Mechanisms of bFGF and NT-4 potentiation of necrotic neuronal death.
The effects of neurotrophic factors on necrotic neuronal death are controversial. In this study we found that both neurotrophin-4 (NT-4) and basic fibroblast growth factor (bFGF) potentiated necrotic neuronal death caused by exposure to oxygen-glucose deprivation or iron-citrate (Fe) in cortical cultures. However, there were significant differences in the actions of the two neurotrophic factors. Neurotrophin-4 protected against apoptotic neuronal death, while bFGF had no effect on apoptotic death in these cultures. Furthermore, potentiation of oxygen-glucose deprivation induced necrotic death by NT-4 required pretreatment (24 h), while pretreatment with bFGF had no effect. However, acute treatment with bFGF during oxygen-glucose deprivation did potentiate neuronal death. Both neurotrophic factors potentiated free radical mediated necrotic neuronal death induced by exposure to Fe. However, the RNA synthesis inhibitor, actinomycin-D, blocked the injury potentiation by NT-4, but not that caused by bFGF. Also, NT-4, but not bFGF, potentiated Fe induced necrotic death in pure neuronal cultures. Expression of mRNA for FGF receptors FGFR1 and FGFR2 was observed at high levels in astrocytes. The results indicate that the injury enhancing effects of bFGF are acute, while those of NT-4 require prolonged exposure and new protein synthesis. Furthermore, the effects of bFGF appear to be mediated through actions on astrocytes, while NT-4 appears to act directly on neurons. The fact that neurotrophic factors from two distinct families can potentiate neuronal death by two different mechanisms suggests that such injury potentiation may be a common concern regarding the use of neurotrophic factors.
Lobner
Doug
D
Department of Biomedical Sciences and Integrative Neuroscience Research Center, Marquette University, 561 N. 15th Street, Rm 426, Milwaukee, WI 53233, USA. doug.lobner@marquette.edu
Ali
Carine
C
D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003609:Dactinomycin; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D005947:Glucose / Q000172:deficiency; D058085:Iron Compounds / Q000633:toxicity; D051379:Mice; D009336:Necrosis; D009414:Nerve Growth Factors / Q000378:metabolism / Q000494:pharmacology*; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009543:Nifedipine / Q000494:pharmacology; D010100:Oxygen; D016133:Polymerase Chain Reaction; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D051496:Receptor, Fibroblast Growth Factor, Type 1; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics; D013997:Time Factors; D014665:Vasodilator Agents / Q000494:pharmacology
D058085:Iron Compounds; D009414:Nerve Growth Factors; D017468:Receptors, Fibroblast Growth Factor; D014665:Vasodilator Agents; D016222:Fibroblast Growth Factor 2; D003609:Dactinomycin; C496349:Fgfr1 protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; D009543:Nifedipine; D005947:Glucose; C073922:neurotrophin 4; D010100:Oxygen