title: Fructose-1,6-biphosphate prevents excitotoxic neuronal cell death in the neonatal mouse brain.
abstract: The excitotoxic cascade may represent an important pathway leading to brain damage and cerebral palsy. Brain lesions induced in newborn mice by ibotenate (acting on N-methyl-D-aspartate receptors) and by S-bromowillardiine (acting on alpha-3-amino-hydroxy-5-methyl-4-isoxazole propionic acid and kainate receptors) mimic some aspects of white matter cysts and transcortical necrosis observed in human perinatal brain damage. Fructose 1,6-biphosphate (FBP) is a high-energy glycolytic pathway intermediate which, in therapeutic doses, is non-toxic and neuroprotective in hypoxic-ischemic models of brain injury. Mechanisms of action include modulation of intracellular calcium through phospholipase C (PLC) activation. The goal of this study was to determine the neuroprotective effects of FBP in a mouse model of neonatal excitotoxic brain injury. Mice that received intraperitoneal FBP had a significant reduction in size of ibotenate-induced (80% reduction) or S-bromowillardiine-induced (40% reduction) cortical plate lesions when compared with control animals. Studies of fragmented DNA and cleaved caspase 3 confirmed the survival promoting effects of FBP. FBP had no detectable effect on excitotoxic white matter lesions. The effects of FBP were antagonized by co-administration of PLC, protein kinase C or mitogen-associated protein kinase inhibitors but not by protein kinase A inhibitor. A moderate, transient cooling of pups immediately after the insult extended the therapeutic window for FBP, as FBP administered 24 h after ibotenate was still significantly neuroprotective in these pups. This data extends the neuroprotective profile of FBP in neonatal brain injury and identifies gray matter lesions involving N-methyl-D-aspartate receptors as a major target for this promising drug.
authors.affiliation: Division of Neonatology, Emory University, Atlanta, GA, USA.
authors.forename: Marta
authors.initials: M
authors.lastname: Rogido
authors.forename: Isabelle
authors.initials: I
authors.lastname: Husson
authors.forename: Christine
authors.initials: C
authors.lastname: Bonnier
authors.forename: Marie Christine
authors.initials: MC
authors.lastname: Lallemand
authors.forename: Claude
authors.initials: C
authors.lastname: Mérienne
authors.forename: George A
authors.initials: GA
authors.lastname: Gregory
authors.forename: Augusto
authors.initials: A
authors.lastname: Sola
authors.forename: Pierre
authors.initials: P
authors.lastname: Gressens
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn / Q000502:physiology*; D001921:Brain / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005635:Fructosediphosphates / Q000494:pharmacology*; D006863:Hydrogen-Ion Concentration; D007051:Ibotenic Acid / Q000494:pharmacology*; D019344:Lactic Acid / Q000378:metabolism; D008297:Male; D051379:Mice; D009026:Mortality; D009474:Neurons / Q000187:drug effects* / Q000502:physiology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009498:Neurotoxins / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D004791:Enzyme Inhibitors; D005635:Fructosediphosphates; D018696:Neuroprotective Agents; D009498:Neurotoxins; C068592:5-bromowillardiine; D007051:Ibotenic Acid; D019344:Lactic Acid; C029063:fructose-1,6-diphosphate; D000409:Alanine