A novel carbazole-based hydrogen-sulfide donor suppresses seizures and upregulates ATP-sensitive potassium channels
A novel carbazole-based hydrogen-sulfide donor suppresses seizures and upregulates ATP-sensitive potassium channels
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DOI：
10.1016/j.apmt.2020.100559
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发表时间：
2020-06
影响因子：
8.3
通讯作者：
Xiaoqing Zhu;Yan He;Zhongrui Liu;Ziting Zhu;Yuehua He;Jiewen Qiu;D. Liu;Mingshu Mo;P. Wang;Xiumei Tian;P. Xu
中科院分区：
文献类型：
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作者：
Xiaoqing Zhu;Yan He;Zhongrui Liu;Ziting Zhu;Yuehua He;Jiewen Qiu;D. Liu;Mingshu Mo;P. Wang;Xiumei Tian;P. Xu
癫痫以反复自发性发作为特征，由于其复杂的发病机制，至今仍无法治疗。低剂量的硫化氢(H_2S)对中枢神经系统具有抗癫痫和保护作用，但用H_2S气体抑制癫痫发作是困难的。在本研究中，我们以醛为原料，采用一锅法合成了一种安全高效的咔唑类H_2S供体，并对其进行了核磁共振、扫描电子显微镜和吸收光谱表征。活体实验表明，该H_2S供体(高达400-μM浓度)具有良好的生物相容性和细胞膜通透性，并能抑制癫痫发作。重要的是，在晚期癫痫大鼠模型中，当将硫化氢供体注射到侧脑室时，大脑中确定了对癫痫的抑制。此外，H_2S供体抑制癫痫发作表达的机制可能与H_2S供体诱导ATP敏感性钾通道(KATP)亚单位Kir6.2和SUR1表达增加有关。综上所述，这些分析表明，我们的新型硫化氢供体可能是一种改善癫痫发作的潜在治疗策略。
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 donorviaproton nuclear magnetic resonance (1HNMR), scanning electron microscopy (SEM), and absorption spectroscopy.In vitroandin vivorisk 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.