Fructose-1,6-biphosphate prevents excitotoxic neuronal cell death in the neonatal mouse brain
(2003) Developmental Brain Research — Vol. 140, n° 2, p. 287-297 (2003)
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- 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.
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Rogido, M., Husson, I., Bonnier, C., Lallemand, M.-C., Mérienne, C., Gregory, G. A., Sola, A., & Gressens, P. (2003). Fructose-1,6-biphosphate prevents excitotoxic neuronal cell death in the neonatal mouse brain. Developmental Brain Research, 140(2), 287-297. https://doi.org/10.1016/s0165-3806(02)00615-6 (Original work published 2003)