癫痫是常见的神经系统疾病，其特征是反复突发性的癫痫发作。服用抗癫痫药来控制癫痫发作是治疗癫痫的常规手段，但仍有超过三分之一的癫痫患者会对抗癫痫药产生耐受，成为耐药性癫痫，又称难治性癫痫。在发作起源于颞叶区的颞叶癫痫患者中，耐药率甚至高达75%。一旦患者罹患难治性癫痫，对其治疗就会变得非常棘手，并且会给患者、家庭及社会带来很大的负担。因此解析癫痫耐药形成的关键并以此寻找特异性的治疗手段或药物靶点就显得尤为迫切，也一直是癫痫研究领域关注的热点问题。
2019年7月24日，陈忠教授课题组在神经病学领域知名期刊《Annals of Neurology》（美国神经病学学会年刊，五年影响因子10.185）在线发表了最新研究成果《Subicular pyramidal neurons gate drug resistance in temporal lobe epilepsy》。该研究是课题组长期以来对于颞叶癫痫发病机制解析的进一步深入，并首次揭示了颞叶癫痫耐药形成的关键“门控”是下托的锥体神经元。海马下托是海马信息输出的重要脑区，陈忠教授课题组前期发现海马下托是1 hz低频电刺激治疗颞叶癫痫的潜在有效靶点，相比其他脑区具有较宽的治疗时间窗 （Neurobiology of Disease, 2013，被F1000推荐）；后续研究进一步解析下托内部的微环路基础，发现存在下托内由氯转运体改变而引起的去极化GABA能信号，会兴奋锥体神经元从而密切参与颞叶癫痫的发病过程 （Neuron，2017，被F1000推荐）。本研究则进一步聚焦解析了下托内兴奋性的锥体神经元与颞叶癫痫耐药形成之间的机制。
本研究首先建立国际经典的大鼠耐苯妥英钠难治性颞叶癫痫模型，并利用在体记录神经元电活动的方法发现抗癫痫药苯妥英钠无法抑制耐药大鼠下托锥体神经元的电活动，且与耐药指标呈现相关性。进一步，利用前沿的光遗传学和药物遗传学（使特定类型神经元表达对光或者药物响应的蛋白，从而实现光照或者药物精准调控神经元兴奋性的方法）选择性抑制下托锥体神经元可以逆转耐药，而将其选择性激活则直接诱导耐药，提示下托锥体神经元对于颞叶癫痫耐药的形成是充分又必要的。而在下托给以具有临床应用前景的低频率电刺激，不但可以抑制下托锥体神经元，并且在行为学上逆转了耐药，控制了癫痫发作。进一步，离体电生理和临床影像学结果发现下托锥体神经元上钠通道功能可能与其介导的耐药密切相关。该研究首次在不同性别的两种大鼠品系中揭示了下托锥体神经元在颞叶癫痫耐药形成中的重要“门控”作用，为将来临床精准治疗难治性颞叶癫痫提供了潜在的干预靶点和治疗新策略。审稿专家均认为该研究对于癫痫领域是非常重要的发现，具有潜在重大的临床应用前景。
该论文的研究历时6年，第一作者为博士后徐层林与汪仪特聘研究员，陈忠教授为通讯作者；研究受到国家自然科学基金委重点项目、创新群体等项目资助。
全文链接：https://onlinelibrary.wiley.com/doi/abs/10.1002/ana.25554
Prof. Zhong Chen’s group published on Annals of Neurology
Nearly 60 million people suffered from epilepsy in the world. Despite using various anti-epileptic drugs (AEDs), more than one third of epilepsy patients are resistant to AEDs leading to drug resistant epilepsy, also called refractory epilepsy. The ratio in temporal lobe epilepsy (TLE) is even higher. Long-term failure of seizure control severely affects patients’ standard of living and may even result in unexpected death. Thusexplanation for the genesis of drug resistance need to be evaluated and further develop better target for precise treatments.
On July 24th, 2019, Prof. Zhong Chen’s group from the College of Pharmaceutical Science, Zhejiang University in China published a research article entitled “Subicular pyramidal neurons gate drug resistance in temporal lobe epilepsy” in Annals of Neurology, uncovering the critical “gating” role of subicular pyramidal neurons in drug resistance TLE. Prof. Zhong Chen’s group have previously shown that low frequency stimulation at subiculum retards epileptogenesis, and the microcircuits in subiculum mediated the genesis of generalized seizures in temporal lobe epilepsy (Neurobiology of disease, 2013; Neuron, 2017). This study focused on the relationship of subicular excitatory pyramidal neurons and drug resistance in TLE.
In vivo neural recording showed that the firing rate of pyramidal neurons in the subiculum, could not be inhibited by antiepileptic drug phenytoin in drug resistant rats. Selective inhibition of subicular pyramidal neurons by optogenetics or chemogenetics reversed drug resistance, while selective activation of subicular pyramidal neurons mimicked drug resistance. Moreover, long-term low frequency stimulation at the subiculum, which is clinically feasible, significantly inhibited the subicular pyramidal neurons and reversed drug resistance. Further, in vitro electrophysiology and clinical neuroimage data revealed that dysfunction of sodium channels of subicular pyramidal neurons were involved in the drug resistance. This study reveal the novel “gating” role of subicular pyramidal neurons in drug resistance TLE, and represent a new potential target for further precise treatments. The reviewers regarded this study as an important paper about drug-resistance with appeal to readers interested in epilepsy.
This study lasts for 6 years. Postdoctor Cenglin Xu and researcher Yi Wang were the co-first authors. Prof. Zhong Chen is the corresponding author. This work was funded by the National Natural Science Foundation of China.
The paper link: https://onlinelibrary.wiley.com/doi/abs/10.1002/ana.25554
