8-O-Acetyl Shanzhiside Methylester From Lamiophlomis Rotata Reduces Neuropathic Pain by Inhibiting the ERK/TNF-α Pathway in Spinal Astrocytes

Wei Zhang,Jian Wang,Yu Qiao,Meng-Ying Li,Na Jia,Tao Chen,Yun-Qing Li,Jing-Wen Wang,Ai-Dong Wen,Yang Bai

doi:10.3389/fncel.2018.00054

Abstract

Lamiophlomis rotata (L. rotata; Benth.) Kudo is an effective traditional herb in the clinical treatment of chronic pain syndromes in China. 8-O-acetyl shanzhiside methylester (8-OaS), a chief component in L. rotata, possesses potent immunosuppressive activities and favorable analgesic effects. This study was proposed to compare the analgesic effects of 8-OaS with those of lidocaine and ketamine in a spinal nerve ligation (SNL) model by behavioral tests, and then investigated its effects upon the expression of spinal glial fibrillary acidic protein (GFAP), phosphorylated extracellular regulated protein kinases (pERK) and tumor necrosis factor-alpha (TNF-α) via immunofluorescence staining and western blot analyses. The data showed consecutive intrathecal injection of 8-OaS for 2 weeks brought about remarkable palliation of neuropathic pain (NP), possessing similar anti-allodynia effects with those of lidocaine and ketamine. Two weeks after surgery, pERK within the spinal dorsal horn was mainly expressed in astrocytes more than neurons and microglia, and 8-OaS inhibited spinal astrocytic activation and TNF-α expression. Finally, co-treatment of 8-OaS and PD98059 (an Extracellular signal-regulated kinase, ERK inhibitor) did not lead to remarkable increase in pain relief or TNF-α expression comparing to rats treated with 8-OaS or PD98059 alone. In conclusion, the anti-nociceptive effects of 8-OaS in the condition of NP relied on the inhibition of SNL-induced astrocyte activation, probably via the down-regulation of the ERK/TNF-α pathway.

Highlights

Neuropathic pain (NP) remains a common clinical syndrome that affects human well-being all over the world
The ED50 for 8-O-acetyl Shanzhiside methylester (8-OaS) on spinal nerve ligation (SNL)-induced mechanical allodynia was 12.58 μg, which paved the way for the selection of drug dose in the comparison of analgesic effects among 8-OaS, lidocaine and ketamine
In order to verify whether SNL-induced NP was accompanied with astrocytic Extracellular signal-regulated kinase (ERK) activation, we investigated astrocyte activation and ERK activation in the spinal dorsal horn

Summary

Introduction

Neuropathic pain (NP) remains a common clinical syndrome that affects human well-being all over the world. Mounting evidence has implicated that spinal glial cells are essential in producing and maintaining NP (Zhuang et al, 2005; Milligan and Watkins, 2009). In the condition of NP, glial cells are activated via neuronal-glial interactions and various pronociceptive mediators, such as cytokines (interleukin-1 beta, IL-1β and tumor necrosis factor-alpha, TNF-α) and neurotrophic factors, are produced to enhance neuronal activity via glialneuronal interactions (Basbaum et al, 2009; Ji et al, 2013, 2016). As a canonical signaling molecule, ERK is activated by nerve injury in microglia and astrocytes sequentially and links the glial activation and the generation of inflammatory factors (Ji and Strichartz, 2004). Targeting spinal neuroinflammation processes renders novel therapeutic hopes for the treatment of NP (Ji et al, 2014)

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