Lentiviral-mediated gene transfer of brain-derived neurotrophic factor is neuroprotective in a mouse model of neonatal excitotoxic challenge

Autor: Pierre Gressens, Isabelle Husson, Muriel Jaquet, Jacques Mallet, Barry E. Kosofsky, Alexis-Pierre Bemelmans
Přispěvatelé: Génétique moléculaire de la neurotransmission et des processus neurodégénératifs (LGMNPN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Physiopathologie, conséquences fonctionnelles et neuroprotection des atteintes du cerveau en développement, Université Paris Diderot - Paris 7 (UPD7)-IFR2-Institut National de la Santé et de la Recherche Médicale (INSERM)
Rok vydání: 2006
Předmět:
Male
Excitotoxicity
MESH: Brain-Derived Neurotrophic Factor
medicine.disease_cause
MESH: Animals
Newborn
MESH: HIV-1
MESH: Recombinant Proteins
Mice
0302 clinical medicine
MESH: Genetic Vectors
Neurotrophic factors
Excitatory Amino Acid Agonists
MESH: Animals
MESH: Lentivirus
0303 health sciences
Gene Transfer Techniques
MESH: Enzyme-Linked Immunosorbent Assay
MESH: Neuroprotective Agents
Recombinant Proteins
MESH: N-Methylaspartate
Neuroprotective Agents
NMDA receptor
Female
MESH: Injections
Intraventricular
medicine.symptom
DNA
Complementary
N-Methylaspartate
MESH: Rats
Genetic Vectors
Green Fluorescent Proteins
Neurotoxins
MESH: Gene Transfer Techniques
Enzyme-Linked Immunosorbent Assay
Brain damage
Biology
Neuroprotection
Viral vector
03 medical and health sciences
Cellular and Molecular Neuroscience
MESH: Green Fluorescent Proteins
medicine
Animals
Humans
[SDV.BBM]Life Sciences [q-bio]/Biochemistry
Molecular Biology
MESH: Mice
MESH: Neurotoxins
Injections
Intraventricular
030304 developmental biology
Brain-derived neurotrophic factor
MESH: Humans
Periventricular leukomalacia
Brain-Derived Neurotrophic Factor
Lentivirus
MESH: DNA
Complementary
medicine.disease
MESH: Male
Rats
MESH: Hela Cells
MESH: Astrocytes
Animals
Newborn
nervous system
Astrocytes
HIV-1
MESH: Excitatory Amino Acid Agonists
MESH: Female
Neuroscience
030217 neurology & neurosurgery
HeLa Cells
Zdroj: Journal of Neuroscience Research
Journal of Neuroscience Research, 2006, 83 (1), pp.50-60. ⟨10.1002/jnr.20704⟩
Journal of Neuroscience Research, Wiley, 2006, 83 (1), pp.50-60. ⟨10.1002/jnr.20704⟩
ISSN: 1097-4547
0360-4012
DOI: 10.1002/jnr.20704
Popis: Excitotoxicity may be a critical factor in the formation of brain lesions associated with cerebral palsy. When injected into the murine neopallium at postnatal day 5, the glutamatergic analog N-methyl-D-aspartate (NMDA) produces transcortical neuronal death and periventricular white matter cysts, which mimic brain damage observed in human term and preterm neonates at risk for developing cerebral palsy. We previously showed that intracerebral injection of brain-derived neurotrophic factor (BDNF) was neuroprotective in this model. Because BDNF does not easily cross the blood-brain barrier, alternative strategies to avoid repeated intracerebral injections of BDNF should be tested, particularly when the goal of such translational research is ultimately to achieve clinical application. The goal of the present study was to assess the protective role of lentiviral-mediated gene transfer of BDNF against excitotoxic lesions induced by NMDA in newborn mice. We first assessed the biological activity of BDNF gene transfer in vitro and determined the efficiency of gene transfer in our in vivo model. We next administered the BDNF-expressing vector by intracerebral injection in neonatal mice, 3 days before inducing NMDA lesions. When compared with a control green fluorescent protein-expressing lentiviral vector, administration of BDNF-expressing vector induced a significant protection of the periventricular white matter and cortical plate against the NMDA-mediated insult. Intraventricular delivery of the BDNF-expressing lentiviral vector was more efficient in terms of neuroprotection than the intraparenchymal route. Altogether, the present study shows that viral-mediated gene transfer of BDNF to newborn mouse brain is feasible and affords significant neuroprotection against an excitotoxic insult.
Databáze: OpenAIRE
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