Necrostatin-1 Ameliorates Peripheral Nerve Injury-Induced Neuropathic Pain by Inhibiting the RIP1/RIP3 Pathway.

Ying-Xia Liang,Nan-Nan Wang,Zhi-Yu Zhang,Zhao-Dong Juan,Can Zhang

doi:10.3389/fncel.2019.00211

Abstract

Necrostatin-1 is an inhibitor of necroptosis, a form of programmed cell death that has been reported to be involved in various neurological diseases. Presently, the role of necroptosis in neuropathic pain induced by peripheral nerve injury is still unclear. This study was focused on investigating the potential effects of necroptosis in the development and progression of neuropathic pain in a rat model and the possible neuroprotective effects of necrostatin-1 in neuropathic pain. The results indicated that the necroptosis-related proteins RIP1 and RIP3 significantly increased postoperation in the spinal cord in a neuropathic pain model and peaked 7 days postoperation, which was consistent with the time-dependent changes of hyperalgesia. Additionally, we found that peripheral nerve injury-related behavioral and biochemical changes were significantly reduced by necrostatin-1. In particular, hyperalgesia was attenuated, and the levels of RIP1 and RIP3 were decreased. Furthermore, the ultrastructure of necrotic cell death and neuroinflammation were alleviated by necrostatin-1. Collectively, these results suggest that necroptosis is an important mechanism of cell death in neuropathic pain induced by peripheral nerve injury and that necrostatin-1 may be a promising neuroprotective treatment for neuropathic pain.

Highlights

Neuropathic pain is a severe disease caused by lesions in the nervous system and may persist for months to years, even after the primary disease or injury has healed (Haanpaa et al, 2011)
We showed that rats treated with necrostatin-1 were dose-dependently relieved of mechanical and thermal allodynia from 7 to 21 days postoperation (∗p < 0.05), unlike rats in the Constriction Injury (CCI) group
Compared to the rats in the CCI group, rats treated with necrostatin-1 exhibited significantly reduced levels of inflammatory cytokines and substance P (∗p < 0.05), indicating a significant decrease in neuroinflammation in the spinal cord of rats with neuropathic pain after administration of necrostatin-1

Summary

Introduction

Neuropathic pain is a severe disease caused by lesions in the nervous system and may persist for months to years, even after the primary disease or injury has healed (Haanpaa et al, 2011) It is a devastating disorder and it reduces the quality of life of millions of people around the world (Gaskin and Richard, 2012). Current analgesic drugs, such as non-steroidal anti-inflammatory drugs, tricyclic antidepressants, and opioids, lack satisfactory efficacy in controlling disease progression, and most of them alleviate symptoms by inhibiting neuronal activity. Targeting the processes and molecules that are involved in neuroinflammation could lead to better treatments for chronic pain (Ji et al, 2014)

Objectives

Methods

Results

Conclusion