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      Antidepressant Effects of Rosemary Extracts Associate With Anti-inflammatory Effect and Rebalance of Gut Microbiota


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          It is currently believed that inflammation acts as a central part in the pathophysiology of depression. Rosemary extracts (RE), the crucial active constituents extracted from Rosmarinus officinalis Linn, have drawn wide concerns because of their potential for anti-inflammatory effects. However, no study has highlighted the antidepressant effects of RE on chronic restraint stress (CRS) mice, and the inflammatory mechanisms related to gut microbiome have not yet been elucidated. This study showed that depressive-like behaviors, gut microbiota dysbiosis, and activation of inflammatory reactions in the hippocampus and serum of CRS mice, as well as activation of inflammatory reactions in BV-2 microglia cells induced by lipopolysaccharide (LPS), could be attenuated by RE. We found that the pretreatment with RE increased the time in the center of open field test (OFT), and decreased immobility duration in tail suspension test (TST) as well as forced swimming test (FST). Furthermore, RE enhanced the sequences proportion of Lactobacillus and Firmicutes, and reduced the sequences proportion of Bacteroidetes and Proteobacteria in feces. Moreover, RE obviously suppressed protein expression of IL-1β, TNF-α, p-NF-κ B p65 and Iba1 in hippocampus, and elevated BDNF as well as p-AKT/AKT expression. Importantly, pre-incubation with RE protected microglia by alleviating protein expression of IL-1β, TNF-α and p-NF-κ B p65 induced by LPS. Additionally, RE downregulated the level of IL-1β and TNF-α in serum. In conclusion, this study showed the antidepressant effects of RE are mediated by anti-inflammatory effects in hippocampus, serum and BV-2 microglia as well as rebalancing gut microbiota.

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          Chronic restraint stress causes anxiety- and depression-like behaviors, downregulates glucocorticoid receptor expression, and attenuates glutamate release induced by brain-derived neurotrophic factor in the prefrontal cortex.

          Stress and the resulting increase in glucocorticoid levels have been implicated in the pathophysiology of depressive disorders. We investigated the effects of chronic restraint stress (CRS: 6 hours × 28 days) on anxiety- and depression-like behaviors in rats and on the possible changes in glucocorticoid receptor (GR) expression as well as brain-derived neurotrophic factor (BDNF)-dependent neural function in the prefrontal cortex (PFC). We observed significant reductions in body weight gain, food intake and sucrose preference from 1 week after the onset of CRS. In the 5th week of CRS, we conducted open-field (OFT), elevated plus-maze (EPM) and forced swim tests (FST). We observed a decrease in the number of entries into open arms during the EPM (anxiety-like behavior) and increased immobility during the FST (depression-like behavior). When the PFC was removed after CRS and subject to western blot analysis, the GR expression reduced compared with control, while the levels of BDNF and its receptors remained unchanged. Basal glutamate concentrations in PFC acute slice which were measured by high performance liquid chromatography were not influenced by CRS. However, BDNF-induced glutamate release was attenuated after CRS. These results suggest that reduced GR expression and altered BDNF function may be involved in chronic stress-induced anxiety--and depression-like behaviors. Copyright © 2012 Elsevier Inc. All rights reserved.
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            The etiology of major depression (MDD), a common and complex disorder, remains obscure. Gene expression profiling was conducted on post-mortem brain tissue samples from Brodmann Area 10 (BA10) in the prefrontal cortex from psychotropic drug-free persons with a history of MDD and age, gender, and post-mortem interval matched normal controls (n=14 pairs of subjects). Microarray analysis was conducted using the Affymetrix Exon 1.0 ST arrays. A list of differential expression changes were determined by dual fold change-probability criteria (|ALR|>0.585 [equivalent to a 1.5-fold difference in either direction], p<0.01), while molecular pathways of interest were evaluated using Gene Set Enrichment Analysis (GSEA) software. The results strongly implicate increased apoptotic stress in the samples from the MDD group. Three anti-apoptotic factors, Y-box binding protein 1 (YBX1), Caspase-1 dominant-negative inhibitor pseudo-ICE (COP1), and the putative apoptosis inhibitor FKGS2 were over-expressed. Gene set analysis suggested up-regulation of a variety of pro- and anti-inflammatory cytokines, including interleukin 1α (IL1α), IL2, IL3, IL5, IL8, IL9, IL10, IL12A, IL13, IL15, IL18, interferon gamma (IFNγ), and lymphotoxin alpha (LTA; TNF super family member 1). The genes showing reduced expression included metallothionein 1M (MT1M), a zinc binding protein with a significant role in the modulation of oxidative stress. The results of this study suggest that post-mortem brain tissue samples from BA10, a region which is involved in reward-related behavior, show evidence of local inflammatory, apoptotic, and oxidative stress in MDD.
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              Functional biomarkers of depression: diagnosis, treatment, and pathophysiology.

              Major depressive disorder (MDD) is a heterogeneous illness for which there are currently no effective methods to objectively assess severity, endophenotypes, or response to treatment. Increasing evidence suggests that circulating levels of peripheral/serum growth factors and cytokines are altered in patients with MDD, and that antidepressant treatments reverse or normalize these effects. Furthermore, there is a large body of literature demonstrating that MDD is associated with changes in endocrine and metabolic factors. Here we provide a brief overview of the evidence that peripheral growth factors, pro-inflammatory cytokines, endocrine factors, and metabolic markers contribute to the pathophysiology of MDD and antidepressant response. Recent preclinical studies demonstrating that peripheral growth factors and cytokines influence brain function and behavior are also discussed along with their implications for diagnosing and treating patients with MDD. Together, these studies highlight the need to develop a biomarker panel for depression that aims to profile diverse peripheral factors that together provide a biological signature of MDD subtypes as well as treatment response.

                Author and article information

                Front Pharmacol
                Front Pharmacol
                Front. Pharmacol.
                Frontiers in Pharmacology
                Frontiers Media S.A.
                02 October 2018
                : 9
                [1] 1School of Pharmaceutical Science & Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University , Kunming, China
                [2] 2School of Basic Medical Sciences, Kunming Medical University , Kunming, China
                [3] 3Library, Yunnan Minzu University , Kunming, China
                [4] 4Department of Zoology, Kunming Medical University , Kunming, China
                Author notes

                Edited by: Emanuela Ricciotti, University of Pennsylvania, United States

                Reviewed by: Mohiuddin Ahmad, The University of Oklahoma Health Sciences Center, United States; Yuji Naito, Kyoto Prefectural University of Medicine, Japan

                *Correspondence: Rongping Zhang, zhrpkm@ 123456163.com Haofei Yu, Yufei5322032@ 123456163.com

                These authors have contributed equally to this work

                This article was submitted to Inflammation Pharmacology, a section of the journal Frontiers in Pharmacology

                Copyright © 2018 Guo, Xie, Li, Yuan, Zhang, Hu, Luo, Yu and Zhang.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                : 12 April 2018
                : 14 September 2018
                Page count
                Figures: 10, Tables: 0, Equations: 0, References: 45, Pages: 13, Words: 0
                Funded by: Applied Basic Research Foundation of Yunnan Province 10.13039/100007471
                Award ID: 2017FE467-160
                Award ID: 2017FE467-024
                Award ID: 2015FB006
                Award ID: 2015FB003
                Original Research

                Pharmacology & Pharmaceutical medicine
                depression,hippocampus,inflammation,gut microbiota,microglia,chronic restraint stress,rosemary extract


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