低剂量雷公藤甲素抗颞叶癫痫作用的神经环路机制研究

由于神经环路的特殊性，颞叶癫痫（TLE）极易对现有抗癫痫药物耐受，是癫痫临床治疗和药物研发的热点难题。申请人在青年基金资助下前期发现内嗅皮层与海马间存在一条由兴奋性谷氨酸能神经元介导的抗癫痫神经通路参与TLE发病，提示从神经环路水平研究TLE发病机制及其治疗的必要性。中医理论中TLE类似“风痫”，与“风邪上扰，脑络瘀阻”有关。雷公藤甲素是中药雷公藤的有效成分之一，具有祛风、活血通络等功效，或有助于干预“风邪”和“脑络瘀阻”。预实验发现低剂量雷公藤甲素在小鼠和耐药性大鼠TLE模型中具有良好的抗癫痫活性，电生理记录初步发现雷公藤甲素可以改善TLE小鼠海马脑电节律、降低海马痫样放电频率及幅度，但其对非TLE小鼠发作脑电没有明显作用，提示其作用可能具有神经环路特异性。因此，本项目拟利用电生理、光遗传学及基因干预等方法，阐明雷公藤甲素抗TLE作用及其调控神经环路机制。

Temporal lobe epilepsy (TLE) is easily resistant to antiepileptic drugs for the particularity and complexity of its underlying neural circuits, which is an important issue for the development of antiepileptic drugs and the clinical treatment of epilepsy. Funding by the National Natural Science Foundation of China, we found a novel “glutamatergic-GABAergic” antiepileptic circuit that mediated by entorhinal principal neuron in TLE mice, which indicate that it is necessary to study TLE and its treatments in a neuronal circuit level. On the other hand, the symptoms of TLE are similar as the “Feng-Xian” or “wind-epilepsy” according to traditional Chinese medicine theory, which is associated with “wind evil attacking the brain” and “stasis in the cerebral collaterals”. Triptolide is a major active component of extracts from the medicinal plant Tripterygium wilfordii Hook F. It can disperse the “wind evil” and “promoting blood circulation”, and hence it may be helpful to treatment of the “wind evil” and “promoting blood circulation” in TLE. In our pilot experiment, we found triptolide, at a very low dose, acted evident antiepileptic effect in mice and intractable rats TLE models. Moreover, by using electrophysiological recording, we found that triptolide adjusted hippocampal EEG rhythm, decreased the frequency and reduced the amplitude of epileptic discharges in TLE mice. However, triptolide did not affect the non-TLE seizures. These results suggest the anti-epileptic effect of triptolide may be related to the specific neuronal circuits in temporal lobe areas. Therefore, by using electrophysiology, optogenetics, genetic manipulation and other related technology methods, this project intends to illuminate the neuronal circuit mechanisms underlying the anti-epileptic effect of triptolide in TLE.