Siwei Jianbu decoction improves painful paclitaxel-induced peripheral neuropathy in mouse model by modulating the NF-κB and MAPK signaling pathways.

Siyan Qiu,Rong Xu,Jing Zhu,Peng Zhang,Ling Zhang,Yuting Lu,Qiuyan Zhang,Jing Meng,Man Wang,Jinshuai Suo,Yangyan Qian

doi:10.1051/rmr/200001

Abstract

Background: Paclitaxel, a commonly used chemotherapeutic agent, is usually associated with peripheral neuropathy. Paclitaxel induced peripheral neuropathy (PIPN) can be dose limiting and may have detrimental influence on patients' quality of life. However, the mechanism of PIPN remains unclear. Medicinal herbs and their formulas might offer neuronal protection with their multitarget and integrated benefits in chemotherapy-induced peripheral neuropathy (CIPN). Siwei Jianbu decoction (J12) is a classic formula of traditional Chinese medicine which can promote blood circulation and treat diabetic nephropathy in clinical with the symptoms of weakness and pain. Methods: The effects of J12 were treated in C57BL/6 mice before injected with Paclitaxel.Behaviour studies: Measurement of mechanical hyperalgesia, thermal nociception and cold allodynia. On the last day at the end of week 6, DRGs were obtained from mice for western blot and immunohistochemical analysis containing NF-κB, p-ERK1/2 and p-SAPK/JNK protein expression. Quantitative real-time polymerase chain reaction: mRNA expression of NF-κB, IL-1β and TNF-α was analyzed. Additionally, the blood samples collected from the eye socket of the mouse were prepared to examine the levels of NF-κB, TNF-α, IL-6 and IL-1β using ELISA assay kits. Results: Hypersensitivity tests and pathology analysis have demonstrated that J12 could improve paclitaxel-induced peripheral pain. J12 acts by inhibiting the activation of (C-Jun N-terminal kinases) JNK, (extracellular signal-regulated kinase) ERK1/2 phosphorylation in (Mitogen-activated protein kinases) MAPK signaling pathway and the nuclear factor-κB (NF-κB) in C57BL/6 mice model, J12 also inhibits the production of inflammatory cytokines including tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β) and IL-6. Conclusion: The present study showed that J12 ameliorates paclitaxel-induced peripheral neuropathic pain.

Highlights

Chemotherapy-induced peripheral neuropathy (CIPN) is the major dose-limiting toxicity associated with chemotherapeutic agents such as paclitaxel, oxaliplatin and vincristine [1]
Pain behavior tests showed that comparison of paclitaxel treatment group with vehicle-treated mice indicated significantly decreases in the paw withdrawal latency from the third week to the 6th week in mechanical hyperalgesia and thermal nociception tests (Fig. 1B and D)
Mice treated with paclitaxel plus J12 or not had no difference on the tail withdrawal latency times compared with vehicle-treated group in cold allodynia test (Fig. 1C, p > 0.05) which indicated that paclitaxel could not induce cold hypersensitivity in the mice

Summary

Introduction

Chemotherapy-induced peripheral neuropathy (CIPN) is the major dose-limiting toxicity associated with chemotherapeutic agents such as paclitaxel, oxaliplatin and vincristine [1]. Patients treated with paclitaxel often suffer from paraesthesia, allodynia and hyperalgesia such as tingling and numbness in hands and feet, severe pain is a serious problem for many patients. CIPN frequently persists long after completion of chemotherapy, thereby reducing quality of Neuroinflammation is shown to be involved in several neuropathic pain models [4,5]. Recent studies have demonstrated proinflammatory immune responses play an important role in chemotherapy-induced peripheral neuropathic pain [8,9]. Studies show that paclitaxel activates NF-kB and MAPKs [12]. These pathways induce the expression of phospho-JNK (p-JNK) and phospho-ERK1/2 (p-ERK1/2) in the dorsal

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