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Neuroprotection in preterm infants: hope or utopy?

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International conference «Actual approaches to the extremely preterm babies: International experience and Ukrainian realities» (Kyiv, Ukraine, March 5-6, 2013)

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Neuroprotection in preterm infants: hope or utopy?

  1. 1. Neuroprotectionin preterm infants:hope or utopy?Olivier BAUD, MD, PhDINSERM U676Children’s Hospital Robert Debré, Paris, FranceThe International Neonatology Conference, Kiev 6th march 2013
  2. 2. Brain damages neonatesTerm HIE StrokePreterm Intraventricular/parenchymal haemorrhage ↓ Cystic white matter damage ↓ Diffuse white matter damage ↑ Volpe, 2001, 2009
  3. 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, involvement of SP neurons leading to reduction in cortical volumes Nosarti et al., 2002 Inder et al., 1999 Woodward et al., 2006
  4. 4. Functional consequences of PVL Motor deficit (Little) Executive 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. 5. WMD and brain development 20 25 32 Post-conceptional weeksNeuronal migration astrocytogenesis oligodendrogenesis Axonal and dendritic growth synaptogenesis Programmed cell death
  6. 6. Perinatal brain lesions: a multiplehit concept Preterm labor Inflammation Free radicals Excitotoxicity WMD Repair
  7. 7. Main targets for neuroprotection inpreterm NMDA AMPA Mg2+ Melatonin X X Topiramate Epo Xenon glutamate Melatonin microglia iNOTetracyclines X E2Steroids inflammation X Oxidative stress Tianeptine Melatonin Quinolones X iNO cytokines Growth factors Cell therapy Repair /plasticity
  8. 8. Shortcomings in neuroprotection of thepreterm brain False candidate molecules Not accurate design or preclinical model Experimental biases Wrong rationale/endpoints Confounding variables (sex, T°C, care, stress…) Methodological biases (power+++, variability…) Responders vs non-responders Sick vs healthy models
  9. 9. Strategies for perinatal neuroprotection 1- Unexpected neuroprotective effect of well-known molecules -Magnesium sulfate -Nitric Oxide -Antibiotics -Tianeptine -Melatonin -Erythropoietin -Allopurinol -NAC 2- New neuroprotective molecules -Growth factors −β-estradiol -A2A rec antagonist -Xenon 3- New neuroprotective strategies -Exogenous stem cells -Neural progenitors
  10. 10. Melatonin and circadian rhythm No rhythmic secretion in newborn Claustrat et al. Restorative Neurology 1998
  11. 11. Melatonin (ROS+inflam+excito) Perinatal oxidative stress excitotoxicity Ctl RCIU A B * *PBS C DMelatonin * * Husson et al., 2002 Olivier et al., 2009
  12. 12. Neuroprotective effects of Melatonin in animal modelsMouse P5: excitotoxicity model Periventricular white matter damageRat P7 : hypoxia-ischemia model Learning disorders Fetal sheep: ischemia model Direct free radical scavenging Mechanisms OLs maturation Excitotoxicity modulation Bouslama et al., 2007 Welin et al., 2007 Villapol et al., 2010
  13. 13. Melatonin as neuroprotectant for preterm infants:a 3-steps proof-of-concept research program Neuroprotection 3 animal models of WM damage Melatonin in Preterm MELIP Melatonin deficiency 1 Pharmacokinetic study Optimal regimen of administration 2 Therapeutic trial WM damage, MRI 40 GA 3
  14. 14. Magnesium sulfate (NMDA) -NMDA receptors blocker Mg2+ -Preclinical prevention of developing WM -Safe for neonates but potential side effects in mothers -Demonstrated benefits (gross motor dysfunction and CP) in preterm infants… … but NNT = 63 mothers to save one CP! -No effect in asphyxiated term infants Marret et al., 1995 Crowther et al., 2003 Doyle et al., 2009
  15. 15. Topiramate (AMPA) excitotoxicity ischaemia 1000Lesion size (µm) 750 * 500 ** * 250 0 Ctrl Ctrl 1 mg/kg 10 mg/kg 30 mg/kg 1 mg/kg 10 mg/kg 30 mg/kg cortical plate white matter Follett et al., 2004 Sfaello et al., 2005 Kurul et al., 2009
  16. 16. Fluroquinolones (inflammation) 15 ED1 * ***ED-1 positive cells / 0,065mm2 * 10 5 0 Ct CTX CIP MBP - Anti-inflammatory effect in situ 60 - OLs maturation 50 - Molecular determinant? MBP-positive fibers (O.D.) *** 40 30 20 10 0 Potential new therapeutic agents Ct CTX CIP Loron et al., 2011 E. Coli infected Le Saché et al., 2011
  17. 17. Inhaled NO & outcome of preterminfants - iNO was finally 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
  18. 18. NO, myelination & neuroprotection 1200 Ctl iNO5 Ctl 1000 iNO20ppm lesion size (µm) * 800 *** 600 *** * 400 * 200 0 Ibo NMDA Will Ibo NMDA Will• Inhaled NO enhances angiogenesis and myelination Cortical plate White matter• Inhaled NO induces neuroprotection Olivier et al., 2010 P7 P14 Pansiot et al. , 2011
  19. 19. NO, myelination& neuroprotection P7 P14 Pham et al., AJRCCM 2012
  20. 20. Inhaled NO & neonatal stroke BT l.PCA r.PCA P Com l.ICA r.ICA ACAsIschemia l.MCA r.MCA ** Azygos ACA Bonnin et al., 2012 Charriaut-Marlangue et al., 2012
  21. 21. iNO is neuroprotective……but not at any time and not at any dose!iNO induces benefits on neonatal stroke only atlow dose and during ischemia
  22. 22. Growth factors & neuroprotection Leptin VIP VEGF BDNF PBS BDNF Epo BDNF Husson et al., 2005 Sizonenko et al., 2007
  23. 23. Cerebral effects of Epo Cellular effects Neuroprotective effects in human adults ↓ apoptosis ↓ lesion size of adult stroke ↑ angiogenesis ↓ handicap ↓ inflammation ↓ paraplegia after medullary section ↓ excitotoxicity ↓ oxidative stress Epo and neuroprotection in human neonates ↑ MDI ↓ CP after HIE High doses safe in preterm Strunk et al., 2004 Zhu et al., Pediatrics, 2009 Brown et al., Pediatrics, 2009
  24. 24. Ranking of potential neuroprotectants in the newborn Melatonine Epo NAC Epo Allopurinol Xenon Vit C&E Memantine Topiramate Adenosine nNOS BH4 mimetics A2A rec antag inhEasy of use 10 10 10 10 7 4 9 3 4 5 1 1Loading 7 7 7 7 8 6 6 5 4 5 1 1doseSAE 10 8 10 8 8 8 6 6 5 8 1 1Neurotox 10 10 10 7 10 8 8 10 9 2 1 1Benefits 8 8 3 6 3 8 4 3 3 5 1 1FDA oui oui oui non oui non oui oui oui non non ouiScore 45 43 40 38 36 34 33 27 25 22 5 5/50Ranking 1 (90%) 2 (86%) 3 (80%) 4 (76%) 5 (72%) 6 (68%) 7 (66%) 8 (54%) 9 (50%) 10 (44%) 11 (10%)% score From Robertson et al., 2012
  25. 25. Human Studies of NeuroprotectantsTreatment Mechanism Study Primary outcomeHypothermia multiple many Proven benefits and NNT 6-8EPO growth factor Jull et al., 2008 High dose EPO safe in ELGA infantsiNO antioxidant Scheiber et al., 2006 - Lower incidence of severe IVH/PVL in ELGA Ballard et al., 2006 - Decreased neurodevelopmental disability in ELGAMelatonin antioxidant Gitto et al., 2004, - Anti-inflammatory effects and 2005, 2012 improves clinical outcome (BPD) - Additional analgesic therapy during procedural pain in LGAAllopurinol antioxidant Clancy et al., 2001 - Neurocardiac protection in HLHS infants Benders et al., 2006 - Postnatal treatment had no effect in HIEMagnesium sulfate Anti-excitotoxic Doyle et al., cochrane Established neuroprotection in 2009 VLGA but NNT 63 Gonzalez and Ferriero, 2009
  26. 26. Cell therapy and neural progenitors Stem cells: • embryonic, • umbilical cord blood, • mesenchymal, • neural… Syková et al., 2007
  27. 27. Umbilical cord: stem cells fromblood and Wharton jelly CBMNC UCMSC
  28. 28. Umbilical cord-derived stem cellsAdvantages• rich source of various stem cells• No potential ethical issues• easily available with no harm to the infant or mother• low immunogenicity• international standards for sampling and storageLimits• Few and conflicting data on efficacy• Major concerns in pre-clinical models (injection route, cell tracking,variability…)• Discrepancy between « emotional infatuation » and scientific reality
  29. 29. Neuroprotective mechanism(s) of UCd stem cells- Immuno-modulation of systemic and/orlocal inflammation- Enhancement of endogenous repair: -growth factor -apoptotic cell death -endogenous stem cells?- Marginal engraftment andtransdifferenciation Van Velthoven et al., 2012 Dalous et al., 2012
  30. 30. Neurogenesis and neuroprotection Neural growth factors Epo Burns et al., JCN 2009
  31. 31. Conclusion Neuroprotection of the developing brain is feasible Many pharmacological strategies based on better understood physiopathology Ongoing proof-of-concept studies : Melatonin EPO iNO … Many new promising strategies in the pipeline
  32. 32. Aknowledgments U676: NICU & Robert Debré: C Charriaut-Marlangue V Biran H Pham C Alberti J Pansiot L Maury G Loron J Dalous P Olivier J Gallego Supports: P Gressens INSERM PremUP PremUP foundation: IKARIA D Evain-Brion Paris Diderot Univ L Bordarier Mairie de Paris ML Hamon

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