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藥學院陳忠教授課題組在Annals of Neurology發文揭示顳葉癲癇耐藥形成的關鍵“門控”

編輯:周舒影 來源:藥學院 時間:2019年09月27日 訪問次數:10  源地址

癲癇是常見的神經系統疾病,其特征是反復突發性的癲癇發作。服用抗癲癇藥來控制癲癇發作是治療癲癇的常規手段,但仍有超過三分之一的癲癇患者會對抗癲癇藥產生耐受,成為耐藥性癲癇,又稱難治性癲癇。在發作起源于顳葉區的顳葉癲癇患者中,耐藥率甚至高達75%。一旦患者罹患難治性癲癇,對其治療就會變得非常棘手,并且會給患者、家庭及社會帶來很大的負擔。因此解析癲癇耐藥形成的關鍵并以此尋找特異性的治療手段或藥物靶點就顯得尤為迫切,也一直是癲癇研究領域關注的熱點問題。

2019年7月24日,陳忠教授課題組在神經病學領域知名期刊《Annals of Neurology》(美國神經病學學會年刊,五年影響因子10.185)在線發表了最新研究成果《Subicular pyramidal neurons gate drug resistance in temporal lobe epilepsy》。該研究是課題組長期以來對于顳葉癲癇發病機制解析的進一步深入,并首次揭示了顳葉癲癇耐藥形成的關鍵“門控”是下托的錐體神經元。海馬下托是海馬信息輸出的重要腦區,陳忠教授課題組前期發現海馬下托是1 hz低頻電刺激治療顳葉癲癇的潛在有效靶點,相比其他腦區具有較寬的治療時間窗 (Neurobiology of Disease, 2013,被F1000推薦);后續研究進一步解析下托內部的微環路基礎,發現存在下托內由氯轉運體改變而引起的去極化GABA能信號,會興奮錐體神經元從而密切參與顳葉癲癇的發病過程 (Neuron,2017,被F1000推薦)。本研究則進一步聚焦解析了下托內興奮性的錐體神經元與顳葉癲癇耐藥形成之間的機制。

本研究首先建立國際經典的大鼠耐苯妥英鈉難治性顳葉癲癇模型,并利用在體記錄神經元電活動的方法發現抗癲癇藥苯妥英鈉無法抑制耐藥大鼠下托錐體神經元的電活動,且與耐藥指標呈現相關性。進一步,利用前沿的光遺傳學和藥物遺傳學(使特定類型神經元表達對光或者藥物響應的蛋白,從而實現光照或者藥物精準調控神經元興奮性的方法)選擇性抑制下托錐體神經元可以逆轉耐藥,而將其選擇性激活則直接誘導耐藥,提示下托錐體神經元對于顳葉癲癇耐藥的形成是充分又必要的。而在下托給以具有臨床應用前景的低頻率電刺激,不但可以抑制下托錐體神經元,并且在行為學上逆轉了耐藥,控制了癲癇發作。進一步,離體電生理和臨床影像學結果發現下托錐體神經元上鈉通道功能可能與其介導的耐藥密切相關。該研究首次在不同性別的兩種大鼠品系中揭示了下托錐體神經元在顳葉癲癇耐藥形成中的重要“門控”作用,為將來臨床精準治療難治性顳葉癲癇提供了潛在的干預靶點和治療新策略。審稿專家均認為該研究對于癲癇領域是非常重要的發現,具有潛在重大的臨床應用前景。


該論文的研究歷時6年,第一作者為博士后徐層林與汪儀特聘研究員,陳忠教授為通訊作者;研究受到國家自然科學基金委重點項目、創新群體等項目資助。

全文鏈接: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


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