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

• Published in: Brain research bulletin Vol. 149; pp. 137 - 147
• Main Authors: Zhou, Kai-Xiang, He, Xiao-Tao, Hu, Xiao-Fan, Zhao, Wen-Jun, Li, Cui-Xia, Zhang, Chen, Zhang, Ting, Gu, Ze-Xu, Deng, Jian-Ping, Dong, Yu-Lin
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.07.2019
• Subjects: Antinociceptive effect; Bone cancer pain; Glial cells; p38; Pro-Inflammatory cytokines; XPro1595; XPro1595; Pro-Inflammatory cytokines; Antinociceptive effect; Glial cells; p38; Bone cancer pain
• ISSN: 0361-9230; 1873-2747
• DOI: 10.1016/j.brainresbull.2019.04.009

•XPro1595 attenuates the mechanical allodynia of BCP in a dose-dependent manner.•XPro1595suppresses the tumor cell inoculation-induced activation of astrocytes and microglia in the SDH.•XPro1595 decreases the upregulation of pro-inflammatory cytokine expression in the SDH of BCP rats.•XPro1595 inhibits the phosphorylation of p38 but not ERK or JNK of MAPK signaling pathway in the SDH of BCP rats. 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.