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A novel carbazole-based hydrogen-sulfide donor suppresses seizures and upregulates ATP-sensitive potassium channels
Applied Materials Today ( IF 8.3 ) Pub Date : 2020-01-20 , DOI: 10.1016/j.apmt.2020.100559
Xiaoqin Zhu , Yan He , Zhongrui Liu , Ziting Zhu , Yuehua He , Jiewen Qiu , Danqiong Liu , Mingshu Mo , Peng Wang , Xiumei Tian , Pingyi Xu

Epilepsy is characterized by repeated spontaneous seizures and remains untreatable due to its complicate pathogenesis. Low-dose hydrogen sulfide (H2S) has been shown to exert antiepileptic and protective effects in the central nervous system, but the administration of H2S gas to suppress seizures is difficult. In the present study, we synthesized a safe and efficient carbazole-based H2S donor from aldehydes with a one-pot procedure and characterized this specific H2S donor via proton nuclear magnetic resonance (1HNMR), scanning electron microscopy (SEM), and absorption spectroscopy. In vitro and in vivo risk assessments demonstrated that the H2S donor (up to a 400-μM concentration) had sufficient biocompatibility and membrane permeability and suppressed epileptic seizures. Importantly, the suppression of seizures was determined in the brain when the H2S donor was injected into the lateral ventricle in a rat model of advanced seizures. Furthermore, the mechanism by which the H2S donor suppressed the expression of seizures may have been related to H2S donor-induced increases in the expressions of the ATP-sensitive potassium channel (KATP) subunits, Kir6.2 and SUR1. Taken together, these assays suggested that our novel H2S donor may represent a potential therapeutic strategy for ameliorating seizures in epilepsy.



中文翻译:

一种基于咔唑的新型硫化氢供体可抑制癫痫发作并上调ATP敏感性钾通道

癫痫病的特征是反复自发发作,并且由于其复杂的发病机理而无法治疗。低剂量的硫化氢(H 2 S)已被证明在中枢神经系统中具有抗癫痫和保护作用,但难以抑制H 2 S气体的给药。在本研究中,我们通过一锅法从醛中合成了一种安全有效的基于咔唑的H 2 S供体,并通过质子核磁共振(1 HNMR),扫描电子显微镜(SEM)对这种特定的H 2 S供体进行了表征。 ,和吸收光谱。体外体内风险评估表明,H 2 S供体(浓度高达400μM)具有足够的生物相容性和膜通透性,并抑制了癫痫发作。重要的是,在晚期癫痫的大鼠模型中,当将H 2 S供体注入侧脑室时,可以确定大脑中癫痫的抑制作用。此外,H 2 S供体抑制癫痫发作表达的机制可能与H 2 S供体诱导的ATP敏感性钾通道(K ATP)亚基Kir6.2和SUR1的表达增加有关。综上所述,这些测定表明我们新颖的H 2S供体可能代表减轻癫痫发作的潜在治疗策略。

更新日期:2020-01-20
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