Fructose-1,6-biphosphate prevents excitotoxic neuronal cell death in the neonatal mouse brain

• Published in: Brain research. Developmental brain research Vol. 140; no. 2; pp. 287 - 297
• Main Authors: Rogido, Marta, Husson, Isabelle, Bonnier, Christine, Lallemand, Marie-Christine, Mérienne, Claude, Gregory, George A, Sola, Augusto, Gressens, Pierre
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 16.02.2003
• Subjects: Alanine - analogs & derivatives; Alanine - pharmacology; Animals; Animals, Newborn - physiology; Brain - cytology; Brain - drug effects; Brain - physiology; Cell Survival - drug effects; Cerebral palsy; Enzyme Inhibitors - pharmacology; Female; Fructose-1,6-biphosphate; Fructosediphosphates - pharmacology; Hydrogen-Ion Concentration; Ibotenic Acid - pharmacology; Lactic Acid - metabolism; Male; Mice; Mortality; Neonatal mouse; Neuronal cell death; Neurons - drug effects; Neurons - physiology; Neuroprotective Agents - pharmacology; Neurotoxins - pharmacology; Signal Transduction - drug effects; Cerebral palsy; Neonatal mouse; Fructose-1,6-biphosphate; Development and regeneration; Neuronal cell death
• ISSN: 0165-3806
• DOI: 10.1016/S0165-3806(02)00615-6

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.