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Brain Res Bull. 2019 Jul;149:137-147. doi: 10.1016/j.brainresbull.2019.04.009. Epub 2019 Apr 16.

XPro1595 ameliorates bone cancer pain in rats via inhibiting p38-mediated glial cell activation and neuroinflammation in the spinal dorsal horn.

Author information

1
Department of Human Anatomy, Histology and Embryology & K.K. Leung Brain Research Centre, Preclinical School of Medicine, The Fourth Military Medical University, Xi'an 710032, PR China; Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an 710038, PR China; Student Brigade, Preclinical School of Medicine, The Fourth Military Medical University, Xi'an 710032, PR China.
2
Department of Human Anatomy, Histology and Embryology & K.K. Leung Brain Research Centre, Preclinical School of Medicine, The Fourth Military Medical University, Xi'an 710032, PR China; 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, PR China.
3
Department of Human Anatomy, Histology and Embryology & K.K. Leung Brain Research Centre, Preclinical School of Medicine, The Fourth Military Medical University, Xi'an 710032, PR China; Institute of Orthopaedics, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, PR China.
4
Department of Human Anatomy, Histology and Embryology & K.K. Leung Brain Research Centre, Preclinical School of Medicine, The Fourth Military Medical University, Xi'an 710032, PR China; Student Brigade, Preclinical School of Medicine, The Fourth Military Medical University, Xi'an 710032, PR China.
5
Departmetn of Orthodontics, State Key Laboratory of Military Stomatology, The Fourth Military Medical University, Xi'an 710032, PR China.
6
Department of Human Anatomy, Histology and Embryology & K.K. Leung Brain Research Centre, Preclinical School of Medicine, The Fourth Military Medical University, Xi'an 710032, PR China.
7
Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an 710038, PR China. Electronic address: dengjianping@yahoo.com.
8
Department of Human Anatomy, Histology and Embryology & K.K. Leung Brain Research Centre, Preclinical School of Medicine, The Fourth Military Medical University, Xi'an 710032, PR China. Electronic address: donganat@fmmu.edu.cn.

Abstract

Bone cancer pain (BCP) profoundly compromises the life quality of patients with bone metastases. Severe side effects of the drugs which were widely used and effective in the various stages of this condition results in a huge challenge for BCP treatment. Here, we investigated the antinociceptive effects of XPro1595, a soluble tumor necrosis factor (solTNF) inhibitor with considerable immunoregulatory efficacy, on BCP, as well as the underlying mechanisms within the spinal dorsal horn (SDH). Walker 256 mammary gland carcinoma cells were intratibially inoculated to induce BCP. Intrathecal administration of XPro1595 alleviated bone cancer-induced chronic pain in a dose-dependent manner, with an ED50 of 9.69 mg/kg. Bone cancer resulted in the activation of astrocytes and microglia in the SDH through the upregulation of mitogen-activated protein kinase (MAPK) pathways, which was accompanied by an over-expression of pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6. XPro1595suppressed bone cancer-evoked glial activation and the consequent neuroinflammation. These inhibitory effects of XPro1595 were, at least partially, mediated by a reduction in the phosphorylation of p38 MAPK in spinal glial cells. In conclusion, inhibition of spinal glia by XPro1595 may have utility in the treatment of bone cancer-induced neuroinflammation, and our results further implicate XPro1595 as a new promising therapeutic agent for BCP.

KEYWORDS:

Antinociceptive effect; Bone cancer pain; Glial cells; Pro-Inflammatory cytokines; XPro1595; p38

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