disease Models, Animal; Female; Green Fluorescent Proteins; Interleukin-1beta; Lipopolysaccharides; Microglia; Oxytocics; Oxytocin; Peptide Fragments; Pregnancy; Prenatal Exposure Delayed Effects; Receptors, Oxytocin; RNA, Messenger; Zebrafish

Topics: Adrenal Insufficiency; Ascites; Brain Injuries; Diabetes Insipidus; Eclampsia; Endocrine System Diseases; Female; Humans; Liver Cirrhosis; Oxytocin; Pregnancy; Vasopressins; Water-Electrolyte Balance

Topics: Birth Injuries; Brain Injuries; Cesarean Section; Female; Fetal Death; Humans; Hyaline Membrane Disease; Hypoxia; Infant Mortality; Infant, Newborn; Labor Presentation; Obstetric Labor Complications; Oxytocin; Parity; Pregnancy; Pulmonary Atelectasis; Statistics as Topic; Vitamin K Deficiency Bleeding