Astragaloside IV Inhibits Mitochondrial-Dependent Apoptosis of the Dorsal Root Ganglion in Diabetic Peripheral Neuropathy Rats Through Modulation of the SIRT1/p53 Signaling Pathway

Abstract

Ying Ben,1,2,* Juan Hao,1,* Zhihong Zhang,1,2 Yunzhao Xiong,1 Cuijuan Zhang,1,2 Yi Chang,1,2 Fan Yang,1,2 Hui Li,1,2 Tianya Zhang,1 Xiangting Wang,1,2 Qingyou Xu1,2 1Hebei University of Chinese Medicine, Shijiazhuang, Hebei, People’s Republic of China; 2Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qingyou XuHebei University of Chinese Medicine, No. 326 Xinshinan Road, Qiaoxi District, Shijiazhuang, Hebei Province, 050090, People’s Republic of ChinaTel [phone]Fax [phone]Email [email protected]: To investigate the effect of astragaloside IV (AS-IV) on mitochondrial-dependent apoptosis in the dorsal root ganglion of diabetic peripheral neuropathy (DPN) rats through the SIRT1/p53 pathway.Methods: Diabetic rat model was induced by high-carbohydrate/high-fat diet and intraperitoneal injection of STZ. Diabetic rats were divided into three groups (n =16 per group): DPN group, AS-IV group (60mg/kg/d) and α-lipoic acid (ALA) group (60mg/kg/d). Weight and blood glucose levels were monitored every 4 weeks for 12 weeks. DPN was evaluated using the Von Frey Filaments Test and nerve conduction velocity. The dorsal root ganglia of rats were isolated and the pathological changes of mitochondria were observed by electron microscopy. The activity of mitochondrial electron transport chain complex, mitochondrial membrane potential, malonaldehyde (MDA) and glutathione (GSH) levels were measured. Neural apoptosis was detected using the Terminal Deoxynucleotidyl Nick-End Labeling (TUNEL) assay kit. The cleaved caspase-3, major proteins in the SIRT1/p53 pathway, including SIRT1, acetyl p53, Drp1, BAX, and BCL-2, were detected using immunohistochemistry and Western blot. Gene expression of major proteins in the SIRT1/p53 pathway was also detected.Results: After 12 weeks of treatment, AS-IV and ALA did not significantly affect body weight or fasting glucose levels, but reduced mechanical abnormal pain in DPN and improved nerve conduction velocity. AS-IV and ALA increased the level of GSH and decreased the level of MDA. Both AS-IV and ALA can reduce mitochondrial damage, improve mitochondrial electron transport chain complex activity and mitochondrial membrane potential, and reduce the percentages of positive cells with DNA fragmentation and the expression of cleaved caspase-3 protein. AS-IV and ALA up-regulated the expression of SIRT1 and down-regulated the expression of acetyl-p53, Drp1 and the ratio of BAX to BCL-2. Changes in gene expression were similar.Conclusion: AS-IV can reduce the occurrence of mitochondrial-dependent apoptosis by regulating the SIRT1/p53 pathway. It has a similar therapeutic effect as ALA and is therefore a promising drug for the potential treatment of DPN.Keywords: astragaloside IV, diabetic peripheral neuropathy, dorsal root ganglion, mitochondria, apoptosis, SIRT1/p53 pathway

Keywords

• astragaloside iv
• diabetic peripheral neuropathy
• dorsal root ganglion
• mitochondria
• apoptosis
• sirt1/p53 pathway