Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON, Canada.
Mood Disorders Program and Women's Health Concerns Clinic, St. Joseph's Healthcare, Hamilton, ON, Canada.
Bipolar Disord. 2021 Feb;23(1):76-83. doi: 10.1111/bdi.13019. Epub 2020 Oct 27.
Bipolar Disorder (BD) is associated with a decrease in cellular resilience. Despite the half a century old discovery of lithium's efficacy for the treatment of BD, its exact mechanisms remain elusive. Accumulating data suggest that lithium's cytoprotective properties involve the modulation of several UPR proteins, such as GRP78. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum resident protein that regulates proteostasis through directly interacting with GRP78. The purpose of this study was to determine whether lithium increases MANF expression using cellular and rodent models and, if so, to elucidate the cellular mechanisms of action.
Mouse striatal neuroblasts were treated with PBS, lithium, or lithium + Activator Protein-1 (AP-1) inhibitor for 24-72 hours. Once cells were harvested, mRNA was extracted. In vivo experiments included, intraperitoneal injections of lithium or saline to male Sprague Dawley rats twice daily for 14 consecutive days. Following drug treatment, brain tissue was isolated, and mRNA was extracted from various regions. MANF gene expression was measured using RT-qPCR.
In vitro studies showed lithium-treated cells displayed a significant increase in MANF mRNA expression compared to controls. In contrast, cells treated with lithium and AP-1 inhibitor showed no increase in expression. Similarly, in vivo studies revealed that lithium-treated rats compared to controls had a significant increase in MANF expression in the PFC and striatum.
Taken together, these data suggest that lithium's therapeutic mechanism involves the maintenance of ER homeostasis via increased MANF gene expression mediated by the AP-1 transcription factor.
双相情感障碍（BD）与细胞弹性的下降有关。尽管锂治疗 BD 的功效已有半个世纪的历史，但确切机制仍不清楚。越来越多的数据表明，锂的细胞保护特性涉及几种 UPR 蛋白的调节，如 GRP78。脑中介星形胶质细胞衍生的神经营养因子（MANF）是一种内质网驻留蛋白，通过与 GRP78 直接相互作用来调节蛋白质稳态。本研究的目的是确定锂是否通过细胞和啮齿动物模型增加 MANF 表达，如果是这样，阐明其作用的细胞机制。
用 PBS、锂或锂+激活蛋白-1（AP-1）抑制剂处理小鼠纹状体神经母细胞瘤 24-72 小时。一旦细胞收获，提取 mRNA。体内实验包括对雄性 Sprague Dawley 大鼠每天两次腹腔注射锂或生理盐水连续 14 天。药物治疗后，分离脑组织，从不同区域提取 mRNA。使用 RT-qPCR 测量 MANF 基因表达。
体外研究表明，与对照组相比，锂处理的细胞显示 MANF mRNA 表达显著增加。相比之下，用锂和 AP-1 抑制剂处理的细胞表达没有增加。同样，体内研究表明，与对照组相比，锂处理的大鼠在 PFC 和纹状体中 MANF 表达显著增加。
综上所述，这些数据表明，锂的治疗机制涉及通过 AP-1 转录因子介导的 MANF 基因表达增加来维持内质网内稳态。
