PMID- 28801265 OWN - NLM STAT- MEDLINE DCOM- 20180509 LR - 20181018 IS - 1873-5177 (Electronic) IS - 0091-3057 (Linking) VI - 160 DP - 2017 Sep TI - Fluoxetine coupled with zinc in a chronic mild stress model of depression: Providing a reservoir for optimum zinc signaling and neuronal remodeling. PG - 30-38 LID - S0091-3057(17)30361-1 [pii] LID - 10.1016/j.pbb.2017.08.003 [doi] AB - BACKGROUND: 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. MATERIAL AND METHODS: 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. RESULTS: 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. CONCLUSION: 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. CI - Copyright (c) 2017 Elsevier Inc. All rights reserved. FAU - Omar, Nesreen Nabil AU - Omar NN AD - Faculty of Pharmacy, Modern University for Technology and Information, Egypt. Electronic address: nesreen.nabil@pharm.mti.edu.eg. FAU - Tash, Reham Fathy AU - Tash RF AD - Department of Anatomy and Embryology, Faculty of Medicine, Ain Shams University Cairo, Egypt. LA - eng PT - Journal Article DEP - 20170809 PL - United States TA - Pharmacol Biochem Behav JT - Pharmacology, biochemistry, and behavior JID - 0367050 RN - 0 (Antidepressive Agents, Second-Generation) RN - 01K63SUP8D (Fluoxetine) RN - 333DO1RDJY (Serotonin) RN - 57-50-1 (Sucrose) RN - J41CSQ7QDS (Zinc) RN - W980KJ009P (Corticosterone) SB - IM MH - Animals MH - Antidepressive Agents, Second-Generation/administration & dosage/*therapeutic use MH - Brain/metabolism MH - Chronic Disease MH - Corticosterone/blood MH - Depression/*drug therapy/pathology MH - *Disease Models, Animal MH - Fluoxetine/administration & dosage/*therapeutic use MH - Male MH - Neurons/*pathology MH - Rats MH - Rats, Sprague-Dawley MH - Real-Time Polymerase Chain Reaction MH - Serotonin/metabolism MH - *Signal Transduction MH - *Stress, Psychological MH - Sucrose/administration & dosage MH - Weight Gain/drug effects MH - Zinc/administration & dosage/*therapeutic use OTO - NOTNLM OT - CMS OT - Fluoxetine OT - Metallothioneins OT - Neuronal plasticity OT - Zinc OT - Zinc signaling EDAT- 2017/08/13 06:00 MHDA- 2018/05/10 06:00 CRDT- 2017/08/13 06:00 PHST- 2017/06/11 00:00 [received] PHST- 2017/07/30 00:00 [revised] PHST- 2017/08/07 00:00 [accepted] PHST- 2017/08/13 06:00 [pubmed] PHST- 2018/05/10 06:00 [medline] PHST- 2017/08/13 06:00 [entrez] AID - S0091-3057(17)30361-1 [pii] AID - 10.1016/j.pbb.2017.08.003 [doi] PST - ppublish SO - Pharmacol Biochem Behav. 2017 Sep;160:30-38. doi: 10.1016/j.pbb.2017.08.003. Epub 2017 Aug 9.