The AMPK/PGC-1α pathway-mediated mitochondrial dysfunction has been supposed to play a crucial role in pathogenesis of diabetic peripheral neuropathy (DPN). The present study investigated the neuroprotective potential of quercetin, a natural AMPK activator. Streptozotocin (STZ)-induced diabetic rats that developed DPN phenotype were orally administrated with quercetin (30 and 60 mg/kg per day) for 6 weeks. The morphologic changes in the sciatic nerves (SN), the pathological structure of neurons in dorsal root ganglion (DRG), and the expressions of myelin proteins were assessed. The ATP content and the mitochondrial ultrastructure were measured. Furthermore, key proteins in the AMPK/PGC-1α pathway were determined. As a result, quercetin administration at both doses improved the paw withdrawal threshold, nerve conduction velocity, and the pathologic changes in SN and DRG of DPN rats. The expressions of myelin basic protein and myelin protein zero were also increased by quercetin. The oxidative stress, decreased ATP generation, and morphological changes of mitochondria were corrected by quercetin. In vitro study found that quercetin treatment significantly decreased the high-glucose-induced generation of reactive oxygen species, as well as attenuated the mitochondrial morphologic injuries and oxidative DNA damages of RSC96 cells. Quercetin treatment promoted the expressions of phosphorylated AMPK, PGC-1α, SIRT1, NRF1, and TFAM under hyperglycemic state in vivo and in vitro. This study revealed that the neuroprotective effect of quercetin was mainly related to mitochondrial protection by activation of the AMPK/PGC-1α pathway for the first time and proved quercetin as a potential therapeutic agent in the management of diabetic neuropathy.

Diabetic peripheral neuropathy (DPN) is a common and devastating complication of diabetes, for which effective therapies are currently lacking. Disturbed energy status plays a crucial role in DPN pathogenesis. However, the integrated profile of energy metabolism, especially the central carbohydrate metabolism, remains unclear in DPN. Here, we developed a metabolomics approach by targeting 56 metabolites using high-performance ion chromatography-tandem mass spectrometry (HPIC-MS/MS) to illustrate the integrative characteristics of central carbohydrate metabolism in patients with DPN and streptozotocin-induced DPN rats. Furthermore, JinMaiTong (JMT), a traditional Chinese medicine (TCM) formula, was found to be effective for DPN, improving the peripheral neurological function and alleviating the neuropathology of DPN rats even after demyelination and axonal degeneration. JMT ameliorated DPN by regulating the aberrant energy balance and mitochondrial functions, including excessive glycolysis restoration, tricarboxylic acid cycle improvement, and increased adenosine triphosphate (ATP) generation. Bioenergetic profile was aberrant in cultured rat Schwann cells under high-glucose conditions, which was remarkably corrected by JMT treatment. In - vivo and in - vitro studies revealed that these effects of JMT were mainly attributed to the activation of adenosine monophosphate (AMP)-activated protein kinase (AMPK) and downstream peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). Our results expand the therapeutic framework for DPN and suggest the integrative modulation of energy metabolism using TCMs, such as JMT, as an effective strategy for its treatment.

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.