Faculty of Pharmacy, Modern University for Technology and Information, Egypt.
Department of Anatomy and Embryology, Faculty of Medicine, Ain Shams University Cairo, Egypt.
Pharmacol Biochem Behav. 2017 Sep;160:30-38. doi: 10.1016/j.pbb.2017.08.003. Epub 2017 Aug 9.
Recently, depression has been envisioned as more than an alteration in neurotransmitters centered around receptor signaling pathways. Consequently, the precise mechanisms of selective serotonin reuptake inhibitor (SSRI) antidepressant drugs such as fluoxetine are being revisited. Zinc is a trace element that has been long implicated in the psychopathology and therapy of depression. Zinc has been found to be sequestered and dispensed during stress and inflammation through a family of proteins called metallothioneins (MTs). In addition, MTs are well known for their antioxidant and therefore cytoprotective action. Changes in MTs, their upstream regulators and downstream effectors in response to fluoxetine have not been yet studied. The aim of the present study is to examine whether depression-induced changes in protein levels and mRNA levels of nuclear factor-erythroid 2-related factor 2 (Nrf2), MTs, antioxidant defensive enzyme heme oxygenase (HO-1), zinc-specific receptor GPR39 and brain derived neurotrophic factor (BDNF) in the hippocampus can be reversed by fluoxetine treatment, zinc supplementation or a combination of the two.
The present study investigated the effect of chronic (4weeks) combined treatment with zinc hydroaspartate (15mg/kg) and fluoxetine (10mg/kg) on a chronic mild stress model (CMS) in male Sprague-Dawley rats.
Hippocampal mRNA and protein levels of Nrf2, HO-1, MTs, GPR39 (protein level only) and BDNF were significantly higher in response to a combined therapy of fluoxetine and zinc than to either monotherapy. Additionally, HO-1 and MTs gene expression was correlated with that of Nrf2 in the FLX-only group.
Fluoxetine therapy activated the expression of MTs and HO-1 through an Nrf2-dependent pathway. When FLX was escorted by zinc, activated MTs had a positive impact on BDNF through the zinc signaling receptor GPR39, resulting in general improvement in neuronal plasticity as well as reduction of neuronal atrophy and neuronal cell loss.
近来，抑郁症已不仅仅被认为是神经递质的改变，其中心是受体信号通路。因此，人们正在重新审视选择性 5-羟色胺再摄取抑制剂（SSRI）类抗抑郁药（如氟西汀）的确切作用机制。锌是一种微量元素，长期以来一直与抑郁症的发病机制和治疗有关。研究发现，锌在应激和炎症过程中通过一组称为金属硫蛋白（MTs）的蛋白质被隔离和释放。此外，MTs 以其抗氧化作用和细胞保护作用而闻名。然而，氟西汀对 MTs 及其上下游效应物的影响尚未得到研究。本研究旨在探讨氟西汀治疗、锌补充或两者联合治疗是否能逆转抑郁引起的海马核因子-红细胞 2 相关因子 2（Nrf2）、MTs、抗氧化防御酶血红素加氧酶（HO-1）、锌特异性受体 GPR39 和脑源性神经营养因子（BDNF）的蛋白水平和 mRNA 水平的变化。
本研究调查了慢性（4 周）联合使用锌天冬氨酸（15mg/kg）和氟西汀（10mg/kg）治疗对雄性 Sprague-Dawley 大鼠慢性轻度应激模型（CMS）的影响。
与氟西汀单药治疗相比，联合治疗组海马 Nrf2、HO-1、MTs、GPR39（仅蛋白水平）和 BDNF 的 mRNA 和蛋白水平均显著升高。此外，FLX 组中 HO-1 和 MTs 的基因表达与 Nrf2 的表达相关。
氟西汀治疗通过 Nrf2 依赖途径激活 MTs 和 HO-1 的表达。当 FLX 与锌一起使用时，激活的 MTs 通过锌信号传导受体 GPR39 对 BDNF 产生积极影响，从而改善神经元可塑性，减少神经元萎缩和神经元细胞丢失。
