Abstract Lithium (Li) is a widely-used medication for the treatment of patients with bipolar disorder. Li causes different complications. One of the most important adverse effects of Li is neurotoxicity. Neurotoxicity is usually irreversible which may lead to very important complications. The symptoms of Li-induced neurotoxicity include tremor, delirium, seizures, coma, and death. In this study, we wanted to evaluate the exact sub-cellular mechanisms of Li-induced neurotoxicity. For this purpose, we used primary neuronal cortical culture for investigating lithium-induced neurotoxicity. We applied the postnatal rat pups for isolating the cortical neurons. After that, we evaluated neural viability, neural reactive oxygen specious (ROS), lipid peroxidation, mitochondrial membrane potential (MMP), lysosomal membrane integrity (LMI), and reduced (GSH) and oxidized (GSSG) glutathione. Our results demonstrated that the cytotoxic effect of Li has mediated through lysosomal membrane leakage associated with ROS formation and reduction of MMP. Furthermore, the incubation of isolated neurons with Li caused rapid GSH depletion (as GSSG efflux) as another marker of cellular oxidative stress. We concluded that Li causes neurotoxicity in a dose-dependent manner. Besides, Li-induced neurotoxicity is a result of the generation of ROS and LP, which leads to mitochondrial/lysosomal toxic cross-talk.

中文翻译：

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使用大鼠神经元皮质培养物研究锂诱导的神经毒性的新方法：氧化应激和溶酶体/线粒体毒性串扰的参与

摘要 锂（Li）是一种广泛用于治疗双相情感障碍患者的药物。Li 会导致不同的并发症。Li最重要的副作用之一是神经毒性。神经毒性通常是不可逆的，这可能会导致非常重要的并发症。锂诱导的神经毒性症状包括震颤、谵妄、癫痫、昏迷和死亡。在这项研究中，我们想评估锂诱导的神经毒性的确切亚细胞机制。为此，我们使用原代神经元皮质培养来研究锂诱导的神经毒性。我们应用出生后的幼鼠来分离皮质神经元。之后，我们评估了神经活力、神经活性氧 (ROS)、脂质过氧化、线粒体膜电位 (MMP)、溶酶体膜完整性 (LMI)、和还原 (GSH) 和氧化 (GSSG) 谷胱甘肽。我们的结果表明，Li 的细胞毒性作用是通过与 ROS 形成和 MMP 减少相关的溶酶体膜渗漏介导的。此外，离体神经元与 Li 的孵育导致 GSH 快速消耗（如 GSSG 外流），这是细胞氧化应激的另一个标志物。我们得出结论，Li 以剂量依赖性方式引起神经毒性。此外，锂诱导的神经毒性是产生 ROS 和 LP 的结果，导致线粒体/溶酶体毒性串扰。离体神经元与 Li 的孵育导致 GSH 快速消耗（作为 GSSG 流出）作为细胞氧化应激的另一个标志物。我们得出结论，Li 以剂量依赖性方式引起神经毒性。此外，锂诱导的神经毒性是产生 ROS 和 LP 的结果，导致线粒体/溶酶体毒性串扰。离体神经元与 Li 的孵育导致 GSH 快速消耗（作为 GSSG 流出）作为细胞氧化应激的另一个标志物。我们得出结论，Li 以剂量依赖性方式引起神经毒性。此外，锂诱导的神经毒性是产生 ROS 和 LP 的结果，导致线粒体/溶酶体毒性串扰。