B14 ameliorates bone cancer pain through downregulating spinal interleukin-1β via suppressing neuron JAK2/STAT3 pathway

Abstract

Curcumin has several pharmacological properties such as anti-inflammatory, antioxidant, and neuroprotective activities. B14 is a curcumin analogue and is considered to be a more potent compound with preserved pharmacodynamic activities. Based on the previous research studies, janus-activated kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway plays a remarkable role in inflammation, chronic pain, and even contributes to the pathogenesis of neuropathic pain. Pro-inflammatory cytokines interleukin-1β is a downstream factor of JAK2/STAT3 signal transition pathway, which participates in neuron injury and inflammation. We hypothesized that this signal transition pathway played an indispensable role in bone cancer pain. We herein established a bone cancer pain model to monitor the variation of JAK2/STAT3 signal transduction pathway and measured the effect of B14. The results in bone cancer pain model showed that (i) the levels of interleukin-1β were elevated, and the ratios of p-JAK2/JAK2 and p-STAT3/STAT3 were increased; (ii) double immunostaining showed that p-JAK2, p-STAT3, and interleukin-1β were colocalized primarily with neurons, rather than with astrocytes or microglial cells; (iii) B14 injection (intraperitoneally) markedly eased bone cancer pain; (iv) Western blotting showed that B14 injection lowered p-JAK2, p-STAT3, and interleukin-1β levels, meanwhile the ratios of p-JAK2/JAK2 and p-STAT3/STAT3 was reduced; (v) immunofluorescence results also confirmed decreased levels of p-JAK2, p-STAT3, and interleukin-1β in B14 treatment group. These findings suggested that B14 injection attenuated bone cancer pain in rats. This intervention inhibited JAK2/STAT3 cascade activation, downregulating interleukin-1β expression in spinal dorsal horn.