Lentiviral-mediated gene transfer of brain-derived neurotrophic factor is neuroprotective in a mouse model of neonatal excitotoxic challenge.
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.
Bemelmans
Alexis-Pierre
AP
CNRS, UMR 7091, Bâtiment CERVI, Hôpital de la Pitié-Salpétrière, Paris, France. alexis.bemelmans@ophtal.vd.ch
Husson
Isabelle
I
Jaquet
Muriel
M
Mallet
Jacques
J
Kosofsky
Barry E
BE
Gressens
Pierre
P
D000818:Animals; D000831:Animals, Newborn / Q000502:physiology*; D001253:Astrocytes / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics*; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D005260:Female; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins / Q000235:genetics; D015497:HIV-1 / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D007276:Injections, Intraventricular; D016086:Lentivirus / Q000235:genetics*; D008297:Male; D051379:Mice; D016202:N-Methylaspartate / Q000633:toxicity; D018696:Neuroprotective Agents; D009498:Neurotoxins / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D051381:Rats; D011994:Recombinant Proteins / Q000494:pharmacology
D019208:Brain-Derived Neurotrophic Factor; D018076:DNA, Complementary; D018690:Excitatory Amino Acid Agonists; D018696:Neuroprotective Agents; D009498:Neurotoxins; D011994:Recombinant Proteins; D049452:Green Fluorescent Proteins; D016202:N-Methylaspartate