Andrographolide Inhibits Mechanical and Thermal Hyperalgesia in a Rat Model of HIV-Induced Neuropathic Pain.

Zhihua Yi,Shanhong Zhao,Guilin Li,Shangdong Liang,Jinpu Yang,Changshui Xu,Tianyu Jia,Huilong Yuan,Lihui Xie,Shuai Ouyang,Chunping Zhang,Yun Gao,Shuangmei Liu,Zhi Fang,Congfa Zhou,Lifang Zou,Liran Shi,Hong Xu,Lin Li

doi:10.3389/fphar.2018.00593

Abstract

Aim: In this study, we investigated whether andrographolide (Andro) can alleviate neuropathic pain induced by HIV gp120 plus ddC treatment and the mechanism of its action.Methods: The paw withdrawal threshold and the paw withdrawal latency were observed to assess pain behaviors in all groups of the rats, including control group, control combined with Andro treatment group, sham group, gp120 combined with ddC treatment group, gp120 plus ddC combined with A438079 treatment group, and gp120 plus ddC combined with Andro treatment by intrathecally injecting at a dose of 25 μg/20 μl group. The protein expression levels of the P2X7 receptor, tumor necrosis factor-α-receptor (TNFα-R), interleukin-1β (IL-1β), IL-10, phospho-extracellular regulated protein kinases (ERK) (p-ERK) in the L4–L6 dorsal root ganglia (DRG) were measured by western blotting. Real-time quantitative polymerase chain reaction was used to test the mRNA expression level of the P2X7 receptor. Double-labeling immunofluorescence was used to identify the co-localization of the P2X7 receptor with glial fibrillary acidic protein (GFAP) in DRG. Molecular docking was performed to identify whether the Andro interacted perfectly with the rat P2X7 (rP2X7) receptor.Results: Andro attenuated the mechanical and thermal hyperalgesia in gp120+ddC-treated rats and down-regulated the P2X7 receptor mRNA and protein expression in the L4–L6 DRGs of gp120+ddC-treated rats. Additionally, Andro simultaneously decreased the expression of TNFα-R and IL-1β protein, increased the expression of IL-10 protein in L4–L6 DRGs, and inhibited the activation of ERK signaling pathways. Moreover, Andro decreased the co-expression of GFAP and the P2X7 receptor in the SGCs of L4–L6 DRG on 14th day after surgery.Conclusion: Andro decreased the hyperalgesia induced by gp120 plus ddC.

Highlights

In 2015, an estimated 36.7 million HIV/AIDS cases reported worldwide, according to statistical data (WHO1)
Andro simultaneously decreased the expression of tumor necrosis factor-α-receptor (TNFα-R) and IL-1β protein, increased the expression of IL-10 protein in L4–L6 dorsal root ganglia (DRG), and inhibited the activation of extracellular regulated protein kinases (ERK) signaling pathways
The present study showed that peripheral nerve exposure to HIV gp120 plus ddC increased mechanical and thermal hyperalgesia in the gp120-plus ddC-treated model rats

Summary

Introduction

In 2015, an estimated 36.7 million HIV/AIDS cases reported worldwide, according to statistical data (WHO1). HIV infection and its associated treatments may cause a variety of peripheral neuropathies (Simpson, 2002; Ferrari et al, 2006; Ellis et al, 2010). The prevalence of peripheral neuropathies is as high as 69.4% in HIV-positive patients (Ghosh et al, 2012), and neuropathic pain is the major complaint of patients living with distal symmetric polyneuropathy (DSP). Painful HIV-DSP may be induced by the envelope glycoprotein gp120 and other proteins (Yuan et al, 2014; Shi et al, 2016), as well as antiretroviral drug-induced neuropathy, including the use of nucleoside reverse transcriptase inhibitors (NRTIs), dideoxynucleosides, zalcitabine (ddC), didanosine (ddI), and stavudine (d4T) (Verma et al, 2005). The combination of HIV-associated pathology and neurotoxic effects of antiretroviral drugs is synergistic for the development of painful neuropathies (Wallace et al, 2007)

Objectives

Methods

Results

Discussion

Conclusion