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Accueil > Agenda > Les séminaires Jean Roche > Impact de la neuroinflammation sur le développement cérébral.

Impact de la neuroinflammation sur le développement (...)

Lundi 8 septembre 2014 - 11 heures.

Docteur Pierre GRESSENS UMR 1141 INSERM, Hôpital Robert Debré, Paris 7.

Impact de la neuroinflammation sur le développement cérébral.

Invitée par José BOUCRAUT – CRN2M UMR7286 - tél : 04 91 69 87 50.

Séminaire ouvert au public.

Nouvelle salle de conférence du secteur Nord de la Faculté de Médecine, rdc nord bâtiment E, 51 boulevard Pierre Dramard CS80011 - 13 344 Marseille cedex 15.

BIBLIOGRAPHIE :

1. Biochem Soc Trans. 2014 Apr ;42(2):557-63. doi : 10.1042/BST20130284. Brain damage of the preterm infant : new insights into the role of inflammation. Van Steenwinckel J, Schang AL, Sigaut S, Chhor V, Degos V1, Hagberg H, Baud O, Fleiss B, Gressens P.

Author information : 1*Inserm, U1141, F-75019 Paris, France. Abstract

Epidemiological studies have shown a strong association between perinatal infection/inflammation and brain damage in preterm infants and/or neurological handicap in survivors. Experimental studies have shown a causal effect of infection/inflammation on perinatal brain damage. Infection including inflammatory factors can disrupt programmes of brain development and, in particular, induce death and/or blockade of oligodendrocyte maturation, leading to myelin defects. Alternatively, in the so-called multiple-hit hypothesis, infection/inflammation can act as predisposing factors, making the brain more susceptible to a second stress (sensitization process), such as hypoxic-ischaemic or excitotoxic insults. Epidemiological data also suggest that perinatal exposure to inflammatory factors could predispose to long-term diseases including psychiatric disorders.

PMID : 24646278 [PubMed - in process]

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2. Clin Perinatol. 2014 Mar ;41(1):133-48. doi : 10.1016/j.clp.2013.09.002. Epub 2013 Dec 12. Stem cell therapy for neonatal brain injury. Fleiss B1, Guillot PV2, Titomanlio L3, Baud O3, Hagberg H4, Gressens P5.

Author information : 1Inserm U676, Paris, 75019, France ; University Paris Diderot, Sorbonne Paris Cité, UMRS 676, Paris, 75019, France ; PremUP, Paris, 75019, France ; Department of Perinatal Imaging and Health, Department of Division of Imaging Sciences and Biomedical Engineering, King’s College London, King’s Health Partners, St. Thomas’ Hospital, London, SE1 7EH, UK. 2UCL Institute for Women’s Health, University College London, London, WC1E 6HX, UK. 3Inserm U676, Paris, 75019, France ; University Paris Diderot, Sorbonne Paris Cité, UMRS 676, Paris, 75019, France ; PremUP, Paris, 75019, France. 4Department of Perinatal Imaging and Health, Department of Division of Imaging Sciences and Biomedical Engineering, King’s College London, King’s Health Partners, St. Thomas’ Hospital, London, SE1 7EH, UK ; Department of Clinical Sciences, Sahlgrenska Academy/East Hospital, 416 85 Gothenburg, Sweden ; Department of Physiology and Neuroscience, Perinatal Center, Sahlgrenska Academy, Gothenburg University, 40530, Gothenburg, Sweden. 5Inserm U676, Paris, 75019, France ; University Paris Diderot, Sorbonne Paris Cité, UMRS 676, Paris, 75019, France ; PremUP, Paris, 75019, France ; Department of Perinatal Imaging and Health, Department of Division of Imaging Sciences and Biomedical Engineering, King’s College London, King’s Health Partners, St. Thomas’ Hospital, London, SE1 7EH, UK. Electronic address : pierre.gressens inserm.fr. Abstract

This article introduces the basic concepts of modeling neonatal brain injury and provides background information regarding each of the commonly used types of stem cells. It summarizes the findings of preclinical research testing the therapeutic potential of stem cells in animal models of neonatal brain injury, reports briefly on the status of clinical trials, and discusses the important ongoing issues that need to be addressed before stem cell therapy is used to repair the injured brain.

Copyright © 2014 Elsevier Inc. All rights reserved.

PMID : 24524451 [PubMed - in process]

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3. Ann Neurol. 2013 May ;73(5):667-78. doi : 10.1002/ana.23868. Epub 2013 Mar 14. G protein-coupled receptor kinase 2 and group I metabotropic glutamate receptors mediate inflammation-induced sensitization to excitotoxic neurodegeneration. Degos V1, Peineau S, Nijboer C, Kaindl AM, Sigaut S, Favrais G, Plaisant F, Teissier N, Gouadon E, Lombet A, Saliba E, Collingridge GL, Maze M, Nicoletti F, Heijnen C, Mantz J, Kavelaars A, Gressens P.

Author information : 1Inserm, U676, Hôpital Robert Debré, Paris, France. Abstract OBJECTIVE :

The concept of inflammation-induced sensitization is emerging in the field of perinatal brain injury, stroke, Alzheimer disease, and multiple sclerosis. However, mechanisms underpinning this process remain unidentified. METHODS :

We combined in vivo systemic lipopolysaccharide-induced or interleukin (IL)-1β-induced sensitization of neonatal and adult rodent cortical neurons to excitotoxic neurodegeneration with in vitro IL-1β sensitization of human and rodent neurons to excitotoxic neurodegeneration. Within these inflammation-induced sensitization models, we assessed metabotropic glutamate receptors (mGluR) signaling and regulation. RESULTS :

We demonstrate for the first time that group I mGluRs mediate inflammation-induced sensitization to neuronal excitotoxicity in neonatal and adult neurons across species. Inflammation-induced G protein-coupled receptor kinase 2 (GRK2) downregulation and genetic deletion of GRK2 mimicked the sensitizing effect of inflammation on excitotoxic neurodegeneration. Thus, we identify GRK2 as a potential molecular link between inflammation and mGluR-mediated sensitization. INTERPRETATION :

Collectively, our findings indicate that inflammation-induced sensitization is universal across species and ages and that group I mGluRs and GRK2 represent new avenues for neuroprotection in perinatal and adult neurological disorders.

Copyright © 2013 American Neurological Association. PMCID : PMC3837433 Free PMC Article

PMID : 23494575 [PubMed - indexed for MEDLINE]

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4. Anesthesiology. 2013 May ;118(5):1123-32. doi : 10.1097/ALN.0b013e318286cf36. Neuroprotective effects of dexmedetomidine against glutamate agonist-induced neuronal cell death are related to increased astrocyte brain-derived neurotrophic factor expression. Degos V1, Charpentier TL, Chhor V, Brissaud O, Lebon S, Schwendimann L, Bednareck N, Passemard S, Mantz J, Gressens P.

Author information : 1Inserm, U676, Paris, France, Université Paris 7, Paris, France. degosv gmail.com Abstract BACKGROUND :

Brain-derived neurotrophic factor (BDNF) plays a prominent role in neuroprotection against perinatal brain injury. Dexmedetomidine, a selective agonist of α2-adrenergic receptors, also provides neuroprotection against glutamate-induced damage. Because adrenergic receptor agonists can modulate BDNF expression, our goal was to examine whether dexmedetomidine’s neuroprotective effects are mediated by BDNF modulation in mouse perinatal brain injury. METHODS :

The protective effects against glutamate-induced injury of BDNF and dexmedetomidine alone or in combination with either a neutralizing BDNF antibody or an inhibitor of the extracellular signal-regulated kinase pathway (PD098059) were compared in perinatal ibotenate-induced cortical lesions (n = 10-20 pups/groups) and in mouse neuronal cultures (300 μM of ibotenate for 6 h). The effect of dexmedetomidine on BDNF expression was examined in vivo and in vitro with cortical neuronal and astrocyte isolated cultures. RESULTS :

Both BDNF and dexmedetomidine produced a significant neuroprotective effect in vivo and in vitro. Dexmedetomidine enhanced Bdnf4 and Bdnf5 transcription and BDNF protein cortical expression in vivo. Dexmedetomidine also enhanced Bdnf4 and Bdnf5 transcription and increased BDNF media concentration in isolated astrocyte cultures but not in neuronal cultures. Dexmedetomidine’s protective effect was inhibited with BDNF antibody (mean lesion size ± SD : 577 ± 148 μm vs. 1028 ± 213 μm, n = 14-20, P < 0.001) and PD098059 in vivo but not in isolated neuron cultures. Finally, PD098059 inhibited the increased release of BDNF induced by dexmedetomidine in astrocyte cultures. CONCLUSION :

These results suggest that dexmedetomidine increased astrocyte expression of BDNF through an extracellular signal-regulated kinase-dependent pathway, inducing subsequent neuroprotective effects. Free Article

PMID : 23353792 [PubMed - indexed for MEDLINE]

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5. Stem Cells. 2013 Apr ;31(4):652-65. doi : 10.1002/stem.1295. Conditional induction of Math1 specifies embryonic stem cells to cerebellar granule neuron lineage and promotes differentiation into mature granule neurons. Srivastava R1, Kumar M, Peineau S, Csaba Z, Mani S, Gressens P, El Ghouzzi V.

Author information : 1Inserm, U676, Paris, France. Abstract

Directing differentiation of embryonic stem cells (ESCs) to specific neuronal subtype is critical for modeling disease pathology in vitro. An attractive means of action would be to combine regulatory differentiation factors and extrinsic inductive signals added to the culture medium. In this study, we have generated mature cerebellar granule neurons by combining a temporally controlled transient expression of Math1, a master gene in granule neuron differentiation, with inductive extrinsic factors involved in cerebellar development. Using a Tetracyclin-On transactivation system, we overexpressed Math1 at various stages of ESCs differentiation and found that the yield of progenitors was considerably increased when Math1 was induced during embryonic body stage. Math1 triggered expression of Mbh1 and Mbh2, two target genes directly involved in granule neuron precursor formation and strong expression of early cerebellar territory markers En1 and NeuroD1. Three weeks after induction, we observed a decrease in the number of glial cells and an increase in that of neurons albeit still immature. Combining Math1 induction with extrinsic factors specifically increased the number of neurons that expressed Pde1c, Zic1, and GABAα6R characteristic of mature granule neurons, formed "T-shaped" axons typical of granule neurons, and generated synaptic contacts and action potentials in vitro. Finally, in vivo implantation of Math1-induced progenitors into young adult mice resulted in cell migration and settling of newly generated neurons in the cerebellum. These results show that conditional induction of Math1 drives ESCs toward the cerebellar fate and indicate that acting on both intrinsic and extrinsic factors is a powerful means to modulate ESCs differentiation and maturation into a specific neuronal lineage.

Copyright © 2012 AlphaMed Press.

PMID : 23225629 [PubMed - indexed for MEDLINE]

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6. Ann Neurol. 2012 Oct ;72(4):536-49. doi : 10.1002/ana.23626. Activation of microglial N-methyl-D-aspartate receptors triggers inflammation and neuronal cell death in the developing and mature brain. Kaindl AM1, Degos V, Peineau S, Gouadon E, Chhor V, Loron G, Le Charpentier T, Josserand J, Ali C, Vivien D, Collingridge GL, Lombet A, Issa L, Rene F, Loeffler JP, Kavelaars A, Verney C, Mantz J, Gressens P.

Author information : 1French Institute of Health and Medical Research U676, Robert Debré Hospital, Paris, France. angela.kaindl charite.de Abstract OBJECTIVE :

Activated microglia play a central role in the inflammatory and excitotoxic component of various acute and chronic neurological disorders. However, the mechanisms leading to their activation in the latter context are poorly understood, particularly the involvement of N-methyl-D-aspartate receptors (NMDARs), which are critical for excitotoxicity in neurons. We hypothesized that microglia express functional NMDARs and that their activation would trigger neuronal cell death in the brain by modulating inflammation. METHODS AND RESULTS :

We demonstrate that microglia express NMDARs in the murine and human central nervous system and that these receptors are functional in vitro. We show that NMDAR stimulation triggers microglia activation in vitro and secretion of factors that induce cell death of cortical neurons. These damaged neurons are further shown to activate microglial NMDARs and trigger a release of neurotoxic factors from microglia in vitro, indicating that microglia can signal back to neurons and possibly induce, aggravate, and/or maintain neurologic disease. Neuronal cell death was significantly reduced through pharmacological inhibition or genetically induced loss of function of the microglial NMDARs. We generated Nr1 LoxP(+/+) LysM Cre(+/-) mice lacking the NMDAR subunit NR1 in cells of the myeloid lineage. In this model, we further demonstrate that a loss of function of the essential NMDAR subunit NR1 protects from excitotoxic neuronal cell death in vivo and from traumatic brain injury. INTERPRETATION :

Our findings link inflammation and excitotoxicity in a potential vicious circle and indicate that an activation of the microglial NMDARs plays a pivotal role in neuronal cell death in the perinatal and adult brain.

Copyright © 2012 American Neurological Association.

PMID : 23109148 [PubMed - indexed for MEDLINE]

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7. Ann Neurol. 2012 Apr ;71(4):444-57. doi : 10.1002/ana.22620. Epub 2012 Feb 14. Inflammation during fetal and neonatal life : implications for neurologic and neuropsychiatric disease in children and adults. Hagberg H1, Gressens P, Mallard C.

Author information : 1Department of Obstetrics and Gynecology, Institute of Clinical Sciences, Sahlgrenska Academy, Gothenburg University, Sweden. henrik.hagberg obgyn.gu.se Abstract

Inflammation is increasingly recognized as being of both physiological and pathological importance in the immature brain. The rationale of this review is to present an update on this topic with focus on long-term consequences of inflammation during childhood and in adults. The immature brain can be exposed to inflammation in connection with viral or bacterial infection during pregnancy or as a result of sterile central nervous system (CNS) insults. Through efficient anti-inflammatory and reparative processes, inflammation may resolve without any harmful effects on the brain. Alternatively, inflammation contributes to injury or enhances CNS vulnerability. Acute inflammation can also be shifted to a chronic inflammatory state and/or adversely affect brain development. Hypothetically, microglia are the main immunocompetent cells in the immature CNS, and depending on the stimulus, molecular context, and timing, these cells will acquire various phenotypes, which will be critical regarding the CNS consequences of inflammation. Inflammation has long-term consequences and could speculatively modify the risk of a variety of neurological disorders, including cerebral palsy, autism spectrum disorders, schizophrenia, multiple sclerosis, cognitive impairment, and Parkinson disease. So far, the picture is incomplete, and data mostly experimental. Further studies are required to strengthen the associations in humans and to determine whether novel therapeutic interventions during the perinatal period can influence the occurrence of neurological disease later in life.

Copyright © 2012 American Neurological Association.

PMID : 22334391 [PubMed - indexed for MEDLINE]

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