巴金森氏症 (Parkinson’s disease, PD)的成因是由於大腦中黑質區多巴胺神經細胞流失所引起的。文獻也指出，粒線體功能障礙導致能量缺乏是造成多巴胺神經細胞死亡的主要原因之一。而在能量缺乏或是代謝壓力的情況下，腺苷單磷酸活化蛋白質激酶 (AMP-activated protein kinase, AMPK)會活化，以維持細胞內的能量恆定。另外，亦有研究顯示運動與二甲雙胍類降血糖藥物metformin治療都能夠活化AMPK，並對PD病患與MPTP誘導之PD小鼠模式有益。這些結果顯示AMPK在PD的致病機制與預防中扮演重要的角色。在本篇研究中，我們想要探討AMPK活性在運動避免MPTP誘導黑質紋狀體多巴胺神經細胞流失和行動失調中的影響。因此，我們使用雄性 C57BL/6小鼠，透過腹腔注射MPTP 建立PD小鼠模型，之後給予跑步機運動訓練四週。跑步前20分鐘會給予AMPK活化劑metformin或抑制劑dorsomorphin。在我們的研究結果顯示運動訓練或metformin處理皆會顯著增加AMPK磷酸化與過氧化體增生劑活化受體γ輔啟動因子-1α (Peroxisome proliferator-activated receptor coactivator-1α, PGC-1α) 蛋白質表現量，並誘發體溫上升。然而，在MPTP誘導PD的小鼠觀察到metformin或dorsomorphin處理會阻斷運動引起的體溫上升與上調PGC-1α表現。此外，四週跑步運動訓練或metformin處理可以避免由MPTP誘發的黑質區多巴胺神經細胞退化與運動功能障礙，而單獨處理metformin則會減弱滾筒式跑步機平衡測試表現。然而在metformin處理的運動小鼠，並未發現運動改善MPTP引起紋狀體多巴胺轉運蛋白表現量下降，且在改善行動功能障礙和挽救多巴胺神經細胞損失沒有加成作用。另外，dorsomorphin處理導致滾筒式跑步機平衡測試表現不佳，黑質紋狀體多巴胺神經細胞顯著的損失，加劇MPTP毒性，並阻礙運動產生的保護神經細胞作用。這些結果闡明適度運動活化AMPK有助於神經保護作用。且AMPK活化劑合併治療 (運動與metformin處理)不僅不具有額外的益處，可能還會減弱各自的保護神經細胞之作用。

Parkinson’s disease (PD) is caused by the degeneration of dopaminergic neurons in the substantia nigra. ATP loss induced by mitochondrial dysfunction had been demonstrated to be one of major causes of nigral dopaminergic neurodegeneration. The decrease of ATP levels activates AMP-activated protein kinase (AMPK) to maintain energy homeostasis. On the other hand, exercise training and metformin administration can also activate AMPK and have beneficial effects for PD patients and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice. These results revealed an important role of AMPK in the pathogenesis and prevention of PD. In the present study, we investigate the effect of AMPK activity on the protective effects of exercise against MPTP-induced nigrostriatal dopaminergic neurodegeneration and motor impairment. Male C57BL/6 mice were injected MPTP (30 mg/kg/day for 5 consecutive days) or vehicle saline and then subjected to treadmill running or not running for 4 weeks. AMPK activator of metformin or inhibitor of dorsomorphin was administrated by intraperitoneal injection 20 minutes before running. Results demonstrated that exercise training or metformin treatment significantly induced AMPK phosphorylation and upregulation of peroxisome proliferator-activated receptor  coactivator-1α (PGC-1α) protein expression and an elevation of body temperature in saline- or MPTP-treated mice. However, the exercise-induced hyperthermia and PGC-1α upregulation were blocked in MPTP mice treated with metformin or dorsomorphin. In addition, 4-week exercise or metformin treatment prevented MPTP-induced nigrostriatal dopaminergic neurodegeneration and motor impairment while metformin itself attenuated rotarod performance. In exercised mice treated with metformin, the exercise-induced protective effect in preventing MPTP-induced downregulation of dopamine transporter in striatum was not found and there was no additive effect in improving motor dysfunction and rescuing nigral dopaminergic neuron loss. Moreover, dorsomorphin treatment induced a poor rotarod performance and significant loss of nigrostriatal dopaminergic neurons, deteriorated MPTP toxicity, and impeded the neuroprotective effects of exercise. These findings elucidate that AMPK activation contributes to the neuroprotective effects of moderate exercise. In addition, the combined treatment of AMPK activators, exercise and metformin, may abrogate respective neuroprotection in MPTP-induced PD mouse model besides no additive benefits.

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