Fibroblast growth factors and neuroprotection.
Several members of the FGF family, in particular FGF2, are intimately involved in neuronal protection and repair after ischemic, metabolic or traumatic brain injury. Expression of Fgf2 mRNA and protein is strongly upregulated after neuronal damage, with glial cells as the predominant source. Given its survival-promoting effects on cultured neurons, exogenous FGF2 was tested in several animal models of stroke and excitotoxic damage, in which it consistently proved protective against neuronal loss. FGF2 affords neuroprotection by interfering with a number of signaling pathways, including expression and gating of NMDA receptors, maintenance of Ca2+ homeostasis and regulation of ROS detoxifying enzymes. FGF2 prevents apoptosis by strengthening anti-apoptotic pathways and promotes neurogenesis in adult hippocampus after injury. The protective action of FGF2 has been linked to its augmenting effect on the lesion-induced upregulation of activin A, a member of the TGF-beta superfamily. Despite the well-documented benefits of FGF2 in animal models of stroke, there is currently no clinical development in stroke, after a phase II/III trial with FGF2 in acute stroke patients was discontinued because of an unfavorable risk-to-benefit ratio. As the molecular targets of FGF2 are going to be unraveled over the next years, new therapeutic strategies will hopefully emerge that enable us to influence the various protective mechanisms of FGF2 in a more specific fashion.
Alzheimer
Christian
C
Institute of Physiology, University of Munich, Pettenkoferstr. 12, D-80336 Munich, Germany.
Werner
Sabine
S
D028341:Activins / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001921:Brain / Q000166:cytology / Q000378:metabolism; D001930:Brain Injuries / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D028322:Inhibin-beta Subunits / Q000378:metabolism; D007608:Kainic Acid / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D005810:Multigene Family; D009457:Neuroglia / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism; D018092:Kainic Acid Receptors / Q000378:metabolism
D028341:Activins; D002118:Calcium; D005346:Fibroblast Growth Factors; D028322:Inhibin-beta Subunits; D007608:Kainic Acid; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D017468:Receptors, Fibroblast Growth Factor; D018092:Kainic Acid Receptors; C422405:activin A