首乌方对L-DOPA诱发异动症模型大鼠的干预作用及其机制研究

Abstract：Up to now，levodopa（L-DOPA）is still provided as the most effective medication for parkinson's disease （PD）, however its long-term usage may result in L-DOPA-induced dyskinesia（LID），which is a clinically robust symptom to deal with. Various researches have demonstrated that the severity of PD is the basis for developing LID and the fluctuation of external L-DOPA levels is the initiation factor. In addition, as showed by our previous study, application of the clinically available Chinese traditional medicine-Shouwu Fang in PD rats, ameliorated plasma pharmacokinetic indicators of L-DOPA and elevated the extracellular striatum Dopamine (DA) levels while reduced the fluctuation. These results implied Shouwu Fang's potential efficacy in treating LID by inhibition of its developmental basis and initiation factor. In this study, we will utilize PD Caenorhabiditis elegans and LID rat and apply Microdialysis-HPLC, Radioimmunoassay (RIA) and other molecular biological techniques, to define the interfering mechanisms of Shouwu Fang on the development of LID from the entire, targeted tissue, cellular and molecular levels and provide the pharmacological evidence for using Showu Fang to control LID. Usage of animal models of PD Caenorhabiditis elegans, pharmacokinetic investigation of L-DOPA in targeted disease tissue and simultaneous analysis of the dynamic levels of multiple neurotransmitters are the highlights of this research.

摘要：迄今为止，左旋多巴（L-DOPA）仍是治疗帕金森病（PD）最为有效的药物，但长期使用会导致异动症（LID）的发生，这是临床治疗十分棘手的问题。研究表明：PD的严重程度是LID的发病基础，外源性L-DOPA的波动性刺激是其始动因素。我们的前期研究发现：临床治疗PD的有效中药首乌方，可以改善PD模型大鼠L-DOPA的血液药动学指标，提高纹状体细胞外液DA递质的水平并减缓其波动性变化，提示了抑制LID发病基础和始动因素的作用，推测其可能干预LID的发生。本研究拟采用线虫和LID大鼠模型，应用微透析-HPLC、放免、分子生物学等方法，从整体、靶组织、细胞、分子水平，明确首乌方对LID的干预作用、靶点及机制，为首乌方治疗LID提供药理学依据。其中，线虫PD模型的使用和病变靶组织L-DOPA药动学与多种神经递质同步动态研究的方法具有特色。

迄今为止，左旋多巴（L-DOPA）仍是治疗帕金森病（PD）最为有效的药物，但长期使用会导致异动症（LID）的发生，这是临床治疗十分棘手的问题。本项目在前期研究的基础上，用PD大鼠模型以美多芭诱LID，同时投与治疗PD有效的中药首乌方，观察到：首乌方对LID发病有一定预防作用，并能减轻其症状。应用微透析-HPLC方法，在清醒动物（自由活动状态下）病变靶组织细胞外液水平，探讨了首乌方在LID关键病理机制中可能发挥的作用：1）首乌方平缓了外源性L-DOPA产生的波动性刺激；2）降低了氧化应激指标；3）抑制了兴奋性氨基酸水平。为中西医结合治疗PD、LID的临床优势，提供了较传统的研究方法更为清晰、可靠的药理学依据。