BDNF-induced white matter neuroprotection and stage-dependent neuronal survival following a neonatal excitotoxic challenge.
Excitotoxicity may be critical in the formation of brain lesions associated with cerebral palsy. When injected into the murine neopallium at postnatal day (P) 5, ibotenate (activating NMDA and metabotropic glutamate receptors) produces neuronal death and white matter cysts. Such white matter cysts resemble those seen in periventricular leukomalacia, a lesion evident in numerous human premature newborns. The goal of this study was to assess BDNF neuroprotection against neonatal excitotoxic lesions. Cortical and white matter lesions induced by ibotenate at P5 were reduced by BDNF by up to 36 and 60%, respectively. BDNF neuroprotection involved TrkB receptors, MAPK pathway and reduced apoptosis. Although BDNF did not prevent the initial appearance of white matter lesions, it promoted secondary decrease of the lesion size. BDNF neuroprotection at P5 was maximal against lesions induced by NMDA or ibotenate but was moderate against lesions produced by an AMPA-kainate agonist. Finally, BDNF exacerbated neuronal death produced by ibotenate at P0 through increased apoptosis and p75(NTR) receptors, while BDNF had no detectable effect on lesions induced at P10. Altogether, these data showed that BDNF neuroprotection against neonatal excitotoxicity is dependent upon the type of activated glutamate receptors, the lesion localization and the developmental stage.
INSERM E 9935 & Service de Neuropédiatrie, Hôpital Robert-Debré, F-75019 Paris, France.
Isabelle
I
Husson
Claire-Marie
CM
Rangon
Vincent
V
Lelièvre
Alexis-Pierre
AP
Bemelmans
Philippe
P
Sachs
Jacques
J
Mallet
Barry E
BE
Kosofsky
Pierre
P
Gressens
D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002547:Cerebral Palsy / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D008297:Male; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D018696:Neuroprotective Agents / Q000494:pharmacology; D009498:Neurotoxins
D019208:Brain-Derived Neurotrophic Factor; D018696:Neuroprotective Agents; D009498:Neurotoxins