Jinmaitong ameliorates diabetes-induced peripheral neuropathy in rats through Wnt/β-catenin signaling pathway

Ethnopharmacological relevance: Jinmaitong (JMT) is a prescription of Traditional Chinese Medicine, which is composed of ten herbal drugs and two animal drugs. It has long been used for the treatment of diabetic peripheral neuropathy (DPN). Aim of study: Wnt/beta-catenin pathway is considered as an essential and direct driver of myelinogenesis. This study aims to evaluate the protective effect of JMT against DPN dynamically during a 16-weeks' treatment, and to investigate the underlying mechanism in which the Wnt/beta-catenin pathway is involved. Materials and methods: Diabetic model was induced by single intraperitoneal injection of Streptozotocin (STZ) using male Sprague-Dawley rats. The model rats were divided into five groups and administrated with JMT at three doses (0.437, 0.875, and 1.75 g/kg per day), neurotropin (positive drug, 2.67 NU/kg per day), and placebo (deionized water), respectively, for continuous 8 weeks (n = 9-10), 12 weeks (n = 8-10), or 16 weeks (n = 7-9). Meanwhile, rats in control group were administrated with placebo (n = 10 for 8 weeks, n = 9 for 12 and 16 weeks, respectively). Blood glucose and body weight were monitored every four weeks. Mechanical allodynia was assessed using mechanical withdrawal threshold (MWT) test. The morphological change of sciatic nerves were observed by transmission electron microscope (TEM) and hematoxylin and eosin (HE) stain. The mRNA and protein levels of targeted genes were evaluated by quantitative real time-PCR and western bolt, respectively. Myelin protein zero (MPZ) and mediators involved in Wnt/beta-catenin pathway, such as beta-catenin, glycogen synthase kinase 3 beta (GSK-3 beta), and WNT inhibitory factor-1 (WIF-1), were compared among different groups after treatment of 8, 12, and 16 weeks, respectively. : The mechanical allodynia and peripheral nerve morphology were degenerated in DPN rats over time, and notably improved after JMT-treatment of 12 and 16 weeks. The decreased MPZ level in DPN rats were also significantly amended by JMT. More importantly, we found that the suppressed Wnt/beta-catenin pathway in sciatic nerves of DPN rats was overtly up-regulated by JMT in a time-dependent manner. Among the three doses, JMT at the middle dose showed the best effect. Conclusions: JMT effectively ameliorated diabetic-induced peripheral neuropathy, which was mediated by the activation of Wnt/beta-catenin signaling pathway. This study provided new perspective to understand the neuroprotective mechanism of JMT.

Automated summary

In this study, it was found that mechanical allodynia and peripheral nerve morphology in DPN rats deteriorated over time, but were notably improved after 12 and 16 weeks of JMT treatment. JMT significantly corrected the decreased MPZ level in DPN rats. Moreover, JMT was found to significantly up-regulate the suppressed Wnt/beta-catenin pathway in a time-dependent manner in the sciatic nerves of DPN rats.