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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

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