Section of Infections of the Nervous System, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Room 7C-103; Bldg. 10, 10 Center Drive, Bethesda, MD, 20892, USA.
Translational Neuroscience Center, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Room 7C-105; Bldg. 10, 10 Center Drive, Bethesda, MD, 20892, USA.
Neurotherapeutics. 2022 Jul;19(4):1313-1328. doi: 10.1007/s13311-022-01265-0. Epub 2022 Jul 13.
There is a continuing unmet medical need to develop neuroprotective strategies to treat neurodegenerative disorders. To address this need, we screened over 2000 compounds for potential neuroprotective activity in a model of oxidative stress and found that numerous antifungal agents were neuroprotective. Of the identified compounds, fluconazole was further characterized. Fluconazole was able to prevent neurite retraction and cell death in in vitro and in vivo models of toxicity. Fluconazole protected neurons in a concentration-dependent manner and exhibited efficacy against several toxic agents, including 3-nitropropionic acid, N-methyl D-aspartate, 6-hydroxydopamine, and the HIV proteins Tat and gp120. In vivo studies indicated that systemically administered fluconazole was neuroprotective in animals treated with 3-nitropropionic acid and prevented gp120-mediated neuronal loss. In addition to neuroprotection, fluconazole also induced proliferation of neural progenitor cells in vitro and in vivo. Fluconazole mediates these effects through upregulation and signaling via the insulin growth factor-1 receptor which results in decreased cAMP production and increased phosphorylation of Akt. Blockade of the insulin growth factor-1 receptor signaling with the selective inhibitor AG1024 abrogated the effects of fluconazole. Our studies suggest that fluconazole may be an attractive candidate for treatment of neurodegenerative diseases due to its protective properties against several categories of neuronal insults and its ability to spur neural progenitor cell proliferation.
目前，开发神经保护策略以治疗神经退行性疾病的需求仍未得到满足。为了满足这一需求，我们在氧化应激模型中筛选了 2000 多种化合物，以寻找潜在的神经保护活性，结果发现许多抗真菌药物具有神经保护作用。在所鉴定的化合物中，氟康唑进一步得到了表征。氟康唑能够预防体外和体内毒性模型中的神经突回缩和细胞死亡。氟康唑以浓度依赖的方式保护神经元，并对几种毒性物质有效，包括 3-硝基丙酸、N-甲基-D-天冬氨酸、6-羟多巴胺和 HIV 蛋白 Tat 和 gp120。体内研究表明，系统给予氟康唑可在 3-硝基丙酸处理的动物中发挥神经保护作用，并防止 gp120 介导的神经元丢失。除了神经保护作用外，氟康唑还能在体外和体内诱导神经祖细胞的增殖。氟康唑通过上调胰岛素样生长因子-1 受体及其信号传导来介导这些作用，从而导致 cAMP 产生减少和 Akt 磷酸化增加。用选择性抑制剂 AG1024 阻断胰岛素样生长因子-1 受体信号传导可消除氟康唑的作用。我们的研究表明，氟康唑可能是治疗神经退行性疾病的一个有吸引力的候选药物，因为它具有针对几类神经元损伤的保护特性，并且能够刺激神经祖细胞的增殖。
