巴金森氏症(PD）的病理機制是由於中腦黑質區多巴胺（DA）神經元產生退化，進而導致行動功能逐漸喪失的一種神經退化性疾病。到目前為止，造成巴金森氏症多巴胺神經元退化的病因目前仍然不清楚。有研究指出，因黑質區內小膠細胞的密度比其他腦區高，所以推測小膠細胞的活化與DA神經元退化有關。這使得發炎所引起的小膠細胞活化成為導致DA神經元退化、巴金森氏症的一個可能病因。脂多醣體（LPS）是由革蘭氏陰性菌所產生的內毒素。動物實驗中被證實LPS能活化小膠細胞，進而產生細胞毒素造成DA神經元退化。此外，運動已知可以保護神經退化、促進神經滋養因子（如BDNF）的分泌等功能。而運動所產生的腦神經滋養因子（BDNF）也已經被證實，會透過與其接受器TrkB結合，活化下游PI-3/Akt訊息傳導路徑來幫助提升神經元的存活。因此，本研究假設運動能保護發炎所導致的黑質腦區中DA神經元退化，而這種保護的機制可能與運動調節BDNF有關。為了驗證這個假設，首先在小鼠腹腔內分別注射LPS或生理食鹽水（對照組），並於不同時間點後做灌流犧牲，觀察腦中DA神經元退化及小膠細胞活化的情形。結果顯示腹腔內注射LPS會造成黑質腦區腦中小膠細胞活化以及多巴胺神經元退化。另外，腹腔內注射LPS也同樣減少了黑質腦區中BDNF與TrkB的含量。五週的跑步運動訓練雖然不能抑制小膠細胞活化，確能完全抑制LPS導致DA神經元的退化。此外，跑步運動訓練有效的增加了黑質中BDNF、TrkB和Akt的含量。至於由LPS所導致老鼠紋狀體DA含量減少，以及運動功能的缺失，也都能透過運動得到改善。本研究的結論是運動能防止由LPS所導致的DA神經元退化，並能維持正常的運動功能。而運動產生的保護效果可能不是透過調節小膠細胞之活化，而是與調節BDNF/Akt路徑有關。從我們的實驗結果發現，運動或許可以提供臨床一個非藥物性治療巴金森氏症的新方針。

Parkinson's disease (PD) is characterized by a progressive and selective degeneration of dopaminergic (DAergic) neurons in substantia nigra (SN), leading to disorders in movements. The mechanisms responsible for the loss of DA neurons in PD are poorly understood. Due to the high density of microglia in SN and high susceptibility of DAergic neurons to microglial activation, it has been suggested that microglia activation predisposes DAergic neuron degeneration. Lipopolysaccharide (LPS), an endotoxin from gram-negative bacteria, is known to induce microglia activation in rodents. On the contrary, physical exercise is known to have beneficial effects on brain functions, such as reducing neurodegeneration. Running exercise has been shown to up-regulate neurotrophic factors, such as brain-derived neurotrophic factor (BDNF) that promote neuronal survival. BDNF binds to its cognate receptor, TrkB, and activates downstream pro-survival pathways. Among them, the PI-3/Akt signaling pathway has been well characterized to enhance cell survival. Therefore, we hypothesize that exercise protects the SN DAergic neuron against inflammation induced injury, and such protection is related to BDNF. Male C57BL/6 mice at eight weeks of age were divided into LPS and saline (vehicle) injection groups. The LPS-treated group received intraperitoneal injection of 1mg/kg LPS. Mice were killed at different time spans after LPS administration and the numbers of reactive microglia and DAergic neurons were recorded. In order to investigate the effect of exercise on the protection of DAergic neurons, some animals were forced to run on treadmill for four weeks before the LPS injection. The sedentary controls were left on immobile treadmill for equal time. The levels of BDNF and TrkB in SN were monitored to seek for potential association between the exercise-induced protective effect and BDNF signaling. The results showed that a single LPS injection induced microglia activation within hours in SN, followed by a reduction of TH+-DA neurons. LPS also reduced the levels of BDNF and its receptor, TrkB in SN. Five weeks of treadmill running (TR) completely prevented the LPS-induced loss of DAergic neurons in SN and DA content levels in striatum. Furthermore, five weeks of TR did not alter the LPS-induced microglia activation, but enhanced the expressions of BDNF and TrkB in SN. The LPS-induced reduction of Akt levels were also inverted by five weeks of TR. Five weeks of TR also prevented the LPS-induced motor movement dysfunctions. In conclusion, five weeks of TR effectively protected the DAergic neuron against LPS-induced DAergic neuron degeneration. The LPS-induced reduction of striatal DA content levels and motor performance deficits were also completely prevented by TR. The TR protective effects apparently were not due to modulation of microglia activation. Our results indicated that the BDNF/Akt signaling pathway may be involved in the TR-induced protection, as the BDNF/Akt signaling has well-known anti-apoptotic effects. Taken together, exercise may offer economic, preventive, and non-pharmaceutical therapeutic strategies for PD.

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