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

Purpose 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.

Astragaloside IV Ameliorates Streptozotocin Induced Pancreatic β-Cell Apoptosis and Dysfunction Through SIRT1/P53 and Akt/GSK3β/Nrf2 Signaling Pathways

“…30 Similar phenomena have also been observed in the dorsal root ganglia of rats with uncle peripheral neuropathy. 18 In the current study, the regulation of SIRT1 and p53 by AS-IV was also observed. After treating STZ pre-incubated INS-1 cells with the SIRT1 inhibitor EX527, the cytoprotective effect of AS-IV was found to be significantly weakened.…”

“…17 In the process of mitochondrialdependent apoptosis in the dorsal root ganglion of rats with diabetic peripheral neuropathy, it was detected that AS-IV can up-regulate the expression of SIRT1 and inhibit the activation of P53. 18 Resveratrol protects the insulin secretion of INS-1 cells induced by ethanol through the SIRT1/UCP2 axis. 19 Whether the mechanism of AS-IV treatment of diabetes involves the SIRT1 signaling pathway remains to be explored.…”

Targeted up-regulation of Drp1 in dorsal horn attenuates neuropathic pain hypersensitivity by increasing mitochondrial fission

“…Our previous study has shown that Drp1 is highly expressed at the spinal cord level [ 33 ]. And many studies have shown different NP contributed to the increased expression of Drp1 [ [34] , [35] , [36] , [37] , [38] , [39] , [40] , [41] , [42] ]. Here we observed the changes of Drp1 in the SDH of the mice during NP by Western blot and qRT-PCR and also confirmed the increased Drp1 expression ( Fig.…”

“…Due to its complexity of pathogenesis and adverse reactions to drugs, its therapeutic treatment remains a challenge. Among all mechanistic studies, accumulating evidence has pointed to mitochondrial dysfunction [ [34] , [35] , [36] , [37] , [38] , [39] , [40] , [41] , [42] , 45 ]. Neurons are dependent on mitochondria, which not only provide energy to power cellular function through oxidative phosphorylation, but also regulate cellular oxidation-reduction status, calcium levels, signal transduction, and apoptosis [ 58 ].…”

“…In different NP model, Drp1 expression or its phosphorylated state is reported to either increase or decrease. It has been reported there was upregulation of Drp1 proteins at dorsal root ganglia (DRG) by immunohistochemical staining in the diabetic NP model [ 34 ], or by Western blot in the chronic constriction injury (CCI) NP model [ 39 , 40 ]. Xie M et al have reported upregulation of Drp1 proteins or mRNAs at spinal cord by Western blot and RT-PCR in Complete Freund's adjuvant (CFA)-induced NP model [ 35 ].…”