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Nutrition et lésion du cerveau en développement: Neuroprotection par la lactoferrin des lésions cérébrales du prématuré

English title Nutritional intervention for developmental brain damage: Neuroprotection with lactoferrin in models of preterm brain injury
Applicant Sizonenko Stéphane
Number 135581
Funding scheme Project funding (Div. I-III)
Research institution Service de Développement et Croissance Département de Pédiatrie Hôpital des Enfants - HUG
Institution of higher education University of Geneva - GE
Main discipline Neurophysiology and Brain Research
Start/End 01.08.2011 - 31.12.2014
Approved amount 288'000.00
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All Disciplines (3)

Discipline
Neurophysiology and Brain Research
Paediatrics
Nutritional Research, Vitaminology

Keywords (7)

Brain injury; Developing brain; hypoxia-ischemia; inflammation; magnetic resonance imaging; preterm infant; Lactoferrin

Lay Summary (English)

Lead
Lay summary

Preterm infants are at high risk ofbrain injury that can lead to severe neurological disorders, cognitivedeficits, delayed neurodevelopment and psychiatric diseases requiring specialeducation and health needs with high human, social and economic costs.

Preterm brain damage, results in acutetissue injury and healing and modification of the subsequent cerebraldevelopment and plasticity leading to a specific pattern of myelination deficitand grey matter loss.

Lactoferrinß (LF) is a milk protein, with roles in the iron metabolism, in the regulation of immune response and has antioxidant activities.Supplementation in preterm infants appears to reduce infection and necrotisingenterocolitis. High level is found in human milk. Secretion in colostrum, milk and transport fromintestine into the brain are highly regulated. A role of lactoferrin in braindevelopment is suggested.

Using a prenatal stress rat model during gestation, we have induced developmentalalteration of brain structure, metabolism and function. Supplementation of damsduring gestation and lactation with LF reverted most of these alterations through neurotrophic factors. Therefore, LF appearsas a promising therapeutic intervention to protect the developing brain acute injury.

We aim to study acute cerebral damage and repair after LF nutritional intervention in the developing brain using a multi-modal approach of high field in vivo magnetic resonance imaging, functional cortical somatosensory evoked potential and behaviour in neonatal rat models of brain injury. The potential of the combination of the in vivo techniques with detailed neuropathological assessment in our models of preterm brain injury will further delineate the effects of therapeutic intervention with LF.

A protective action of LF on thedeveloping brain in addition to the recently described protective effects ongut inflammation and systemic infection in the preterm infant, would give tothis nutritional supplement a major role in neonatal care of preterm infants. 

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Lactoferrin and prematurity: a promising milk protein?
T. J. Ochoa, S. V. Sizonenko (2017), Lactoferrin and prematurity: a promising milk protein?, in Biochemestry and Cell Biology, 95, 22-30.
Lactoferrin during lactation reduces lipopolysaccharide-induced brain injury
Vanessa Ginet, Yohan van de Looij, Volodymyr Petrenko, Audrey Toulotte, Jozsef Kiss, Petra S. Hüppi, Ste phane V Sizonenko (2016), Lactoferrin during lactation reduces lipopolysaccharide-induced brain injury, in Biofactors, 42(3), 323-336.
Lactoferrin during lactation protects the immature hypoxic- ischemic rat brain
Van de Looij Yohan, Ginet Vanessa, Chatagner Alexandra, Toulotte Audrey, Huppi Petra, Sizonenko Stéphane (2014), Lactoferrin during lactation protects the immature hypoxic- ischemic rat brain, in Annals of Clinical and Translational Neurology, 1-13.
MRI of animal models of developmental disorders and translation to human imaging
Van de Looij Yohan, Vasung Lana, Sizonenko stéphane, Huppi Petra (2014), MRI of animal models of developmental disorders and translation to human imaging, in Current Opinion in Neurology, 27(2), 157-167.
Investigation of field and diffusion time dependence of the diffusion-weighted signal at ultrahigh magnetic fields
Kunz Nicolas, Sizonenko Stéphane V., Huppi Petra S., Gruetter Rolf, van de Looij Yohan (2013), Investigation of field and diffusion time dependence of the diffusion-weighted signal at ultrahigh magnetic fields, in NMR in Biomedicine, 26(10), 1251-1257.

Collaboration

Group / person Country
Types of collaboration
Prof Jozsef Kiss. Départ. De Neurosciences Fondamentales, Faculté de Médecine de Genève Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
- Exchange of personnel

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
European Academy of Paediatrics Talk given at a conference Lactoferrin: a milk protein to protect the developing brain?. 22.10.2016 Genève, Switzerland Sizonenko Stéphane;
European Society for Pediatric Research Poster LACTOFERRIN IN INFLAMMATORY NEONATAL RAT BRAIN INJURY: 
 A NUTRIENT FOR NEUROPROTECTION? 18.10.2014 Barcelone, Spain Gruetter Rolf; Sizonenko Stéphane;
NICU and Brain Development conference Talk given at a conference Brain injury in the preterm brain : A translational approach 23.09.2014 Shangai, China Sizonenko Stéphane;
European Neonatal Brain Club Talk given at a conference Nutrient for neuroprotection : Lactoferrin ? 05.09.2014 Noordwijk, Netherlands Sizonenko Stéphane;
The Hershey conference on Developmental Brain Injury Poster Neuroprotective effect of Lactoferrin in inflammatory neonatal rat brain injury 03.06.2014 St Michaels, Maryland, United States of America Sizonenko Stéphane;
International Society for Magnetic Resonance in Medicine Talk given at a conference Neuroprotective effect of Lactoferrin following inflammatory injury in the developing rat brain assessed by high-field 1H-MR Spectroscopy 10.05.2014 Milan, Italy Gruetter Rolf; Hüppi Petra; Van de Looij Yohan;
International Society for Magnetic Resonance in Medicine Poster Correlations between different sources of contrast at 9.4T: diffusion vs. susceptibility. 10.05.2014 Milan, Italy Hüppi Petra; Van de Looij Yohan; Gruetter Rolf;
Paediatric Academic Societies-Society for Paediatric Research Talk given at a conference Neuroprotective effect of Lactoferrin in inflammatory neonatal rat brain injury assessed by high-field 1H-MR Spectroscopy 03.05.2014 Vancouver, United States of America Hüppi Petra; Sizonenko Stéphane;
International Union of Nutritional Science Talk given at a conference Advanced imaging techniques to study brain development in nutritional interventions. Biomarkers of response to dietary interventions. 19.10.2013 Grenade, Spain Sizonenko Stéphane;
Société Suisse de Pédiatrie Talk given at a conference Food for neuroprotection: Assessment of lactoferrin after hypoxic-ischemic injury in the neonatal rat brain 20.06.2013 Genève, Switzerland Hüppi Petra; Sizonenko Stéphane;
Experimental Biology Talk given at a conference Understanding brain imaging and translating outcomes: Structural and functional MRI techniques in early development. 20.04.2013 Boston, United States of America Sizonenko Stéphane;
European Society for Pediatric Research Poster Nutrient for neuroprotection: MRI assessment of Lactoferrin supplementation after HI injury in the P3 rat brain 06.10.2012 Istanbul, Turkey Sizonenko Stéphane; Hüppi Petra;
The Hershey Conference on Developmental Brain Injury Poster Nutrient for neuroprotection: Lactoferrin supplementation after the P3 rat brain HI injury. Structural and metabolic assessment using multimodal MRI. 03.05.2012 Londres, Great Britain and Northern Ireland Sizonenko Stéphane;
Paediatric Academic Societies Talk given at a conference Neuroprotective Effect of Dam Lactoferrin Supplementation on P3 Rat Brain HI Injury: Structural and Metabolic Assessment Using Multimodal MRI. 01.05.2012 Boston, United States of America Hüppi Petra; Sizonenko Stéphane; Van de Looij Yohan; Chatagner Alexandra;
International Society for Magnetic Resonance in Medicine Poster Lactoferrin supplementation following Hypoxia-Ischemia in the immature rat brain: macro-, micro-structural and metabolic assessment of the neuroprotective effect using multimodal MR 13.04.2012 Melbourne, Australia Hüppi Petra; Van de Looij Yohan; Gruetter Rolf;


Knowledge transfer events

Active participation

Title Type of contribution Date Place Persons involved
International Life Science Institute Europe, Symposium 2014 Talk 21.03.2014 Bruxelles, Belgium Sizonenko Stéphane;


Awards

Title Year
Magna Cum Laude Merit Award for the 20th Annual ISMRM meeting. Y. van de Looij, A. Chatagner, P. Hüppi, R. Gruetter, S. Sizonenko. Lactoferrin supplementation following Hypoxia-Ischemia in the immature rat brain: macro-, micro-structural and metabolic assessment of the neuroprotective effect using multimodal MR. ISMRM 2012, Melbourne, Australia. 2012

Associated projects

Number Title Start Funding scheme
112233 Neuroprotection in perinatal brain injury: Multi-modal approach using advanced magnetic resonance imaging, histopathological and somatosensory functional analysis 01.01.2007 Project funding (Div. I-III)
124101 From cortex to classroom: enhancing brain development for premature infants 01.10.2009 SPUM

Abstract

1.Research summaryPreterm infants are at high risk of brain injury that can lead to severe neurological disorders, cognitive deficits, delayed neurodevelopment and psychiatric diseases requiring special education and health needs with high human, social and economic costs.Hypoxia-Ischemia (HI) and inflammation (INF) are major triggers of preterm brain damage, with acute tissue injury and healing and with modification of the subsequent cerebral development and plasticity leading to a specific pattern of myelination deficit and grey matter loss. Despite similar pattern of resulting damage, the mechanisms of acute injury are different. Lactoferrin ß (LF) is an iron-binding glycoprotein, with roles in the iron uptake and homeostasis, in the regulation of immune response and it has antioxidant activities. Supplementation in pre-term infants appears to reduce sepsis and necrotising enterocolitis. High level is found in human milk. Secretion in colostrum, milk and transport from intestine to brain are highly regulated. LF binding sites are present in brain endothelial capillary cells and it is actively transported into the brain. A role of lactoferrin in brain development is suggested. Using a prenatal stress rat model by dexamethasone exposure during gestation, we have induced developmental alteration of brain structure, metabolism and function. Supplementation of dams during gestation and lactation with LF reverted most of these alterations possibly through the neurotrophic factors BDNF and NGF. Therefore, LF appears as a promising therapeutic interven-tion to protect the developing brain.We aim to study cerebral damage and repair after LF nutritional intervention in the developing brain using a multi-modal approach of high field in vivo magnetic resonance imaging, functional cortical somatosensory evoked potential and behaviour in neonatal rat models of cerebral HI and INF injuries. The potential of the combination of the in vivo techniques with detailed neuro-pathological assessment in HI and INF models will further delineate the effects of therapeutic intervention with LF.A protective action of LF on the developing brain in addition to the recently described protective effects on gut inflammation and systemic infection in the preterm infant, would give to this nutri-tional supplement a major role in neonatal therapies.
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