新型钠通道开放剂角蒿酯碱的药理学机制研究

Natural product incarvillateine was found to produce strong antinociceptive effect, however, its molecular target remains unkown. Our prelimary data suggest that incarvillateine is a putative Nav1.1 sodium channel activator, it might exert antinociceptive effect by enhancing neuronal excitability of GABAergic interneurons and increasing inhibitory neurotransmitter GABA release. To test the hypothesis, we will utilize patch clamp technique performed in both slice and cell line, calcium imaging, two electrode voltage clamp, RNAi and knockout mice. We aim to investigate: 1) different sensitivities of sodium channel subtypes to incarvillateine; 2) whether incarvillateine selectively activates sodium channels; 3) how incarvillateine regulates neuronal excitability of inhibitory GABAergic neurons in cortical areas involved in pain processing. Our prelimary findings that incarvillateine is a putative sodium channel specific activator provide foundations for investigating the neuropharmacological mechanism of incarvillateine.

天然产物角蒿酯碱作为潜在的候选药物，具有很强的镇痛活性，但是其作用靶点尚不清楚。我们的前期研究结果提示，角蒿酯碱可能是钠通道的特异性开放剂。基于钠通道成员的镇痛/致痛研究和表达谱分析，我们推测：角蒿酯碱通过影响Nav1.1通道亚型，提高GABA能中间神经元的兴奋性,促进抑制性神经递质释放,从而发挥镇痛作用。为了检验这一学说，本项目拟通过脑片和细胞膜片钳技术、钙荧光成像、双极电压钳、RNAi、基因敲除小鼠等多种方法： 1）确证角蒿酯碱为钠通道的选择性开放剂； 2）研究角蒿酯碱对不同亚型的钠通道的药理学作用；3）探讨其对痛觉传导通路中GABA能神经元电活动和兴奋性的影响，以期阐明角蒿酯碱镇痛作用的分子机制。我们的前期工作提示，角蒿酯碱可能是钠通道的特异性开放剂，为深入探讨其镇痛活性的神经药理学机制提供了切入点和基础。本项目研究有望获得结构新颖、特异性高、具有潜在临床价值的钠通道开放剂。