目前研究證實氧化壓力和神經滋養因子含量降低可能是巴金森氏症中多巴胺神經元死亡的原因。除了廣為人知的多種神經滋養因子之外，纖維母細胞生長因子9已知是多種細胞的存活因子，然而纖維母細胞生長因子9對多巴胺神經元的作用仍未被探討。研究證實給予抗氧化物可阻斷因氧化壓力導致的神經滋養因子表現量下降，給予神經滋養因子亦被證實可提升抗氧化酵素的表現量，因此可知氧化壓力與神經滋養因子表現量下降之間的具有交互作用，本研究主要是探討在以1-methyl-4-phenylpyridinium (MPP+)誘發的巴金森氏症模式中纖維母細胞生長因子9的角色與氧化壓力和纖維母細胞生長因子9表現量下降之間的交互作用。此研究主要分為三部份，第一部份是探討纖維母細胞生長因子9否保護多巴胺神經元免於MPP+的神經毒殺，第二部份是探討MPP+是否透過增加氧化壓力而調控纖維母細胞生長因子9的表現量，第三部份為探討抗氧化防禦系統是否參與纖維母細胞生長因子9的神經保護功能。首先，我們在初代皮質神經細胞培養(primary cortical neuron culture)模式下發現MPP+處理細胞後可觀察到纖維母細胞生長因子9的mRNA與蛋白質表現量會在藥物處理4小時與8小時後降低，且在藥物處理48小時後引起神經細胞死亡。在初代皮質神經細胞培養模式與中腦神經細胞培養模式(primary mesencephalic neuron culture)下給予纖維母細胞生長因子9可以保護皮質神經元(cortical neuron)與多巴胺神經細胞免於MPP+的神經毒殺作用。除此之外在以紋狀體注射MPP+的巴金森氏症動物模式中，我們也發現注射纖維母細胞生長因子9到大腦黑質區可以保護神經細胞免於MPP+造成的多巴胺神經細胞流失。因此這些結果指出MPP+造成神經細胞死亡的原因是因為抑制纖維母細胞生長因子9的表現量而致。接著我們發現以過氧化氫(H2O2)處理細胞和MPP+的作用一樣均會降低細胞中纖維母細胞生長因子9 的mRNA表現量，而且抗氧化物褪黑激素可阻斷MPP+造成纖維母細胞生長因子9表現量下降與神經細胞死亡。我們更進一步證明纖維母細胞生長因子9中和抗體(neutralizing antibody)的處理會阻斷褪黑激素的保護多巴胺神經細胞免於MPP+神經毒殺的功能。除此之外在以MPP+誘發的巴金森氏症動物模式中亦可觀察到褪黑激素可保護多巴胺神經細胞與阻斷纖維母細胞生長因子9表現量下降的功能。因此這部份的研究結果證實MPP+是透過增加氧化壓力而使纖維母細胞生長因子9表現量下降，且纖維母細胞生長因子9參與褪黑激素的神經保護功能。最後我們發現纖維母細胞生長因子9可降低活性氧分子的含量、增加抗氧化物glutathione含量、提升抗氧化酵素-glutamylcysteine synthetase (GCS，為glutathione生合成的速率限制酵素) 與heme oxygenase-1 (HO-1)的表現量。而給予GCS與HO-1的抑制劑則可阻斷纖維母細胞生長因子9降低MPP+所造成的活性氧分子的含量增加與保護神經細胞的功能。更進一步我們也發現纖維母細胞生長因子9可活化extracellular regulated kinase 1/2 (ERK1/2)與Akt，而且給予ERK1/2與Akt的活性抑制劑則可阻斷前述纖維母細胞生長因子9的作用，其中包含提升GCS與HO-1 mRNA與蛋白質的表現量、增加glutathione的含量、降低活性氧分子的含量與神經保護功能，除此之外我們也發現在中腦細胞培養模式下，纖維母細胞生長因子9可保護多巴胺神經元免於MPP+所誘發的神經死亡，但其神經保護作用亦會被GCS、HO-1、ERK1/2與PI3K/Akt的抑制劑所阻斷。以上的結果證實纖維母細胞生長因子9可透過活化ERK1/2與Akt訊息傳遞路徑而提升抗氧化酵素GCSc與HO-1進而保護神經細胞免於MPP+的神經毒殺作用。我們的研究結果證實纖維母細胞生長因子9在以MPP+誘發的神經死亡中具有神經保護功能，而且也發現抗氧化防禦系統與纖維母細胞生長因子9在多巴胺神經元的神經保護機轉中具有交互作用。因為MPP+誘發的神經死亡被廣泛的用來探討巴金森氏症的致病機轉，而我們的結果指出纖維母細胞生長因子9可作為治療巴金森氏症的新方向。

Oxidative stress and down-regulation of trophic factors are involved in nigrostriatal dopaminergic neurodegeneration in Parkinson’s disease (PD). Besides the well-known trophic factors, fibroblast growth factor 9 (FGF9) is a survival factor of several types of cell; however, the function of FGF9 in dopaminergic neurons has not been investigated. Moreover studies shown that antioxidant supplement prevents oxidative stress-decreased neurotrophic factor and increasing trophic factor up-regulates antioxidant enzyme expression. These results suggest that there is an interaction between oxidative stress and trophic factor reduction. Therefore, my study was to explore the neuroprotective mechanism of FGF9 in 1-methyl-4-phenylpyridinium (MPP+)-induced parkinsonian model and the interaction between FGF9 down-regulation and oxidative stress. The specific aims of study were to : (1) examine whether FGF9 protected dopaminergic neurons from MPP+ intoxication, (2) examine whether MPP+-induced ROS over-production regulated FGF9 expression, (3) identify the neuroprotective mechanism of FGF9: the involvement of antioxidant defense system. Firstly, we found that MPP+ down-regulated FGF9 mRNA and protein expression 4 h and 8 h after treatment, and caused neuron death 24 h after treatment in primary cortical neurons. Treating neurons with recombinant FGF9 protein inhibited MPP+-induced neuron death in primary cortical neurons and mesencephalic dopaminergic neurons. Intra-striatal infusion of MPP induced dopaminergic neuron loss in substantia nigra (SN) of rats was also inhibited by intra-nigral injection of recombinant FGF9 protein. Results indicated that MPP+ down-regulated FGF9 expression to cause dopaminergic neuron death. Secondly, we found that similar to MPP+, hydrogen peroxide (H2O2) treatment down-regulated FGF9 mRNA expression and antioxidant melatonin prevented MPP+-induced FGF9 down-regulation and neuron death in primary cortical neurons. We also found that FGF9 neutralizing antibody inhibited melatonin-mediated neuroprotection in primary mesencephalic dopaminergic neurons. On the other hand, melatonin prevented MPP+-down-regulated FGF9 mRNA and protein expression in striatum and SN of rats. The results suggested that MPP+ induced oxidative stress to down-regulate FGF9 expression and the involvement of FGF9 in antioxidant melatonin-mediated neuroprotection. Thirdly, we found that FGF9 treatment alone induced a decrease in ROS level, an increase in glutathione content, and up-regulation of catalytic subunit of -glutamylcysteine synthetase (GCSc, a rate limiting enzyme of glutathione biosynthesis) and heme oxygenase-1 (HO-1) expression in primary cortical neurons. Inhibition of GCSc or HO-1 prevented the inhibitory effect of FGF9 on MPP+-induced ROS production and neuron death in primary mesencephalic dopaminergic neurons and cortical neurons. We further found that FGF9 activated extracellular regulated kinase 1/2 (ERK1/2) and phosphatidylinositol 3-kinase (PI3K)/Akt pathway. The inhibition of ERK1/2 and PI3K/Akt prevented FGF9-mediated neuroprotection, ROS reduction, glutathione elevation, and GCSc and HO-1 up-regulation. These results indicated that FGF9 enhanced antioxidant defense system to protect cortical and dopaminergic neurons from MPP+-induced oxidative insult through ERK1/2 and PI3K/Akt pathways. In conclusion, the study indicated that FGF9 is a neuroprotective role in MPP+-induced neurotoxicity and suggested that there is a close interaction between antioxidant defense system and FGF9 in dopaminergic neuroprotection. Because MPP+-induced neuron death is widely considered as parkinsonian model, our results provide a new insight in the potential role of FGF9 on the treatment of PD.

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