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      Role of Inflammatory Bone Markers in the Antidepressant Actions of ( R)-Ketamine in a Chronic Social Defeat Stress Model

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          Abstract

          Background

          A recent study demonstrated that inflammatory bone markers play a role in the antidepressant functions of ( R,S)-ketamine in treatment-resistant patients with depression. We examined the effect of inflammatory bone markers in the antidepressant functions of ( R)-ketamine and ( S)-ketamine in a chronic social defeat stress model.

          Methods

          Behavioral tests for antidepressant actions were performed after a single administration of ( R)-ketamine or ( S)-ketamine. We measured inflammatory bone marker levels in the plasma, which included osteoprotegerin, receptor activator of nuclear factor κB ligand, and osteopontin.

          Results

          ( R)-ketamine’s antidepressant effects were more potent than those of ( S)-ketamine in the behavioral tests. Furthermore, ( R)-ketamine but not (S)-ketamine significantly attenuated increased plasma levels of receptor activator of nuclear factor κB ligand in chronic social defeat stress-susceptible mice. We found a positive correlation between sucrose preference and osteoprotegerin/receptor activator of nuclear factor κB ligand ratio.

          Conclusions

          Our findings demonstrate that inflammatory bone markers may play a role in the antidepressant effects of ( R)-ketamine.

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          Most cited references24

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          Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants.

          Depression is a common, devastating illness. Current pharmacotherapies help many patients, but high rates of a partial response or no response, and the delayed onset of the effects of antidepressant therapies, leave many patients inadequately treated. However, new insights into the neurobiology of stress and human mood disorders have shed light on mechanisms underlying the vulnerability of individuals to depression and have pointed to novel antidepressants. Environmental events and other risk factors contribute to depression through converging molecular and cellular mechanisms that disrupt neuronal function and morphology, resulting in dysfunction of the circuitry that is essential for mood regulation and cognitive function. Although current antidepressants, such as serotonin-reuptake inhibitors, produce subtle changes that take effect in weeks or months, it has recently been shown that treatment with new agents results in an improvement in mood ratings within hours of dosing patients who are resistant to typical antidepressants. Within a similar time scale, these new agents have also been shown to reverse the synaptic deficits caused by stress.
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            Functions of RANKL/RANK/OPG in bone modeling and remodeling.

            The discovery of the RANKL/RANK/OPG system in the mid 1990s for the regulation of bone resorption has led to major advances in our understanding of how bone modeling and remodeling are regulated. It had been known for many years before this discovery that osteoblastic stromal cells regulated osteoclast formation, but it had not been anticipated that they would do this through expression of members of the TNF superfamily: receptor activator of NF-kappaB ligand (RANKL) and osteoprotegerin (OPG), or that these cytokines and signaling through receptor activator of NF-kappaB (RANK) would have extensive functions beyond regulation of bone remodeling. RANKL/RANK signaling regulates osteoclast formation, activation and survival in normal bone modeling and remodeling and in a variety of pathologic conditions characterized by increased bone turnover. OPG protects bone from excessive resorption by binding to RANKL and preventing it from binding to RANK. Thus, the relative concentration of RANKL and OPG in bone is a major determinant of bone mass and strength. Here, we review our current understanding of the role of the RANKL/RANK/OPG system in bone modeling and remodeling.
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              R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects

              Although the efficacy of racemate ketamine, a rapid onset and sustained antidepressant, for patients with treatment-resistant depression was a serendipitous finding, clinical use of ketamine is limited, due to psychotomimetic side effects and abuse liability. Behavioral and side-effect evaluation tests were applied to compare the two stereoisomers of ketamine. To elucidate their potential therapeutic mechanisms, we examined the effects of these stereoisomers on brain-derived neurotrophic factor (BDNF)–TrkB signaling, and synaptogenesis in selected brain regions. In the social defeat stress and learned helplessness models of depression, R-ketamine showed a greater potency and longer-lasting antidepressant effect than S-ketamine (esketamine). Furthermore, R-ketamine induced a more potent beneficial effect on decreased dendritic spine density, BDNF–TrkB signaling and synaptogenesis in the prefrontal cortex (PFC), CA3 and dentate gyrus (DG) of the hippocampus from depressed mice compared with S-ketamine. However, neither stereoisomer affected these alterations in the nucleus accumbens of depressed mice. In behavioral tests for side effects, S-ketamine, but not R-ketamine, precipitated behavioral abnormalities, such as hyperlocomotion, prepulse inhibition deficits and rewarding effects. In addition, a single dose of S-ketamine, but not R-ketamine, caused a loss of parvalbumin (PV)-positive cells in the prelimbic region of the medial PFC and DG. These findings suggest that, unlike S-ketamine, R-ketamine can elicit a sustained antidepressant effect, mediated by increased BDNF–TrkB signaling and synaptogenesis in the PFC, DG and CA3. R-ketamine appears to be a potent, long-lasting and safe antidepressant, relative to S-ketamine, as R-ketamine appears to be free of psychotomimetic side effects and abuse liability.
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                Author and article information

                Journal
                Int J Neuropsychopharmacol
                Int. J. Neuropsychopharmacol
                ijnp
                International Journal of Neuropsychopharmacology
                Oxford University Press (US )
                1461-1457
                1469-5111
                November 2018
                19 July 2018
                19 July 2018
                : 21
                : 11
                : 1025-1030
                Affiliations
                [1 ]Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan
                [2 ]Wuxi Mental Health Center, Nanjing Medical University, Wuxi, China
                Author notes
                Correspondence: Kenji Hashimoto, PhD, Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba 260–8670, Japan ( hashimoto@ 123456faculty.chiba-u.jp ).
                Article
                pyy065
                10.1093/ijnp/pyy065
                6209851
                30032169
                d018e815-01eb-4731-9a40-21a8b1394288
                © The Author(s) 2018. Published by Oxford University Press on behalf of CINP.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

                History
                : 10 May 2018
                : 29 June 2018
                : 17 July 2018
                Page count
                Pages: 6
                Funding
                Funded by: Japan Agency for Medical Research and Development 10.13039/100009619
                Award ID: JP18dm0107119
                Categories
                Brief Report

                Pharmacology & Pharmaceutical medicine
                antidepressant,(r)-ketamine,(s)-ketamine,inflammation,bone
                Pharmacology & Pharmaceutical medicine
                antidepressant, (r)-ketamine, (s)-ketamine, inflammation, bone

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