The physiological and pharmacological role of basic fibroblast growth factor in the dopaminergic nigrostriatal system.
Basic fibroblast growth factor (FGF-2) is a physiological relevant neurotrophic factor in the nigrostriatal system and hence a promising candidate for the establishment of alternative therapeutic strategies in Parkinson's disease. FGF-2 and its high-affinity receptors (FGFR) display an expression in the developing, postnatal, and adult substantia nigra (SN) and in the striatum. Exogenous application promoted survival, neurite outgrowth and protection from neurotoxin-induced death of dopaminergic (DA) neurons both in vitro and in vivo. In animal models of Parkinson's disease, co-transplantation of fetal DA cells with FGF-2 expressing cells increased survival and functional integration of the grafted DA neurons resulting in improved behavioral performance. Analyzing the physiological function of the endogenous FGF-2 system during development and after neurotoxin-induced lesion revealed for the DA neurons of the SNpc a dependence on FGFR3 signaling during development. In addition, in the absence of FGF-2 an increased number of DA neurons was found, whereas enhanced levels of FGF-2 resulted in a reduced DA cell density. Following neurotoxin-induced lesion of DA neurons, FGF-2-deleted mice displayed a higher extent of DA neuron death whereas in FGF-2 overexpressing mice more DA neurons were protected. According to the data, FGF-2 seems to promote DA neuron survival via FGFR3 during development, whereas absence of this ligand could be compensated by other members of the FGF family. In contrast, in the adult organism, FGF-2 cannot be compensated by other factors under lesion conditions suggesting a central role for this molecule in the nigrostriatal system.
Grothe
Claudia
C
Department of Neuroanatomy, Hannover Medical School, OE 4140, Center for Systems Neuroscience Hannover (ZSN), Carl-Neuberg-Strasse 1, 30625 Hannover, Germany. grothe.claudia@mh-hannover.de
Timmer
Marco
M
D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D003342:Corpus Striatum / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010300:Parkinson Disease / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D017468:Receptors, Fibroblast Growth Factor / Q000819:agonists / Q000378:metabolism; D013378:Substantia Nigra / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism*
D017468:Receptors, Fibroblast Growth Factor; D016222:Fibroblast Growth Factor 2; D004298:Dopamine