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研究生:石靜婷
研究生(外文):Ching-TingShih
論文名稱:跑步運動訓練活化 TrkB/ERK路徑進而抑制MPP+所誘發的 Nrf2 表現量下降及多巴胺神經元死亡
論文名稱(外文):TrkB/ERK signal is involved in exercise-induced the prevention of Nrf2 downregulation and neuron loss after MPP+treatment
指導教授:莊季瑛莊季瑛引用關係
指導教授(外文):Jih-Ing Chuang
學位類別:碩士
校院名稱:國立成功大學
系所名稱:生理學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2012
畢業學年度:100
語文別:英文
論文頁數:65
中文關鍵詞:帕金森氏症運動TrkBNrf2
外文關鍵詞:exerciseTrkBNrf2
相關次數:
  • 被引用被引用:0
  • 點閱點閱:173
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  • 下載下載:8
  • 收藏至我的研究室書目清單書目收藏:0
帕金森氏症是一種常見的神經退化性疾病,病理特徵是中腦的黑質組織內的多巴胺細胞退化死亡,因而會導致動作失常。實驗室先前的結果指出跑步運動訓練可以抑制1-methyl-4-phenylpyridinium (MPP+) 所導致的多巴胺神經元死亡以及nuclear factor erythroid 2-related factor 2 (Nrf2,一個會調控抗氧化酵素的轉錄因子) 的表現量下降。許多文獻也顯示跑步運動訓練會短暫的增加brain-derived neurotrophic factor (BDNF)的表現以及持續的活化TrkB (BDNF的受體)的表現。並且過去的文獻指出TrkB的下游PI3K/AKT和MAPK/ERK這兩條路徑都會活化Nrf2。因此我假設跑步運動訓練可藉由活化TrkB/ERK的路徑,進而抑制MPP+所誘發的Nrf2表現量下降以及多巴胺神經元死亡。我們發現在大鼠的紋狀體注射MPP+ 24和72小時後,TrkB、磷酸化TrkB和細胞核內的Nrf2表現量都會顯著下降。在給予四周的跑步運動訓練可抑制MPP+(72小時)所造成的紋狀體中tyrosine hydroxylase (TH,是多巴胺神經元的指標) 、磷酸化TrkB、TrkB和核內的Nrf2的表現量下降。為了更進一步得知跑步運動訓練是否是透過TrkB的活化達到保護多巴胺神經元的作用,我們分別利用TrkB的抑制劑K252a和利用腺病毒送入shTrkB去抑制TrkB的表現及活化。發現抑制TrkB後,在紋狀體給予MPP+ 72 小時會明顯的降低跑步運動訓練所預防的MPP+造成的TH、TrkB、p-TrkB、p-ERK以及細胞核內的Nrf2的表現量下降。另外,抑制TrkB後,在黑質區同樣也發現透過跑步運動訓練阻止Nrf2表現量的下降也失去效用。研究結果指出跑步運動訓練可能是透過調控TrkB/ERK路徑去抑制MPP+造成的細胞核內的Nrf2的表現量下降以及神經毒性。
Parkinson's disease (PD) is a movement disorder involved in progressive loss of dopaminergic (DA) neurons in the substantia nigra. Our previous studies showed that treadmill exercise prevented the 1-methyl-4-phenylpyridinium (MPP+)-induced nigrostriatal DA neurodegeneration and Nrf2 (nuclear factor erythroid 2-related factor 2, a key transcription factor in the regulation of antioxidant enzymes) inactivation. Other reports also showed that exercise training induced a transient increase in brain-derived neurotrophic factor (BDNF) level and sustained upregulation of TrkB (a receptor of BDNF) protein expression. The downstream PI3K/AKT and MAPK/ERK pathway of TrkB receptor have been shown to be involved in Nrf2 activation. Therefore, we hypothesize that treadmill exercise upregulates the TrkB-AKT/ERK pathway to prevent MPP+-induced Nrf2 downregulation and DA neuron loss in nigrostriatal DA system. We found that the protein expression of total TrkB, phosphorylated TrkB (p-TrkB), and nuclear Nrf2 was significantly decreased in the striatum of rats at 24 and 72 h after intra-striatal MPP+ injection. Treadmill exercise for 4 weeks prevented the MPP+-induced downregulation of tyrosine hydroxylase (TH, a marker enzyme of DA neurons), p-TrkB, TrkB and nuclear Nrf2 protein expression 72 h after MPP+ treatment. To identify the essential role of TrkB, we treated rats with TrkB inhibitor K252a or shTrkB. The results showed TrkB inhibition significantly attenuated the effect of exercise in reducing the downregulation of TH, TrkB and p-TrkB, p-ERK and nuclear Nrf2 protein expression in striatum 72 h after MPP+ treatment. The effect of TrkB inhibition in blocking exercise-induced prevention of Nrf2 downregulation was also found in the substantia nigra. These results demonstrate that treadmill exercise may regulate TrkB/ERK signaling pathway to prevent MPP+-induced Nrf2 downregulation and neurotoxicity.
中文摘要 ................................................. 3
Abstract................................................. 4
Contents ................................................ 7
List of figures ......................................... 10
Introduction ............................................ 11
Parkinson’s disease .................................. 11
Potential pathogenic mechanisms of PD ................ 11
Animal models of Parkinson’s disease ................. 12
Nrf2-regulated antioxidant defense system ............ 13
The role of Nrf2 in neurodegenerative diseases ....... 14
Beneficial effect of chronic exercise ................ 15
Beneficial effect of chronic exercise in
neurodegenerative diseases ........................... 16
BDNF and TrkB receptor in PD ......................... 16
Exercise regulated AKT and ERK signaling ............. 17
Research rationale ...................................... 19
Hypothesis .............................................. 19
Specific aims ........................................... 20
Materials and methods ................................... 21
Animals .............................................. 21
Chemicals and antibodies.............................. 21
Exercise training protocol ........................... 22
Animal surgery ....................................... 22
Intrastriatal injection of DMSO/K252a into right striatum
...................................................... 24
Intrastriatal injection of shTrkB/shScramble into right
striatum ............................................. 24
Preparation of nuclear and cytosolic extracts ........ 25
Protein concentration ................................ 26
Western blot ......................................... 26
Antibodies for Western blot ........................ 27
Statistical analysis ................................. 27
Results ................................................. 28
Treadmill exercise prevents MPP+-induced downregulation
of tyrosine hydroxylase, TrkB and nuclear Nrf2 protein
expression in striatum. .............................. 28
TrkB inhibition blocks exercise-induced prevention of
neuron loss and TrkB/ERK/Nrf2 downregulation in striatum
after MPP+ treatment. ................................ 29
TrkB inhibition blocks the exercise-induced prevention of
Nrf2 downregulation in substantia nigra. ............. 30
Knockdown of TrkB attenuates exercise-induced prevention
of neuron loss and protein downregulation after MPP+
treatment in striatum. ............................... 30
Discussion .............................................. 32
Exercise effect and Parkinson disease ................ 32
Parkinson disease with BDNF states ................... 34
Modulating the TrkB signaling in Parkinson disease ... 35
Mechanism of AKT in Parkinson disease ................ 36
Mechanism of ERK in Parkinson disease ................ 37
AKT and ERK signaling cascades that mediate Nrf2
regulation ........................................... 38
Nrf2 as a therapeutic target in Parkinson’s disease
...................................................... 39
The mechanisms of MPP+-induced neurotoxicity ......... 41
Conclusion .............................................. 43
References............................................... 44
Figures.................................................. 54
Figure 1. Treadmill exercise prevents MPP+-induced TH
downregulation in striatum. .......................... 54
Figure 2. Treadmill exercise prevents MPP+-induced p-TrkB
and TrkB downregulation in striatum. ................. 55
Figure 3. Treadmill exercise prevents MPP+-induced a
decrease of Nrf2 expression in striatum. ............. 56
Figure 4. TrkB inhibition blocks exercise-induced
prevention of TH, TrkB and p-TrkB downregulation after
MPP+ treatment in striatum. .......................... 57
Figure 5. TrkB inhibition prevents exercise-induced the
prevention of ERK downregulation in striatum. ........ 58
Figure 6. TrkB inhibition blocks the exercise-induced
prevention of Nrf2 downregulation in striatum after MPP+
treatment. ........................................... 59
Figure 7. MPP+-induced TrkB downregulation in substantia
nigra. ............................................... 60
Figure 8. TrkB inhibition blocks the exercise-induced
prevention of Nrf2 downregulation after MPP+ treatment in
substantia nigra. .................................... 61
Figure 9. Knockdown of TrkB attenuates exercise-induced
prevention of TrkB downregulation after MPP+ treatment in
striatum. .................................... ........62
Figure 10. TrkB knockdown attenuates exercise-induced the
prevention of ERK downregulation after MPP+ treatment in
striatum. ............................................ 63
Figure 11. Knockdown of TrkB significantly attenuated
exercise-induced the prevention of Nrf2 downregulation
after MPP+ treatment in striatum ..................... 64
Figure 12. Working model of TrkB/ERK signals are involved
in exercise-induced prevention of Nrf2 downregulation and
neuron loss after MPP+ treatment. .................... 65

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