川芎和青风藤有效组分配伍（CQM）脑内药动学相互作用及分子机制研究

Neuropathic pain (NP) is imposing increasing threat on human health physically and emotionally. However, existing therapy for NP has marginal efficacy and significant side effects. We previously found CQM, a component compatibility from Chuanxiong Rhizoma and Sinomenii Caulis, was effective towards NP, with no tolerance observed in long-term use. It has been demonstrated that sinomenine from Sinomenii Caulis has direct anti-NP activity and ligustrazine from Chuanxiong Rhizoma shows obvious inhibitory effect on P-gp. We, therefore, hypothesized the in vivo fate of CQM in the brain (Neuropharmacokinetics) affected by the pharmacokinetic interactions within blood-brain barrier is critical for the therapeutic beneficial of CQM. Our aims are: 1) to determine the pharmacokinetic properties of ligustrazine and sinomenine, as well as their interactions within brain; 2) to analyze the underlying the molecular mechanisms. We will use different models, including in vivo microdialysis, in situ brain perfusion and in vitro brain microvascular endothelial cells. The present study will provide basis for understanding the therapeutic effects of CQM on NP, and facilitate novel anti-NP drug development from Chinese medicine.

神经病理性疼痛（NP），严重危害人类身心健康。课题组前期发现川芎和青风藤有效组分配伍（CQM）治疗NP效果显著，连续使用无耐受性。已证实，青风藤组分有治疗NP的中枢活性，川芎组分能抑制血脑屏障（BBB）P-gp等的功能和表达。我们认为川芎组分可能通过调节BBB如P-gp的功能，增加青风藤组分脑内的药物浓度和中枢性镇痛作用。这种脑内药动学的相互作用，可能是CQM治疗NP药效明显且不易产生耐受性的重要机制之一。本课题拟以CQM及各配伍组分为研究对象，从药物相互作用对血浆蛋白结合率的影响开始，通过在体和离体BBB模型，观察各组分在BMECs上的摄取和转运特征、对P-gp和BBB功能的影响，以组分-组分间相互作用-药动学/药效学协同作用的研究模式，从整体、器官、细胞、分子多层次揭示其科学内涵，为CQM镇痛作用的中枢机制研究提供依据，也为其它具有中枢神经作用的中药研发和药理机制研究提供新的思路。