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      The analgesic effects of triptolide in the bone cancer pain rats via inhibiting the upregulation of HDACs in spinal glial cells

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          Abstract

          Background

          Bone cancer pain (BCP) severely compromises the quality of life, while current treatments are still unsatisfactory. Here, we tested the antinociceptive effects of triptolide (T10), a substance with considerable anti-tumor efficacies on BCP, and investigated the underlying mechanisms targeting the spinal dorsal horn (SDH).

          Methods

          Intratibial inoculation of Walker 256 mammary gland carcinoma cells was used to establish a BCP model in rats. T10 was intrathecally injected, and mechanical allodynia was tested by measuring the paw withdrawal thresholds (PWTs). In mechanism study, the activation of microglia, astrocytes, and the mitogen-activated protein kinase (MAPK) pathways in the SDH were evaluated by immunofluorescence staining or Western blot analysis of Iba-1, GFAP, p-ERK, p-p38, and p-JNK. The expression and cellular localization of histone deacetylases (HDACs) 1 and 2 were also detected to investigate molecular mechanism.

          Results

          Intrathecal injection of T10 inhibited the bone cancer-induced mechanical allodynia with an ED 50 of 5.874 μg/kg. This effect was still observed 6 days after drug withdrawal. Bone cancer caused significantly increased expression of HDAC1 in spinal microglia and neurons, with HDAC2 markedly increased in spinal astrocytes, which were accompanied by the upregulation of MAPK pathways and the activation of microglia and astrocytes in the SDH. T10 reversed the increase of HDACs, especially those in glial cells, and inhibited the glial activation.

          Conclusions

          Our results suggest that the upregulation of HDACs contributes to the pathological activation of spinal glial cells and the chronic pain caused by bone cancer, while T10 help to relieve BCP possibly via inhibiting the upregulation of HDACs in the glial cells in the SDH and then blocking the neuroinflammation induced by glial activation.

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          Most cited references52

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          Ethical guidelines for investigations of experimental pain in conscious animals.

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            Compromised MAPK signaling in human diseases: an update.

            The mitogen-activated protein kinases (MAPKs) in mammals include c-Jun NH2-terminal kinase (JNK), p38 MAPK, and extracellular signal-regulated kinase (ERK). These enzymes are serine-threonine protein kinases that regulate various cellular activities including proliferation, differentiation, apoptosis or survival, inflammation, and innate immunity. The compromised MAPK signaling pathways contribute to the pathology of diverse human diseases including cancer and neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. The JNK and p38 MAPK signaling pathways are activated by various types of cellular stress such as oxidative, genotoxic, and osmotic stress as well as by proinflammatory cytokines such as tumor necrosis factor-α and interleukin 1β. The Ras-Raf-MEK-ERK signaling pathway plays a key role in cancer development through the stimulation of cell proliferation and metastasis. The p38 MAPK pathway contributes to neuroinflammation mediated by glial cells including microglia and astrocytes, and it has also been associated with anticancer drug resistance in colon and liver cancer. We here summarize recent research on the roles of MAPK signaling pathways in human diseases, with a focus on cancer and neurodegenerative conditions.
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              Pathological pain and the neuroimmune interface.

              Reciprocal signalling between immunocompetent cells in the central nervous system (CNS) has emerged as a key phenomenon underpinning pathological and chronic pain mechanisms. Neuronal excitability can be powerfully enhanced both by classical neurotransmitters derived from neurons, and by immune mediators released from CNS-resident microglia and astrocytes, and from infiltrating cells such as T cells. In this Review, we discuss the current understanding of the contribution of central immune mechanisms to pathological pain, and how the heterogeneous immune functions of different cells in the CNS could be harnessed to develop new therapeutics for pain control. Given the prevalence of chronic pain and the incomplete efficacy of current drugs--which focus on suppressing aberrant neuronal activity--new strategies to manipulate neuroimmune pain transmission hold considerable promise.
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                Author and article information

                Contributors
                86-29-84773087 , jinlian@fmmu.edu.cn
                86-29-84777735 , dengjianping@yahoo.com
                86-29-84773074-8001 , donganat@fmmu.edu.cn
                Journal
                J Neuroinflammation
                J Neuroinflammation
                Journal of Neuroinflammation
                BioMed Central (London )
                1742-2094
                2 November 2017
                2 November 2017
                2017
                : 14
                : 213
                Affiliations
                [1 ]ISNI 0000 0004 1761 4404, GRID grid.233520.5, Department of Human Anatomy & K.K. Leung Brain Research Centre, Preclinical School of Medicine, , The Fourth Military Medical University, ; Xi’an, 710032 China
                [2 ]Department of Orthopedics, Xijing Hospital, The Fourth Military Medical University, Xi’an, 710032 China
                [3 ]ISNI 0000 0004 1761 4404, GRID grid.233520.5, State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Disease, Department of Periodontology, School of Stomatology, , The Fourth Military Medical University, ; Xi’an, 710032 China
                [4 ]Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University, Xi’an, 710038 China
                [5 ]ISNI 0000 0004 1761 4404, GRID grid.233520.5, Student Brigade, The Fourth Military Medical University, ; Xi’an, 710032 China
                Author information
                http://orcid.org/0000-0001-6375-7957
                Article
                988
                10.1186/s12974-017-0988-1
                5668986
                29096654
                b29d0916-7458-41a0-9c33-3bb9a8f64ff4
                © The Author(s). 2017

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 10 July 2017
                : 26 October 2017
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 31671087
                Award ID: 81671197
                Award Recipient :
                Funded by: The Intramural Grant of the Fourth Military Medical University
                Award ID: 4139C4IAA1
                Award Recipient :
                Funded by: The International Scientific and Technological Cooperation and Exchange Program of Shaan'Xi Province
                Award ID: 2016KW-019
                Award Recipient :
                Categories
                Research
                Custom metadata
                © The Author(s) 2017

                Neurosciences
                bone cancer pain,triptolide,antinociceptive effect,glial cell,histone deacetylase
                Neurosciences
                bone cancer pain, triptolide, antinociceptive effect, glial cell, histone deacetylase

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