Fibroblast growth factor 9 prevents MPP+-induced death of dopaminergic neurons and is involved in melatonin neuroprotection in vivo and in vitro.
Oxidative stress and down-regulated trophic factors are involved in the pathogenesis of nigrostriatal dopamine(DA)rgic neurodegeneration in Parkinson's disease. Fibroblast growth factor 9 (FGF9) is a survival factor for various cell types; however, the effect of FGF9 on DA neurons has not been studied. The antioxidant melatonin protects DA neurons against neurotoxicity. We used MPP(+) to induce neuron death in vivo and in vitro and investigated the involvement of FGF9 in MPP(+) intoxication and melatonin protection. We found that MPP(+) in a dose- and time-dependent manner inhibited FGF9 mRNA and protein expression, and caused death in primary cortical neurons. Treating neurons in the substantia nigra and mesencephalic cell cultures with FGF9 protein inhibited the MPP(+)-induced cell death of DA neurons. Melatonin co-treatment attenuated MPP(+)-induced FGF9 down-regulation and DA neuronal apoptosis in vivo and in vitro. Co-treating DA neurons with melatonin and FGF9-neutralizing antibody prevented the protective effect of melatonin. In the absence of MPP(+), the treatment of FGF9-neutralizing antibody-induced DA neuronal apoptosis whereas FGF9 protein reduced it indicating that endogenous FGF9 is a survival factor for DA neurons. We conclude that MPP(+) down-regulates FGF9 expression to cause DA neuron death and that the prevention of FGF9 down-regulation is involved in melatonin-provided neuroprotection.
Huang
Jui-Yen
JY
Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Hong
Yu-Ting
YT
Chuang
Jih-Ing
JI
D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity*; D000818:Animals; D000831:Animals, Newborn; D000906:Antibodies / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D051525:Fibroblast Growth Factor 9 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006540:Herbicides / Q000633:toxicity*; D008297:Male; D008550:Melatonin / Q000494:pharmacology*; D008636:Mesencephalon / Q000166:cytology; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013778:Tetrazolium Salts; D013844:Thiazoles; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D000906:Antibodies; C498813:Fgf20 protein, rat; D051525:Fibroblast Growth Factor 9; D005904:Glial Fibrillary Acidic Protein; D006540:Herbicides; C489787:MAP2 protein, rat; D008869:Microtubule-Associated Proteins; D018696:Neuroprotective Agents; D013778:Tetrazolium Salts; D013844:Thiazoles; D005346:Fibroblast Growth Factors; D014446:Tyrosine 3-Monooxygenase; C022616:thiazolyl blue; D008550:Melatonin; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine