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Neuroprotection in preterm infants: hope or utopy?
- 1. Neuroprotection in preterm infants: hope or utopy? Olivier BAUD, MD, PhD INSERM U676 Children’s Hospital Robert Debré, Paris, France The International Neonatology Conference, Kiev 6th march 2013
- 2. Brain damages neonates Term HIE Stroke Preterm Intraventricular/parenchymal haemorrhage ↓ Cystic white matter damage ↓ Diffuse white matter damage ↑ Volpe, 2001, 2009
- 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. 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. WMD 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 Preterm labor Inflammation Free radicals Excitotoxicity WMD Repair
- 7. Main targets for neuroprotection in preterm NMDA AMPA Mg2+ Melatonin X X Topiramate Epo Xenon glutamate Melatonin microglia iNO Tetracyclines X E2 Steroids inflammation X Oxidative stress Tianeptine Melatonin Quinolones X iNO cytokines Growth factors Cell therapy Repair /plasticity
- 8. Shortcomings in neuroprotection of the preterm 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. 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. Melatonin and circadian rhythm No rhythmic secretion in newborn Claustrat et al. Restorative Neurology 1998
- 11. Melatonin (ROS+inflam+excito) Perinatal oxidative stress excitotoxicity Ctl RCIU A B * * PBS C D Melatonin * * Husson et al., 2002 Olivier et al., 2009
- 12. Neuroprotective effects of Melatonin in animal models Mouse P5: excitotoxicity model Periventricular white matter damage Rat 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. 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. 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. Topiramate (AMPA) excitotoxicity ischaemia 1000 Lesion 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. 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. Inhaled NO & outcome of preterm infants - 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. 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. NO, myelination & neuroprotection P7 P14 Pham et al., AJRCCM 2012
- 20. Inhaled NO & neonatal stroke BT l.PCA r.PCA P Com l.ICA r.ICA ACAs Ischemia l.MCA r.MCA ** Azygos ACA Bonnin et al., 2012 Charriaut-Marlangue et al., 2012
- 21. iNO is neuroprotective… …but not at any time and not at any dose! iNO induces benefits on neonatal stroke only at low dose and during ischemia
- 22. Growth factors & neuroprotection Leptin VIP VEGF BDNF PBS BDNF Epo BDNF Husson et al., 2005 Sizonenko et al., 2007
- 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. 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 inh Easy of use 10 10 10 10 7 4 9 3 4 5 1 1 Loading 7 7 7 7 8 6 6 5 4 5 1 1 dose SAE 10 8 10 8 8 8 6 6 5 8 1 1 Neurotox 10 10 10 7 10 8 8 10 9 2 1 1 Benefits 8 8 3 6 3 8 4 3 3 5 1 1 FDA oui oui oui non oui non oui oui oui non non oui Score 45 43 40 38 36 34 33 27 25 22 5 5 /50 Ranking 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. Human Studies of Neuroprotectants Treatment Mechanism Study Primary outcome Hypothermia multiple many Proven benefits and NNT 6-8 EPO growth factor Jull et al., 2008 High dose EPO safe in ELGA infants iNO antioxidant Scheiber et al., 2006 - Lower incidence of severe IVH/PVL in ELGA Ballard et al., 2006 - Decreased neurodevelopmental disability in ELGA Melatonin antioxidant Gitto et al., 2004, - Anti-inflammatory effects and 2005, 2012 improves clinical outcome (BPD) - Additional analgesic therapy during procedural pain in LGA Allopurinol antioxidant Clancy et al., 2001 - Neurocardiac protection in HLHS infants Benders et al., 2006 - Postnatal treatment had no effect in HIE Magnesium sulfate Anti-excitotoxic Doyle et al., cochrane Established neuroprotection in 2009 VLGA but NNT 63 Gonzalez and Ferriero, 2009
- 26. Cell therapy and neural progenitors Stem cells: • embryonic, • umbilical cord blood, • mesenchymal, • neural… Syková et al., 2007
- 27. Umbilical cord: stem cells from blood and Wharton jelly CBMNC UCMSC
- 28. Umbilical cord-derived stem cells Advantages • 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 storage Limits • 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. Neuroprotective mechanism(s) of UCd stem cells - Immuno-modulation of systemic and/or local inflammation - Enhancement of endogenous repair: -growth factor -apoptotic cell death -endogenous stem cells? - Marginal engraftment and transdifferenciation Van Velthoven et al., 2012 Dalous et al., 2012
- 30. Neurogenesis and neuroprotection Neural growth factors Epo Burns et al., JCN 2009
- 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. 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