neuroprotection in preterm infants: hope or utopy?
DESCRIPTION
International conference «Actual approaches to the extremely preterm babies: International experience and Ukrainian realities» (Kyiv, Ukraine, March 5-6, 2013)TRANSCRIPT
NeuroprotectionNeuroprotection
in preterm infants:in preterm infants:
hope or hope or utopyutopy? ?
Olivier BAUD, MD, PhD
INSERM U676
Children’s Hospital Robert Debré, Paris, France
The International Neonatology Conference, Kiev 6th march 2013
Brain damages neonatesBrain damages neonates
� Term
� HIE
� Stroke
� Preterm� Intraventricular/parenchymal haemorrhage↓� Cystic white matter damage ↓� Diffuse white matter damage ↑
Volpe, 2001, 2009
Non cystic PVL: Non cystic PVL: the the ““newnew”” white matter damagewhite 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
Functional consequences of PVLFunctional 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
WMD and WMD and brainbrain developmentdevelopment
20 25 32
Neuronal migrationNeuronal migration
astrocytogenesisastrocytogenesis
oligodendrogenesisoligodendrogenesis
AxonalAxonal and and dendriticdendritic growthgrowth
synaptogenesissynaptogenesis
ProgrammedProgrammed cellcell deathdeath
Post-conceptional weeks
PerinatalPerinatal brainbrain lesionslesions: a multiple : a multiple hit concepthit concept
Preterm labor
Inflammation Free radicals
Excitotoxicity
WMD
Repair
Main Main targetstargets for for neuroprotectionneuroprotection in in pretermpreterm
RepairRepair //plasticityplasticity
glutamate
inflammation Oxidative stress
NMDA AMPA
microglia
cytokines
X
X XMg2+
Melatonin
Epo
Xenon
Topiramate
Tianeptine
Quinolones
X
Melatonin
iNO
E2
Melatonin
iNO
Growth factors
Cell therapy
Tetracyclines
Steroids
X
ShortcomingsShortcomings in in neuroprotectionneuroprotection of the of the
pretermpreterm brainbrain
� 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
StrategiesStrategies for for perinatalperinatal neuroprotectionneuroprotection
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
MelatoninMelatonin and and circadian rhythmcircadian rhythm
Claustrat et al. Restorative Neurology 1998
No rhythmic secretion in newborn
A B
C D
* *
* *
Ctl RCIU
Me
lato
nin
PB
S
MelatoninMelatonin (ROS+(ROS+inflaminflam++excitoexcito))
Husson et al., 2002
Olivier et al., 2009
Perinatal oxidative stress excitotoxicity
Bouslama et al., 2007
Welin et al., 2007
Villapol et al., 2010
Mouse P5: excitotoxicity model
Rat P7 : hypoxia-ischemia model
Fetal sheep: ischemia model
NeuroprotectiveNeuroprotective effects of Melatonineffects of Melatonin
in animal modelsin animal models
Learning disorders
Periventricular white matter damage
Mechanisms
Direct free radical scavenging
OLs maturation
Excitotoxicity modulation
Neuroprotection
Melatonin in Preterm
3 animal models
of WM damage
MELIP
Melatonin deficiency
Pharmacokinetic studyOptimal regimen of administration
Therapeutic trial
WM damage, MRI 40 GA
MelatoninMelatonin as as neuroprotectantneuroprotectant for for pretermpreterm infants: infants:
a 3a 3--stepssteps proofproof--ofof--concept concept researchresearch programprogram
1
2
3
MagnesiumMagnesium sulfate sulfate (NMDA)(NMDA)
MgMg2+2+
-NMDA receptors blocker
-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
Ctr
l
1 m
g/kg
10 m
g/kg
30 m
g/kg
Ctr
l
1 m
g/kg
10 m
g/kg
30 m
g/kg
0
250
500
750
1000
cortical plate white matter
*
**
*Lesi
on s
ize
(µm
)
TopiramateTopiramate (AMPA)(AMPA)
Follett et al., 2004
Sfaello et al., 2005
Kurul et al., 2009
excitotoxicity ischaemia
FluroquinolonesFluroquinolones (inflammation)(inflammation)
Ct CTX CIP0
5
10
15 *
****
ED-1
pos
itive
cel
ls /
0,06
5mm
2
Ct CTX CIP0
10
20
30
40
50
60
***
MB
P-po
sitiv
e fib
ers
(O.D
.)
E. Coli infectedLoron et al., 2011
Le Saché et al., 2011
ED1
MBP - Anti-inflammatory effect in situ
- OLs maturation
- Molecular determinant?
Potential new therapeutic agents
Schreiber et al., 2003
Van Meurs et al., 2005
Mestan et al., 2005
InhaledInhaled NO & NO & outcomeoutcome of of pretermpreterminfantsinfants
- 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
NO, NO, myelinationmyelination& & neuroprotectionneuroprotection
P7 P14
• Inhaled NO enhances angiogenesis and myelination
• Inhaled NO induces neuroprotection
Ctl iNO5
Olivier et al., 2010
Pansiot et al. , 2011
0
200
400
600
800
1000
1200
Cortical plate White matter
CtliNO20ppm
lesi
on s
ize
(µm
)Ibo NMDA Will Ibo NMDA Will
******
*
*
*
NO, NO, myelinationmyelination& & neuroprotectionneuroprotection
P7 P14 Pham et al., AJRCCM 2012
Ischemia
ACAs
BT
r.PCAl.PCA
r.MCAl.MCA
Azygos ACA
P Com
r.ICAl.ICA
**
InhaledInhaled NO & NO & neonatalneonatal strokestroke
Bonnin et al., 2012
Charriaut-Marlangue et al., 2012
iNOiNO isis neuroprotectiveneuroprotective……
……but not but not atat anyany time and not time and not atat anyany dose!dose!
iNO induces benefits on neonatal stroke only at
low dose and during ischemia
GrowthGrowth factorsfactors & & neuroprotectionneuroprotection
� Leptin
� VIP
� VEGF
� BDNF
� Epo
BDNF
Husson et al., 2005
Sizonenko et al., 2007
PBS BDNF
CerebralCerebral effectseffects of Epoof Epo
� Cellular effects
� ↓↓↓↓ apoptosis
� ↑↑↑↑ angiogenesis
� ↓↓↓↓ inflammation
� ↓↓↓↓ excitotoxicity
� ↓↓↓↓ oxidative stress
� Neuroprotective effects in human adults
� ↓↓↓↓ lesion size of adult stroke
� ↓↓↓↓ handicap
� ↓↓↓↓ paraplegia after medullarysection
� 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
Melatonine Epo NAC Epo
mimetics
Allopurinol Xenon Vit C&E Memantine Topiramate Adenosine
A2A rec antag
nNOS
inh
BH4
Easy of use 10 10 10 10 7 4 9 3 4 5 1 1
Loading
dose
7 7 7 7 8 6 6 5 4 5 1 1
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
/50
45 43 40 38 36 34 33 27 25 22 5 5
Ranking
% score
1 (90%) 2 (86%) 3 (80%) 4 (76%) 5 (72%) 6 (68%) 7 (66%) 8 (54%) 9 (50%) 10 (44%) 11 (10%)
Ranking of potential Ranking of potential
neuroprotectants in the newbornneuroprotectants in the newborn
From Robertson et al., 2012
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
Ballard et al., 2006
- Lower incidence of severe IVH/PVL in ELGA- Decreased neurodevelopmental disability in ELGA
Melatonin antioxidant Gitto et al., 2004, 2005, 2012
- Anti-inflammatory effects and improves clinical outcome (BPD)- Additional analgesic therapy during procedural pain in LGA
Allopurinol antioxidant Clancy et al., 2001
Benders et al., 2006
- Neurocardiac protection in HLHS infants- Postnatal treatment had no effect in HIE
Magnesium sulfate Anti-excitotoxic Doyle et al., cochrane 2009
Established neuroprotection in VLGA but NNT 63
HumanHuman StudiesStudies of of NeuroprotectantsNeuroprotectants
Gonzalez and Ferriero, 2009
Cell therapy and neural progenitorsCell therapy and neural progenitors
Stem cells:• embryonic, • umbilical cord blood,• mesenchymal, • neural…
Syková et al., 2007
Umbilical cord: stem cells from Umbilical cord: stem cells from
blood and Wharton jellyblood and Wharton jelly
CBMNCCBMNC UCMSCUCMSC
Umbilical cordUmbilical cord--derived stem cellsderived 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
NeuroprotectiveNeuroprotective mechanismmechanism(s) of (s) of
UCdUCd stem stem cellscells
- 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
NeurogenesisNeurogenesis and and neuroprotectionneuroprotection
Burns et al., JCN 2009
Neural growth factorsEpo
ConclusionConclusion
� Neuroprotection of the developing brain is feasible
� Many pharmacological strategies based on better underst ood physiopathology
� Ongoing proof-of-concept studies :� Melatonin� EPO� iNO� …
� Many new promising strategies in the pipeline
AknowledgmentsAknowledgments
� U676:� C Charriaut-Marlangue� H Pham� J Pansiot� G Loron� J Dalous� P Olivier� J Gallego� P Gressens
� NICU & Robert Debré:� V Biran� C Alberti� L Maury
� PremUP foundation:� D Evain-Brion� L Bordarier� ML Hamon
� Supports:� INSERM� PremUP� IKARIA� Paris Diderot Univ� Mairie de Paris