A Metabolic Insight Into the Neuroprotective Effect of Jin-Mai-Tong (JMT) Decoction on Diabetic Rats With Peripheral Neuropathy Using Untargeted Metabolomics Strategy.

Qian Zhang,Xiaohu Shi,Bintao Qiu,Yue Shi,Xiuting Chen,Xiaochun Liang,Jun Xie,Wei Song

doi:10.3389/fphar.2020.00221

Abstract

Jin-Mai-Tong (JMT) decoction is a traditional Chinese compound prescription for treating diabetic peripheral neuropathy (DPN). The aim of this study is to investigate the neuroprotective effect of JMT decoction on diabetic rats with peripheral neuropathy and to elucidate the potential mechanism based on a metabolomics approach. Sprague-Dawley (SD) rats were randomly divided into four groups: control group, Streptozotocin (STZ) induced model group, JMT low dose (JMT-L) treated group and JMT high dose (JMT-H) treated group. After 12 weeks of treatment, behavioral changes, small fiber loss, and histopathological damages of sciatic nerves were estimated. Serum samples were collected for untargeted metabolomics analysis based on UPLC/QTOF-MS and multivariate statistics. As a result, JMT treatment at two dosages (13.9 and 27.8 g/kg⋅d) evidently improved the mechanical pain threshold (P < 0.05), increased the intraepidermal nerve fiber density (IENFD) and subepidermal nerve fiber density (SNFD) (P < 0.05), and renovated the demyelination and axonal atrophy of sciatic nerves on DPN rats. Furthermore, metabolomics study revealed that the serum metabolic profiles altered significantly among the control group and the STZ-induced model group. A total of 21 metabolites were identified as potential biomarkers related to the therapeutic effect of JMT decoction. Among them, 16 biomarkers were found in both JMT-H and JMT-L treated groups, while the five others were specific to JMT-H group. These metabolites mainly involved in lipid metabolism, tricarboxylic acid (TCA) cycle, amino acid metabolism, and so on. Besides, correlation analysis indicated that both mechanical pain threshold and distal nerve fiber density were negatively correlated with the serum levels of metabolites from lipid metabolism and TCA cycle. In conclusion, the results demonstrated that JMT decoction has an obvious protective effect against DPN, which could be mediated via ameliorating the metabolic disorders in diabetic rats with peripheral neuropathy.

Highlights

Diabetic peripheral neuropathy (DPN) is a common and longterm complication of both type 1 and type 2 diabetes, which leads to neuropathic pain (Pop-Busui et al, 2017), and increases the risk factor of foot ulcer and amputation (Holman et al, 2012; Boulton, 2013; Vas and Edmonds, 2016)
The regulation of glucose metabolism was marginal as the blood glucose level of JMT high dose (JMT-H) treated diabetic rat was much higher than healthy normal rat
The animal model employed in this study was type 1 diabetic rat model induced by STZ-injection, which is in absolute deficiency of insulin, so the potential hypoglycemic effect of JMT decoction observed here might not be insufficient to demonstrate its clinical significance

Summary

Introduction

Diabetic peripheral neuropathy (DPN) is a common and longterm complication of both type 1 and type 2 diabetes, which leads to neuropathic pain (Pop-Busui et al, 2017), and increases the risk factor of foot ulcer and amputation (Holman et al, 2012; Boulton, 2013; Vas and Edmonds, 2016). Pathophysiological processes of DPN include enhanced activity of the polyol pathway, protein kinase C activation, increased advanced glycation end-products, oxidative stress, and so on (Feldman et al, 2017). Glucose and polyol intermediates in the peripheral nervous tissues of STZ-induced diabetic rats were significantly increased when compared to healthy rats, and the sciatic nerves of diabetic rats exhibited striking upregulation of mitochondrial oxidative phosphorylation and disorder of lipid metabolism (Freeman et al, 2016). Despite extensive efforts into treatment of DPN, drugs targeting casual mechanism such as antioxidants, aldose reductase inhibitors, and growth factors still have limited efficacy in clinical practices (Farmer et al, 2012). Additional novel treatment strategies which are beneficial to the whole metabolic profile need to be explored

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