how to protect the immature brain?
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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 - PowerPoint PPT PresentationTRANSCRIPT
How to protect the How to protect the immature brain? immature brain?
Chrisitane CHARRIAUT-MARLANGUE, PhD
INSERM/AVENIR U676Children’s Hospital Robert Debré, Paris, France
The Royal Society of MedicineOverseas Meeting, Paris 2010
Brain damages neonatesBrain damages neonates
Term HIE Stroke
Preterm Intraventricular/parenchymal haemorrhage Cystic white matter damage Diffuse white matter damage
Volpe, 2001
Non cystic PVL: Non cystic PVL: the “new” white matter damagethe “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., 2002Inder et al., 1999
Functional consequences of PVLFunctional 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
« PVL window » and brain « PVL window » and brain developmentdevelopment
20 25 32
Neuronal migrationNeuronal migration
astrocytogenesisastrocytogenesis
oligodendrogenesisoligodendrogenesis
Axonal and dendritic growthAxonal and dendritic growth
synaptogenesissynaptogenesis
Programmed cell deathProgrammed cell death
Post-conceptional weeks
Perinatal brain lesions: a Perinatal brain lesions: a multiple hit conceptmultiple hit concept
Perinatal oxidative stress
Inflammation Free radicals
Excitotoxicity
WMD
Repair
New strategies for New strategies for neuroprotection in pretermneuroprotection in preterm
Repair /plasticityRepair /plasticity
glutamate
inflammation Oxidative stress
NMDA AMPA
microglia
cytokines
X
X XMg2+
Mélatonine*Epo*
Topiramate*
Tianeptine*Quinolones*
X
Mélatonine*NO*-estradiol
Mélatonine*NO*Growth factorsCell therapy
Tetracyclines* X
New strategies for perinatal New strategies for perinatal neuroprotectionneuroprotection
Unexpected neuroprotective effect of well-known molecules-Nitric Oxide-Antibiotics-Tianeptine-Melatonin-Erythropoietin-Cannabinoids
New neuroprotective molecules-Magnesium sulfate-Growth factors-estradiol
New neuroprotective strategies-Exogenous stem cells-Neural progenitors
Magnesium sulfate & Magnesium sulfate & excitoxicityexcitoxicity
MgMg2+2+
-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
Marret et al., 1995Crowther et al., 2003Doyle et al., 2009
Fluroquinolones & reduced Fluroquinolones & reduced inflammationinflammation
Ct CTX CIP0
5
10
15 *
*
***
ED
-1 p
ositi
ve c
ells
/ 0
,065m
m2
Ct CTX CIP0
10
20
30
40
50
60
***
MB
P-p
ositi
ve f
ibers
(O
.D.)
E. Coli infectedLoron et al., Ann Neurol revision
ED1
MBP - Anti-inflammatory effect in situ- OLs maturation- Molecular determinant?
Potential new therapeutic agents
Ctrl
1 m
g/kg
10 m
g/kg
30 m
g/kg
Ctrl
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
Follett et al., 2004Sfaello et al., 2005Kurul et al., 2009
excitotoxicity ischaemia
A B
C D
* *
* *
Ctl RCIU
Mel
ato
nin
e
n
on
tra
ité
Mélatonine et Mélatonine et neuroprotectionneuroprotection
Husson et al., 2002Olivier et al., 2009
Perinatal oxidative stress excitotoxicity
Schreiber et al., 2003Van Meurs et al., 2005Mestan et al., 2005
Inhaled NO & outcome of Inhaled NO & outcome of preterm infantspreterm 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
NO, myelination & NO, myelination & neuroprotectionneuroprotection
P7 P14
• Inhaled NO enhances angiogenesis and mylination
• Inhaled NO induces neuroprotection
Ctl iNO5
Olivier et al., JNENPansiot et al. , PlosONE
0
200
400
600
800
1000
1200
Cortical plate White matter
CtliNO20ppm
lesi
on
siz
e (µ
m)
Ibo NMDA Will Ibo NMDA Will
******
*
*
*
Ischemia
ACAs
BT
r.PCAl.PCA
r.MCAl.MCA
Azygos ACA
P Com
r.ICAl.ICA
**
Inhaled NO & neonatal strokeInhaled NO & neonatal stroke
Growth factors & neuroprotectionGrowth factors & neuroprotection
Leptin VIP VEGF BNDF Epo
BDNF
Husson et al., 2005Sizonenko et al., 2007
Cerebral effects of EpoCerebral 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, 2009Brown et al., Pediatrics, 2009
Cell therapy and neural progenitorsCell therapy and neural progenitors
Stem cells:• embryonic, • umbilical cord blood,• mesenchymal, • neural…
Syková et al., 2007
Stem cells from umbilical Stem cells from umbilical cord (hUCMBC, MSC)cord (hUCMBC, MSC)
0
200
400
600
800
1000
1200
PBS (n=20)hUCBMSCs (n=19)
**
taill
e d
e lé
sio
ns
(µm
)
SB
cortex
Neurogenesis and Neurogenesis and neuroprotectionneuroprotection
Burns et al., JCN 2009
Neural growth factorsEpo
Fernando Gómez-Pinilla, 2008
Nutrition & Nutrition & neuroprotectionneuroprotection
- Energy, DHA, parenteral nutrition- Impact on partial brain volume, MDI, verbal IQ
ConclusionConclusion
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