Huang Jui-Yen, Hong Yu-Ting, Chuang Jih-Ing
Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
J Neurochem. 2009 Jun;109(5):1400-12. doi: 10.1111/j.1471-4159.2009.06061.x. Epub 2009 Mar 25.
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.
氧化应激和营养因子下调参与帕金森病黑质纹状体多巴胺能神经变性的发病机制。成纤维细胞生长因子9（FGF9）是多种细胞类型的存活因子；然而，FGF9对多巴胺能神经元的作用尚未得到研究。抗氧化剂褪黑素可保护多巴胺能神经元免受神经毒性。我们使用MPP（+）在体内和体外诱导神经元死亡，并研究FGF9在MPP（+）中毒和褪黑素保护中的作用。我们发现，MPP（+）以剂量和时间依赖性方式抑制FGF9 mRNA和蛋白表达，并导致原代皮层神经元死亡。用FGF9蛋白处理黑质和中脑细胞培养物中的神经元可抑制MPP（+）诱导的多巴胺能神经元细胞死亡。褪黑素联合处理可减轻MPP（+）在体内和体外诱导的FGF9下调和多巴胺能神经元凋亡。用褪黑素和FGF9中和抗体共同处理多巴胺能神经元可阻止褪黑素的保护作用。在没有MPP（+）的情况下，FGF9中和抗体处理可诱导多巴胺能神经元凋亡，而FGF9蛋白可减少凋亡，这表明内源性FGF9是多巴胺能神经元的存活因子。我们得出结论，MPP（+）下调FGF9表达导致多巴胺能神经元死亡，而预防FGF9下调参与了褪黑素提供的神经保护作用。
