Quercetin Attenuates Diabetic Peripheral Neuropathy by Correcting Mitochondrial Abnormality via Activation of AMPK/PGC-1α Pathway in vivo and in vitro.

Qian Zhang,Xiaohu Shi,Bin Yan,Jun Xie,Xiaochun Liang,Wei Song,Bingjia Zhao,Qing Sun,Guoqing Tian

doi:10.3389/fnins.2021.636172

Abstract

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.

Highlights

Diabetic peripheral neuropathy (DPN), a long-term complication of diabetes, affects more than 50% diabetic patients (Feldman et al, 2017)
Previous studies have discovered the neuroprotective potential of quercetin on DPN (Anjaneyulu and Chopra, 2003; Yang et al, 2019), we further explored the underlying molecular mechanism, in which the mitochondrial function and adenosine -monophosphate activated protein kinase (AMPK)/PGC-1 α axis were explicitly estimated
Recent studies have confirmed that the activation of AMPK was inhibited in the peripheral nervous system of rodent models with type 1 or type 2 diabetes (Fernyhough, 2015; Yerra et al, 2018; Wang et al, 2018; Atef et al, 2019), which was in accordance with our findings that the AMPK levels (P-AMPK and AMPKα) in both sciatic nerves (SN) of DPN rats and high-glucose group (HG)-exposed Schwann cells model were remarkably reduced

Summary

Introduction

Diabetic peripheral neuropathy (DPN), a long-term complication of diabetes, affects more than 50% diabetic patients (Feldman et al, 2017). DPN leads to neuropathic pain, abnormal sensation, and loss of life quality in patients. It increases the risk factor of lower-limb amputation (Holman et al, 2012; Boulton, 2013; Vas and Edmonds, 2016) and contributes to diabetes-related and all-cause mortality in people with diabetes (Hsu et al, 2012). Few specific treatments for nerve damage are currently available in addition to optimized glycemic control as early as possible (Farmer et al, 2012; Pop-Busui et al, 2017; American Diabetes Association, 2019). A substantial proportion of diabetic patients develop DPN despite intensive glycemic control. New rational treatment is still in demand to prevent or reverse nerve injury of diabetic patients

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Conclusion