Jinmaitong Alleviates Diabetic Neuropathic Pain Through Modulation of NLRP3 Inflammasome and Gasdermin D in Dorsal Root Ganglia of Diabetic Rats

Xiaochun Liang,Qunli Wu,Rui Zhang,Dan Yang,Xiaowei Xue,Qing Sun,Chao Wang,Bin Yan

doi:10.3389/fphar.2021.679188

Abstract

Jinmaitong (JMT) is a compound prescription of traditional Chinese medicine that has been used to treat diabetic neuropathic pain (DNP) for many years. Here, we investigated the effects of JMT on the activation of NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome and pyroptosis in Dorsal root ganglia (DRG) of diabetic rats. Streptozotocin (STZ)-induced diabetic rats were gavaged with JMT (0.88 g/kg/d) or alpha-lipoic acid (ALA, positive control, 0.48 mmol/kg/d) for 12 weeks. Distilled water was administered as a vehicle control to both diabetic and non-affected control rats. Blood glucose levels and body weights were measured. Behavioral changes were tested with mechanical withdrawal threshold (MWT) and tail-flick latency (TFL) tests. Morphological injury associated with DRG was observed with hematoxylin and eosin (H&E) and Nissl’s staining. mRNA and protein levels of NLRP3 inflammasome components (NLRP3, ASC, caspase-1), downstream IL-1β and gasdermin D (GSDMD) were evaluated by immunohistochemistry, quantitative real time-PCR and western blot. The results showed that JMT had no effect on blood glucose levels and body weights, but significantly improved MWT and TFL behavior in diabetic rats, and attenuated morphological damage in the DRG tissues. Importantly, JMT decreased the mRNA and protein levels of components of NLRP3 inflammasome, including NLRP3, ASC and caspase-1. JMT also down-regulated the expression of IL-1β and GSDMD in the DRG of DNP rats. In addition, ALA treatment did not perform better than JMT. In conclusion, JMT effectively relieved DNP by decreasing NLRP3 inflammasome activation and pyroptosis, providing new evidence supporting JMT as an alternative treatment for DNP.

Highlights

Peripheral neuropathy is the most prevalent diabetes-associated complication with an overall prevalence of 50–60% (Pop-Busui et al, 2017)
At 12 weeks after STZ injection, blood glucose levels were significantly increased in diabetic rats (Figure 1A), and body weights decreased by about 50% in diabetic rats compared with the Con group (Figures 1B,C)
While JMT and Alphalipoic acid (ALA) treatment had hypoglycemic and weight gaining trends, there was no significant difference in either body weights or blood glucose levels between the DM group and the JMT or ALA-treated DM groups (p > 0.05)

Summary

Introduction

Peripheral neuropathy is the most prevalent diabetes-associated complication with an overall prevalence of 50–60% (Pop-Busui et al, 2017). Diabetic neuropathic pain (DNP) is a common type of diabetic peripheral neuropathy, accounting for approximately 25% of patients, which occurs in the early stage of diabetes and even in the stages of impaired glucose tolerance (Davies et al, 2006). Symptoms of chronic DNP can last for years and can severely impair quality of life (Benbow et al, 1998), leading to anxiety, depression and other psychological problems. This results in a substantial economic and social burden for patients experiencing DNP. Stable glycemic control and pain management are the only modifiable treatments for DNP, calling for investigation into new, more effective treatments (Feldman et al, 2017)

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Discussion

Conclusion