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How to protect the immature brain?

How to protect the immature brain?. Chrisitane CHARRIAUT-MARLANGUE, PhD INSERM/AVENIR U676 Children’s Hospital Robert Debré, Paris, France. The Royal Society of Medicine Overseas Meeting, Paris 2010. Brain damages neonates. Term HIE Stroke Preterm

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How to protect the immature brain?

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  1. How to protect the immature brain? Chrisitane CHARRIAUT-MARLANGUE, PhD INSERM/AVENIR U676 Children’s Hospital Robert Debré, Paris, France The Royal Society of Medicine Overseas Meeting, Paris 2010

  2. Brain damages neonates • Term • HIE • Stroke • Preterm • Intraventricular/parenchymal haemorrhage • Cystic white matter damage • Diffuse white matter damage Volpe, 2001

  3. Non cystic PVL: the “new” white matter damage • Mostly observed in very preterm infant: MRI features detected near term • Risk factors: VLBW-ELBW, perinatal infection/inflammation, postnatal steroids, BPD • Associated with myelination defect, reduction in cortical volumes Nosarti et al., 2002 Inder et al., 1999

  4. Functional consequences of PVL • Motor deficit (Little) • Oral, constructional dyspraxia • Visual-perceptal impairment (optic radiations) • Feeding and deglutition disorders • Cognitive impairment • Comportemental deficits (ADHD) • Psychiatric disorders (autism) +++ - Axonal damage (association and projection fibers) - Quantitative decrease of Oligodendrocytes

  5. « PVL window » and brain development 20 25 32 Post-conceptional weeks Neuronal migration astrocytogenesis oligodendrogenesis Axonal and dendritic growth synaptogenesis Programmed cell death

  6. Perinatal brain lesions: a multiple hit concept Perinatal oxidative stress InflammationFree radicals Excitotoxicity WMD Repair

  7. New strategies for neuroprotection in preterm AMPA NMDA X X Mg2+ Mélatonine* Epo* Topiramate* glutamate Mélatonine* NO* b-estradiol microglia X Tetracyclines* X Oxidative stress inflammation Tianeptine* Quinolones* Mélatonine* NO* Growth factors Cell therapy X cytokines Repair /plasticity

  8. New strategies for perinatal neuroprotection • Unexpected neuroprotective effect of well-known molecules • Nitric Oxide • Antibiotics • Tianeptine • Melatonin • Erythropoietin • Cannabinoids • New neuroprotective molecules • Magnesium sulfate • Growth factors • b-estradiol • New neuroprotective strategies • Exogenous stem cells • Neural progenitors

  9. Magnesium sulfate & excitoxicity • NMDA receptors blocker • Preclinical prevention of developing WM • No perinatal side effects • Demonstrated benefits (gross motor dysfunction and CP) in preterm infants • No effect in asphyxiated term infants Mg2+ Marret et al., 1995 Crowther et al., 2003 Doyle et al., 2009

  10. Fluroquinolones & reduced inflammation ED1 MBP - Anti-inflammatory effect in situ - OLs maturation - Molecular determinant? Potential new therapeutic agents E. Coli infected Loron et al., Ann Neurol revision

  11. Topiramate ischaemia excitotoxicity Follett et al., 2004 Sfaello et al., 2005 Kurul et al., 2009

  12. Mélatonine et neuroprotection Perinatal oxidative stress excitotoxicity Ctl RCIU B A * * Melatonine non traité C D * * Husson et al., 2002 Olivier et al., 2009

  13. Inhaled NO & outcome of preterm infants - INO was associated with a lower incidence of brain damage in preterm infants - 2y outcome revealed a better MDI - No side effect - These data must be confirmed Schreiber et al., 2003 Van Meurs et al., 2005 Mestan et al., 2005

  14. NO, myelination & neuroprotection Ctl iNO5 * *** *** * * Ibo NMDA Will Ibo NMDA Will • Inhaled NO enhances angiogenesis and mylination • Inhaled NO induces neuroprotection Olivier et al., JNEN Pansiot et al. , PlosONE P14 P7

  15. BT r.PCA l.PCA ** P Com l.ICA r.ICA ACAs Ischemia l.MCA r.MCA Azygos ACA Inhaled NO & neonatal stroke

  16. Growth factors & neuroprotection Leptin VIP VEGF BNDF Epo BDNF Husson et al., 2005 Sizonenko et al., 2007

  17. Cerebral effects of Epo • Cellular effects •  apoptosis •  angiogenesis •  inflammation •  excitotoxicity •  oxidative stress • Neuroprotective effects in animal models •  lesion size of adult stroke •  handicap •  paraplegia after medullary section • Epo and neuroprotection in human •  MDI •  CP after HIE • High doses safe in preterm Strunk et al., 2004 Zhu et al., Pediatrics, 2009 Brown et al., Pediatrics, 2009

  18. Celltherapy and neural progenitors • Stem cells: • embryonic, • umbilical cord blood, • mesenchymal, • neural… Syková et al., 2007

  19. Stem cellsfromumbilicalcord (hUCMBC, MSC) cortex SB

  20. Neurogenesis and neuroprotection Neural growth factors Epo Burns et al., JCN 2009

  21. Nutrition & neuroprotection - Energy, DHA, parenteral nutrition - Impact on partial brain volume, MDI, verbal IQ Fernando Gómez-Pinilla, 2008

  22. Conclusion Neuroprotection of the developing brain is feasible Many pharmacological strategies based on better understood physiopathology Proof of concept studies in progress: Melatonin EPO NO … Many new promising strategies in the pipeline

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