Institute for Drug Research, School of Pharmacy, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel (F.F., Y.M., S.B., P.D., M.M., O.D., A.P., B.T.); Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Madrid, Spain (V.F., P.R., I.G.-M., Á.M.V.); Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERdem), ISCIII, Madrid, Spain (V.F., P.R., I.G.-M., Á.M.V.); and Department of Biochemistry and Molecular Biology, IMRIC, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel (E.G.).
Institute for Drug Research, School of Pharmacy, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel (F.F., Y.M., S.B., P.D., M.M., O.D., A.P., B.T.); Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Madrid, Spain (V.F., P.R., I.G.-M., Á.M.V.); Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERdem), ISCIII, Madrid, Spain (V.F., P.R., I.G.-M., Á.M.V.); and Department of Biochemistry and Molecular Biology, IMRIC, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel (E.G.)
J Pharmacol Exp Ther. 2020 Sep;374(3):452-461. doi: 10.1124/jpet.119.264481. Epub 2020 Jun 17.
Schizophrenia is a mental disease that results in decreased life expectancy and well-being by promoting obesity and sedentary lifestyles. Schizophrenia is treated by antipsychotic drugs. Although the second-generation antipsychotics (SGA), Olanzapine and Aripiprazole, are more effective in treating schizophrenia, they display a higher risk of metabolic side effects, mostly by development of diabetes and insulin resistance, weight gain, and dyslipidemia. Endoplasmic reticulum (ER) stress is induced when ER homeostasis of lipid biosynthesis and protein folding is impaired. This leads to the activation of the unfolded protein response (UPR), a signaling cascade that aims to restore ER homeostasis or initiate cell death. Chronic conditions of ER stress in the liver are associated with diabetes and perturbed lipid metabolism. These metabolic dysfunctions resemble the pharmacological side effects of SGAs. We therefore investigated whether SGAs promote the UPR in human and mouse hepatocytes. We observed full-fledged activation of ER stress by Aripiprazole not by Olanzapine. This occurred at low micromolar concentrations and to variable intensities in different cell types, such as hepatocellular carcinoma, melanoma, and glioblastoma. Mechanistically, Aripiprazole caused depletion of ER calcium, leading to activation of inositol-requiring enzyme 1 (IRE1)and protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), two major transducers of the UPR. Cells underwent apoptosis with Aripiprazole treatment, which coincided with UPR induction, and this effect was reduced by adding glutathione without affecting UPR itself. Deletion of IRE1 from HepG2, a human liver cancer cell line, protected cells from Aripiprazole toxicity. Our study reveals for the first time a cytotoxic effect of Aripiprazole that involves the induction of ER stress. SIGNIFICANCE STATEMENT: The antischizophrenic drug Aripiprazole exerts cytotoxic properties at high concentrations. This study shows that this cytotoxicity is associated with the induction of endoplasmic reticulum (ER) stress and IRE1 activation, mechanisms involved in diet-induced obesity. Aripiprazole induced ER stress and calcium mobilization from the ER in human and mouse hepatocytes. Our study highlights a new mechanism of Aripiprazole that is not related to its effect on dopamine signaling.
精神分裂症是一种导致预期寿命和幸福感降低的精神疾病，它通过促进肥胖和久坐的生活方式来实现。精神分裂症的治疗方法是使用抗精神病药物。虽然第二代抗精神病药物（SGA）奥氮平和阿立哌唑在治疗精神分裂症方面更有效，但它们显示出更高的代谢副作用风险，主要表现为糖尿病和胰岛素抵抗、体重增加和血脂异常的发展。内质网（ER）应激是由脂质生物合成和蛋白质折叠的 ER 稳态受损引起的。这导致未折叠蛋白反应（UPR）的激活，这是一种信号级联反应，旨在恢复 ER 稳态或启动细胞死亡。肝脏中 ER 应激的慢性状态与糖尿病和脂质代谢紊乱有关。这些代谢功能障碍类似于 SGA 的药理学副作用。因此，我们研究了 SGA 是否会促进人源和鼠源肝细胞中的 UPR。我们观察到阿立哌唑而非奥氮平充分激活了 ER 应激。这种情况发生在低微摩尔浓度下，并且在不同的细胞类型（如肝癌、黑色素瘤和神经胶质瘤）中强度不同。从机制上讲，阿立哌唑导致 ER 钙耗竭，导致肌醇需求酶 1（IRE1）和蛋白激酶 R（PKR）样内质网激酶（PERK）的激活，这是 UPR 的两个主要传感器。用阿立哌唑处理会导致细胞凋亡，这与 UPR 诱导同时发生，并且这种作用可以通过添加谷胱甘肽来降低，而不影响 UPR 本身。在人肝癌细胞系 HepG2 中删除 IRE1 可保护细胞免受阿立哌唑的毒性。我们的研究首次揭示了阿立哌唑的细胞毒性作用，涉及 ER 应激的诱导。意义：抗精神分裂症药物阿立哌唑在高浓度下具有细胞毒性。这项研究表明，这种细胞毒性与内质网（ER）应激和 IRE1 激活有关，这些机制与饮食诱导的肥胖有关。阿立哌唑诱导人源和鼠源肝细胞内质网应激和 ER 钙动员。我们的研究强调了阿立哌唑的一个新机制，与它对多巴胺信号的作用无关。
