Oxytocin receptor agonist reduces perinatal brain damage by targeting microglia

Mairesse, Jérôme; Zinni, Manuela; Pansiot, Julien; Hassan-Abdi, Rahma; Demené, Charlie; Colella, Marina Pereira; Charriaut‐Marlangue, Christiane; Novais, Aline Rideau Batista; Tanter, Mickaël; Maccari, Stefania; Gressèns, Pierre; Vaiman, Daniel; Soussi-Yanicostas, Nadia; Baud, Olivier

doi:10.1002/glia.23546

Cited by 73 publications

(64 citation statements)

References 56 publications

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“…A combination of perinatal brain injury induced by a gestational low-protein diet and postnatal injections of interleukin-1β (IL-1β), caused an upregulation of inflammation-related gene sets and an increase in microglial cell number in cortical white matter at P4. Cultured microglial cells from P2 low-protein-diet animals displayed a more amoeboid morphology and released higher concentrations of several pro-inflammatory cytokines with respect to controls [45].…”

Section: Prenatal Environmental Agents and Infectionmentioning

confidence: 88%

“…Recently, Amini-Khoei et al (2017) demonstrated that intracerebral administration of OXT reduced pro-inflammatory gene expression related to microglia activity, including TNF-α, IL-1β, and TLR4, in the HIP of adult animals exposed to MS [128]. In a double-hit model using a low-protein diet to induce perinatal brain damage followed by postnatal injections of IL-1β during early life, the accompanying administration of the OXT receptor agonist carbetocin was found to prevent microglial activation and reduce the effects of the low-protein diet and IL-1β injections on genes associated with microglial activation throughout the brain [45].…”

Section: Early Preventative Interventionsmentioning

confidence: 95%

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Microglial Function in the Effects of Early-Life Stress on Brain and Behavioral Development

Catale

Gironda

Iacono

et al. 2020

JCM

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The putative effects of early-life stress (ELS) on later behavior and neurobiology have been widely investigated. Recently, microglia have been implicated in mediating some of the effects of ELS on behavior. In this review, findings from preclinical and clinical literature with a specific focus on microglial alterations induced by the exposure to ELS (i.e., exposure to behavioral stressors or environmental agents and infection) are summarized. These studies were utilized to interpret changes in developmental trajectories based on the time at which the stress occurred, as well as the paradigm used. ELS and microglial alterations were found to be associated with a wide array of deficits including cognitive performance, memory, reward processing, and processing of social stimuli. Four general conclusions emerged: (1) ELS interferes with microglial developmental programs, including their proliferation and death and their phagocytic activity; (2) this can affect neuronal and non-neuronal developmental processes, which are dynamic during development and for which microglial activity is instrumental; (3) the effects are extremely dependent on the time point at which the investigation is carried out; and (4) both pre- and postnatal ELS can prime microglial reactivity, indicating a long-lasting alteration, which has been implicated in behavioral abnormalities later in life.

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Section: Prenatal Environmental Agents and Infectionmentioning

confidence: 88%

Section: Early Preventative Interventionsmentioning

confidence: 95%

Microglial Function in the Effects of Early-Life Stress on Brain and Behavioral Development

Catale

Gironda

Iacono

et al. 2020

JCM

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“…We developed a preclinical model of perinatal brain injury associated with IUGR by combining gestational LPD (29) with IL-1b injection of the pups. Animals exposed to this double-hit insult showed neuro-inflammation and microglial hyperactivity, detected not only in vivo but also in cultured microglia sorted from the neonatal brain (25,30).…”

Section: Discussionmentioning

confidence: 99%

“…Microglial cells were isolated from CTRL and LPD/IL-1β animals at P4 and P7 and cultured as previously reported (25). CTRL microglial cells were treated with LY 379268 (0.…”

Section: Primary Microglial Cell Culture: Real-time Qpcr and Morpholomentioning

confidence: 99%

mGlu3 receptor regulates microglial cell reactivity in neonatal rats

Zinni

Mairesse

Pansiot

et al. 2020

Preprint

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Background: Perinatal inflammation is a key factor of brain vulnerability in neonates born preterm or with intra-uterine growth restriction (IUGR), two leading conditions associated with brain injury and responsible for neurocognitive and behavioral disorders. Systemic inflammation is recognized to activate microglia, known to be the critical modulators of brain vulnerability. Although some evidence support a role for metabotropic glutamate receptor 3 (mGlu3 receptor) in modulation of neuroinflammation, its functions are still unknown in the developing microglia.Methods: We used a double-hit rat model of perinatal brain injury induced by a gestational low-protein diet combined with interleukin-1β injections (LPD/IL-1β), mimicking both IUGR and prematurity-related inflammation. The effect of LPD/IL-1β on mGlu3 receptor expression and the effect of mGlu3 receptor modulation on microglial reactivity were investigated using a combination of pharmacological, histological, and molecular approaches.Results: Exposure to LPD/IL-1β significantly down-regulated Grm3 gene expression in the developing microglia. Both transcriptomic analyses and pharmacological modulation of mGlu3 receptor demonstrated its central position in the control of inflammation in resting and activated microglia. Microglia hyper-reactivity to inflammatory challenge induced by LPD/IL-1β exposure was reduced by an mGlu3 receptor agonist. Conversely, both specific pharmacological blockade and siRNA knock-down of mGlu3 receptors in control microglia mimicked the pro-inflammatory phenotype observed in microglial cells exposed to LPD/IL-1β.Conclusions: Overall, these data show that Grm3 plays a central role in the regulation of microglial reactivity in the immature brain. Selective pharmacological activation of mGlu3 receptors may prevent inflammatory-induced perinatal brain injury.

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“…Oestrogen and oxytocin levels change in sires . Using different lesion techniques, these hormones have been investigated as possible neuroprotective agents (oestrogen and oxytocinmediated neuroprotection). As a result of the complexity of parental adaptations occurring in the male, more experiments are needed to address the possibility that these hormones, differentially regulated in sires, have a role in the neuroprotective effects observed in the present study.…”

Section: Discussionmentioning

confidence: 99%

Fatherhood diminishes the hippocampal damaging action of excitotoxic lesioning in mice

Anagnostou¹,

Morales²

2019

J Neuroendocrinology

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Parental experience imposes neuroplasticity in the hippocampus of females and males. In lactating rat dams, the hippocampus is protected against excitotoxic damage by kainic acid lesioning, although it is still unknown whether paternity can provide such protection to male rodents. To evaluate the protective effects of fatherhood against excitotoxic lesions, we paired male mice with females and co‐housed them until the day of parturition (PPD0), when we randomly assigned them to two groups: (i) the pregnancy group (males housed individually overnight and injected i.c.v. with 100 ng per 1 μL of kainic acid or vehicle on PPD1) and (ii) the sire group (males housed with the dam and pups until PPD8, when injected i.c.v. after evaluation of parental behaviour). Individually housed virgin adult male mice formed the control group. Markers of neurodegeneration (NeuN, Fluoro‐Jade C) and astrogliosis (glial fibrillary acidic protein) were evaluated in fixed cerebral tissue containing the dorsal CA1, CA3 and CA4 hippocampal subfields. The CA1 subfield did not suffer damage in any of the experimental groups. The sire group exhibited less neurodegeneration and astrogliosis in the CA3 and CA4 subfields compared to their respective controls, independently of the expression of parental behaviour. Western blot analysis was conducted for prolactin (PRL), PRL receptor and related intracellular pathways. Monomeric PRL was lower in the hippocampus of sires in the first week postpartum with a parallel rise of a 48‐kDa dimerised isoform compared to virgin controls. The long isoform of PRL receptor did not change, and signal transducer and activator of transcription 5 (STAT5) was not detected in the hippocampus. However, a sustained rise in pAkt, a signalling molecule that participates in cell survival, was observed in the sire group. These results indicate that the hippocampus of sires housed with the dam and pups is less sensitive to neurotoxic injury, which might not be primarily regulated by PRL‐STAT5‐modulated mechanisms.

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Oxytocin receptor agonist reduces perinatal brain damage by targeting microglia

Cited by 73 publications

References 56 publications

Microglial Function in the Effects of Early-Life Stress on Brain and Behavioral Development

Microglial Function in the Effects of Early-Life Stress on Brain and Behavioral Development

mGlu3 receptor regulates microglial cell reactivity in neonatal rats

Fatherhood diminishes the hippocampal damaging action of excitotoxic lesioning in mice

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