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

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MBP - Anti-inflammatory effect in situ- OLs maturation- Molecular determinant?

Potential new therapeutic agents

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500

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TopiramateTopiramate

Follett et al., 2004Sfaello et al., 2005Kurul et al., 2009

excitotoxicity ischaemia

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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

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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)

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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