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

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.

• Authors: Kai-Xiang Zhou, Xiao-Tao He, Xiao-Fan Hu, Wen-Jun Zhao, Cui-Xia Li, Chen Zhang, Ting Zhang, Ze-Xu Gu, Jian-Ping Deng, Yu-Lin Dong
• Journal: Brain research bulletin (Brain Res Bull) Vol. 149 Pg. 137-147 (07 2019) ISSN: 1873-2747 [Electronic] United States
• PMID: 31002915 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier Inc. All rights reserved.

Chemical References

• Cytokines
• Tumor Necrosis Factor-alpha
• XENP 1595
• p38 Mitogen-Activated Protein Kinases

Topics

• Animals
• Astrocytes (drug effects, metabolism, pathology)
• Bone Neoplasms (drug therapy, metabolism, pathology)
• Cancer Pain (drug therapy, metabolism, pathology)
• Cytokines (metabolism)
• Female
• Injections, Spinal (methods)
• Microglia (drug effects, metabolism, pathology)
• Neuroglia (drug effects, metabolism, pathology)
• Rats
• Rats, Sprague-Dawley
• Spinal Cord Dorsal Horn (drug effects, metabolism, pathology)
• Tumor Necrosis Factor-alpha (antagonists & inhibitors, metabolism, pharmacology)
• p38 Mitogen-Activated Protein Kinases (antagonists & inhibitors)