The Actions and Mechanisms of P2X7R and p38 MAPK Activation in Mediating Bortezomib-Induced Neuropathic Pain.

Yan Guo,Xiaobo Xu,Zhen Liu,Jingyi Huang,Zhenzhong Li,Zhen Wang

doi:10.1155/2020/8143754

Yan Guo, Xiaobo Xu + Show 4 more

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https://doi.org/10.1155/2020/8143754

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Abstract

The proteasome inhibitor bortezomib (BTZ) is a potent first-line anticancer drug for multiple myeloma; nonetheless, it induced peripheral neuropathy. It has been suggested that many cytokines may play a role in mediating neuropathic pain, but the underlying molecular mechanism is not fully understood. Recent studies have shown that neuropathic pain is closely related to the purinergic ligand-gated ion channel 7 receptor (P2X7R), one of the P2X receptors, which is richly expressed in glial cells. P2X7-p38 pathway is correlated with microglia- and satellite glial cell- (SGC-) mediated neuropathic pain. However, the association of P2X7R and p38MAPK in mediating BTZ-induced neuropathic pain remains unclear. In this study, the relationship between P2X7R activation and p38 phosphorylation in the dorsal root ganglion (DRG) and spinal dorsal horn (SDH) in the development and maintenance of BTZ-induced neuropathic pain was elucidated. The results showed that BTZ increased mechanical thresholds in rats, accompanied with upregulation of P2X7R expression and p38MAPK phosphorylation, indicating that P2X7R and p38MAPK are key molecules in the development and maintenance of BTZ-induced neuropathic pain. Inhibiting p38MAPK phosphorylation with SB203580 resulted in downregulation of P2X7R expression levels. Inhibition of P2X7R with Brilliant Blue G (BBG) reversed neuropathic pain might decrease through the expression of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6 via inhibiting p38MAPK phosphorylation. The P2X7R/p38MAPK signaling pathway in SGCs of DRG and microglia of SDH might be a potential pharmacological target behind this mechanism as an opportunity to relieve BTZ-induced neuropathic pain.

Highlights

Proteasome inhibitors used for treating cancers have been identified to result in a significant higher risk for inducing sensory peripheral neuropathy [1]
Application of Brilliant Blue G (BBG) alone in naïve rats did not affect p38 mRNA and p-p38 expression in dorsal root ganglion (DRG) neurons. These results suggested that activation of P2X7 receptor (P2X7R) in satellite glial cells (SGCs) is closely related to p38 phosphorylation in DRG neurons from BTZ-induced neuropathic rats
The results showed that the elevated IL-1β, IL-6, and tumor necrosis factor-α (TNF-α) mRNA levels in both DRG and spinal dorsal horn (SDH) tissues induced by BTZ treatment could be significantly blocked by administration of the p38 selective inhibitor SB203580 (Figure 7)

Summary

Introduction

Proteasome inhibitors used for treating cancers have been identified to result in a significant higher risk for inducing sensory peripheral neuropathy [1]. Bortezomib (BTZ), a proteasome inhibitor, is a commonly used antitumor drug which has highly effective results on relieving cancer symptoms [2, 3]. Bortezomib-induced peripheral neuropathy (BIPN) is a major and debilitating side effect with persistent exacerbation of neuropathic pain during anticancer therapy, which causes drug dose limitation or application discontinuation and worsens cancer prognosis [4]. Studies have confirmed that proinflammatory cytokines like tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6 can activate p38MAPK, while activated p38 can lead to the release of inflammatory mediators [6]. It leads to the induction and expansion of neuropathic pain status. It leads to the induction and expansion of neuropathic pain status. p38MAPK phosphorylation in the central nervous system [7, 8] and peripheral nervous system [9,10,11] is closely correlated with neuroinflammation and neuropathic pain

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