巴金森氏症最主要的特徵是在黑質的多巴胺神經退化，導致運動功能失調 及認知功能障礙。目前臨床上用來治療巴金森症的藥物尚無法減緩多巴胺神經 退化和疾病的惡化。左多巴胺是臨床上最常用來治療巴金森氏症的藥物。但許 多臨床報告指出左多巴胺會導致許多副作用，包括噁心及嘔吐。此外也有更嚴 重的副作用，例如精神方面及癲癇的發生。 微膠細胞的活化和中樞神經系統的發炎反應非常相關，這也是導致導致包 含巴金森氏症的許多神經退化性疾病發生的原因。許多研究報告指出在老鼠的 黑質區打入LPS 會誘發微膠細胞活化，引起多巴胺神經細胞受損。我們查閱文 獻發展對抗神經性發炎的藥物，或許是發展針對巴金森氏症一個治療方針。我 們初步的結果發現小蘗鹼能抑制LPS 或IFN-刺激微膠細胞活化，也會抑制神 經性發炎物質iNOS、COX-2 及前發炎細胞激素的表現。分析小蘗鹼抑制神經性 發炎的訊息傳遞機轉是有助於發展對抗巴金森氏症的策略。我們初步的結果發現小蘗 鹼抑制神經性發炎的作用可能是透過活化AMPK 的訊息分子而來的。因此本研究計 劃第一年將探討小蘗鹼是否能有效抑制神經退化，進而觀察小蘗鹼調節的訊息調 節機轉。 之前的研究報告指出中腦膠質神經細胞培養是用來探討神經性發炎和神經 退化很好的評估工具。是否小蘗鹼可以保護LPS誘發神經性發炎引起的多巴胺神經 死亡的作用，將是本研究計畫第二年要探討。本計劃第三年將進一步利用活體動物模 式探討小蘗鹼在抑制神經性發炎和神經保護作用的可能性。我們使用公的SD品系的大 白鼠，將其麻醉並置於立體定位儀上，將LPS局部打入黑質區。在七天後評估神經行 為、多巴胺含量及神經毒性的測量。此外我們也將在評估大腦的微膠細胞的活化和神 經性發炎反應。因此本計劃除了利用神經性發炎造成神經細胞死亡的動物模式觀察是 否小蘗鹼可以抑制神經性發炎及神經保護的作用，而這些結果將有助於瞭解巴金森氏 症形成的機轉及抗神經性發炎藥物發展的基礎。
Parkinson’s disease (PD) is characterized by the progressive loss of nigrostriatal dopamine (DA) neurons leading to motor disturbances and cognitive impairment. Current pharmacotherapies relieve PD symptoms temporarily but fail to prevent or slow down the disease progression. Levodopa is the most common drug used to treat Parkinson's disease. It has been reported that levodopa may cause some side effects including nausea and vomiting. In addition, the potentially serious side effects of levodopa include psychiatric problems and seizures. An inflammatory response in the central nervous system mediated by the activation of microglia is an important role of the development of neurodegenerative diseases, including Parkinson's disease. Numerous reports showed that intranigral injection of lipopolysaccharide (LPS), leads to marked microglial activation in substantia nigra (SN) and the neuronal death of dopaminergic neurons. Based on data base search, we speculate that development of anti-neuroinflammatory agent may be a good strategy in Parkinsonisam therapy. Our preliminary data show that berberine inhibited LPS- or IFN-r-induced microglia activation. In addition, berberine also inhibited iNOS, COX-2 and proinflammatory cytokines expression in microglia. The analysis of cell signaling for berberine in anti-neuroinflammatory is crucial for the development of novel approaches for treatment of Parkinsonism. Our preliminary data show that AMPK activation was found to associate with the anti-neuroinflammatory after treatment with berberine in microglia. Involvement of anti-neuroinflammatory by berberine in microglia will be examined in the first year of this research plan. It has been reported that mesencephalic cell cultures is the useful tool for determine neuroinflammation and neurotoxicity. Whether berberine protect the LPS-mediated dopmaineergic neuron toxicity will be examined in the second year of this plan. In the third year, we will examine the anti-neuroinflammatory and neuroprotective effect by berberine in vivo. Male SD rats were used for this study. Rats were anesthetized and positioned in a stereotaxic apparatus to microinjection of LPS into the SN pars compacta (SNpc). After 7 days, the neurologic behavior, dopamine content and neurotoxicity were measured. The microglia activation and neuroinflammatory response will also be evaluated. The present study will provide a new strategy to treat neuroinflammatory and Parkinsonism. The results will be also helpful for the development of Chinese Medicine.
