Combined analysis of network pharmacology and transcriptomics deciphers the pharmacological mechanism of Huangqi Guizhi Wuwu decoction attenuates oxaliplatin-induced peripheral neuropathy via regulating Sirt1.

Abstract

ETHNOPHARMACOLOGICAL RELEVANCE: Huangqi Guizhi Wuwu decoction (HGWD) is firstly recorded in the ancient Chinese ethnomedical manuscript "Synopsis of the Golden Chamber" with nourishing qi and blood for the treatment of limb numbness and ache in patients. Nowadays, accumulating evidence suggests that it could effectively alleviate symptoms of pain in oxaliplatin-induced peripheral neuropathy (OIPN). However, the therapeutic mechanism of HGWD against OIPN is necessary to be further clarified. METHODS: The mice model of OIPN was established using the behavioral tests and histopathological observation to assess the therapeutic effect of HGWD against OIPN in vivo. The UHPLC-ESI-Q-TOF-MS/MS was used to identify the potential bioactive components from HGWD in drug-containing rat plasma. The integrated network pharmacology and transcriptomics strategy was performed to deciphers the mechanism of HGWD against OIPN with experimental verification. RESULTS: HGWD could improve pain sensitivity symptom and alleviate the damage of dorsal root ganglia (DRG) neurons or intraepidermal nerve fibers in the mice model of OIPN. Through the integrated analysis of transcriptome and network pharmacology, Sirtuin 1 (Sirt1) was considered as the vital target for HGWD against OIPN. Via virtual screening and the ND7 cell viability assay, Formononetin (FN) and Oxypaeoniflorin (OPRA) from HGWD showed preliminary neuroprotective effects. In addition, OPRA can reduce Sterile alpha and toll interleukin receptor motif-containing protein 1 (SARM1) levels, improve axonal degeneration, and alleviate OIPN through the Sirt1 pathway. CONCLUSION: HGWD could effectively alleviate the pain and nerve injury symptoms in mice with oxaliplatin-induced peripheral neuropathy. The therapeutic mechanism of HGWD against OIPN was relevant to the Sirt1 for the function of anti-oxidative stress in DRG. OPRA can reduce SARM1 levels, improve axonal degeneration, and alleviate OIPN through the Sirt1 pathway.