Haloperidol Prevents Oxytosis/Ferroptosis by Targeting Lysosomal Ferrous Ions in a Manner Independent of Dopamine D2 and Sigma-1 Receptors
Haloperidol Prevents Oxytosis/Ferroptosis by Targeting Lysosomal Ferrous Ions in a Manner Independent of Dopamine D2 and Sigma-1 Receptors
复制标题
DOI：
10.1021/acschemneuro.2c00398
复制
发表时间：
2022-09-01
影响因子：
5
通讯作者：
Furuta, Kyoji
中科院分区：
文献类型：
--
作者：
Hirata, Yoko;Oka, Kohei;Furuta, Kyoji
氟哌啶醇是一种广泛使用的抗精神病药物，通过对多巴胺D2受体的强烈拮抗作用发挥抗精神病作用。此外，氟哌啶醇被归类为sigma-1受体（S1R）拮抗剂，可防止培养细胞中的内源性氧化应激。然而，氟哌啶醇抗氧化应激的药理作用尚不清楚。氧中毒/铁中毒是铁依赖性的非凋亡性氧化细胞死亡，被认为是同一细胞死亡途径的两个名称，并且提出了氧中毒/铁中毒在多种疾病中的潜在生理相关性。在本研究中，我们研究了氟哌啶醇对s1r敲除小鼠海马HT22细胞氧中毒/铁中毒的影响。结果表明氟哌啶醇是一种独立于S1R的强氧中毒/铁下垂抑制剂。新开发的荧光探针对HT22细胞成像显示，氟哌啶醇定位于晚期核内体和溶酶体，减少溶酶体亚铁离子的积累，从而减少细胞内活性氧的产生，抑制细胞死亡。这些结果表明氟哌啶醇不仅是一种有效的抗精神病药物，而且通过不同的机制作为抗内源性氧化应激的神经保护剂。此外，溶酶体靶向铁下垂抑制剂可用于治疗各种疾病，包括癌症、缺血再灌注损伤和神经退行性疾病，这些疾病与铁下垂有关。
Haloperidol is a widely used antipsychotic agent that exerts antipsychotic effects through a strong antagonism of dopamine D2 receptors. In addition, haloperidol is classified as a sigma-1 receptor (S1R) antagonist that prevents endogenous oxidative stress in cultured cells. However, pharmacological activities of haloperidol against oxidative stress remain unclear. Oxytosis/ferroptosis are iron-dependent nonapoptotic oxidative cell deaths that are regarded as two names for the same cell death pathway and the potential physiological relevance of oxytosis/ ferroptosis in multiple diseases is suggested. In the present study, the effects of haloperidol on oxytosis/ferroptosis were investigated in S1R-knockdown mouse hippocampal HT22 cells. The results indicate that haloperidol is a strong inhibitor of oxytosis/ ferroptosis independent of S1R. Imaging of HT22 cells with a newly developed fluorescent probe showed that haloperidol was localized to late endosomes and lysosomes and reduced the accumulation of lysosomal ferrous ions, resulting in reduced production of intracellular reactive oxygen species and inhibition of cell death. These results indicate that haloperidol is useful not only as an antipsychotic agent but also as a neuroprotective agent against endogenous oxidative stress via distinct mechanisms. Furthermore, lysosome-targeting ferroptosis inhibitors could be useful for the treatment of various diseases, including cancers, ischemiareperfusion injury, and neurodegenerative disorders, which have been associated with ferroptosis.