Miconazole exerts disease-modifying effects during epilepsy by suppressing neuroinflammation via NF-?B pathway and iNOS production
Miconazole exerts disease-modifying effects during epilepsy by suppressing neuroinflammation via NF-?B pathway and iNOS production
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DOI：
10.1016/j.nbd.2022.105823
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发表时间：
2022-07-26
影响因子：
6.1
通讯作者：
Jiang, Peifang
中科院分区：
文献类型：
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作者：
Gong, Lifen;Zhu, Tao;Jiang, Peifang
神经炎症有助于癫痫的产生，并已被提出作为有效的治疗靶点。最近的研究发现了抗真菌药物咪康唑通过抑制神经炎症来治疗各种脑部疾病的潜在作用，但尚未在癫痫中进行研究。在这里，我们研究了不同剂量的咪康唑（5，20，80 mg/kg）的癫痫发作阈值，炎性细胞因子的释放，和神经胶质细胞活化的毛果芸香碱（PILO），戊四唑（PTZ），和海马内红藻氨酸（IHKA）模型的影响。我们证明，5和20 mg/kg咪康唑增加癫痫发作阈值，但只有20 mg/kg咪康唑减少炎症细胞因子释放，胶质细胞活化，并在诱导后早期（24小时，3天）的形态学改变。我们进一步研究了20 mg/kg咪康唑对癫痫的影响（KA注射后4周）。我们发现，咪康唑显着衰减细胞因子的产生，胶质细胞活化，小胶质细胞的形态学变化，频率和持续时间的复发性海马阵发性放电（HPDs），神经元和突触损伤的海马癫痫。此外，咪康唑抑制KA诱导的NF-κ B通路的激活和iNOS的产生。我们的研究结果表明，咪康唑是一种有效的药物，在癫痫疾病的改善效果，这可能是通过减轻神经炎症通过抑制NF-κ B激活和iNOS的生产。在适当的剂量下，咪康唑可能是一种安全有效的批准药物，可以很容易地重新定位为临床实践。
Neuroinflammation contributes to the generation of epilepsy and has been proposed as an effective therapeutic target. Recent studies have uncovered the potential effects of the anti-fungal drug miconazole for treating various brain diseases by suppressing neuroinflammation but have not yet been studied in epilepsy. Here, we investigated the effects of different doses of miconazole (5, 20, 80 mg/kg) on seizure threshold, inflammatory cytokines release, and glial cells activation in the pilocarpine (PILO) pentylenetetrazole (PTZ), and intrahippocampal kainic acid (IHKA) models. We demonstrated that 5 and 20 mg/kg miconazole increased seizure threshold, but only 20 mg/kg miconazole reduced inflammatory cytokines release, glial cells activation, and morphological alteration during the early post-induction period (24 h, 3 days). We further investigated the effects of 20 mg/kg miconazole on epilepsy (4 weeks after KA injection). We found that miconazole significantly attenuated cytokines production, glial cells activation, microglial morphological changes, frequency and duration of recurrent hippocampal paroxysmal discharges (HPDs), and neuronal and synaptic damage in the hippocampus during epilepsy. In addition, miconazole suppressed the KA-induced activation of the NF-kappa B pathway and iNOS production. Our results indicated miconazole to be an effective drug for disease-modifying effects during epilepsy, which may act by attenuating neuroinflammation through the suppression of NF-kappa B activation and iNOS production. At appropriate doses, miconazole may be a safe and effective approved drug that can easily be repositioned for clinical practice.