Study On Material Basis And Mechanism Of Huangqi Guizhi Wuwu Decoction For Alleviating Paclitaxel-induced Peripheral Neuropathy

Paclitaxel,a widely used natural antineoplastic agent,also have larger probability associated with peripheral neuropathy side effects,which causes pain to patients and reduce the quality of their life.Unfortunately,there is no exactly effective treatment measures for paclitaxel-induced peripheral neuropathy(PIPN),which become the most main application of paclitaxel chemotherapy dose limiting factors and one of the significant clinical problems to be solved.Our previous study confirmed that Huangqi Guizhi Wuwu Decoction(HGWD)has a good prevention and treatment effect on oxaliplatin-induced peripheral neuropathy(OIPN),but its effect on PIPN is still unknown.The purpose of this study is to analyze the in vivo and in vitro material basis of HGWD and its pharmacodynamic effect on PIPN,and also to try to clarify its possible mechanism.The first part carries on the theory and literature research,which lays the theoretical foundation for the follow-up research.This part mainly through both literature review and theoretical analysis,respectively to study peripheral neuropathy(PN),PIPN and HGWD,and found that the attending disease of HGWD which is called Xue Bi(blood-arthralgia)has larger associated with PN,and both herbs and the whole prescription shows good nerve protective effect,thus HGWD is a potential prevention and treatment of PIPN,which is worthy of further study.The second part is about the in vivo and in vitro chemical composition analysis of HGWD,which study the chemical composition of HGWD and the drug-containing serum of it by using UHPLC-Q-TOF-MS/MS.The results identified 103 compounds and 39 prototype components,while parsing Characteristic compound structure and the secondary mass spectrometry cleavage law of the five herbs in HGWD,and also found 46 metabolic components which have high correlation with the prototype components.The third part is the pharmacodynamics research.Through the establishment of PIPN model in rat,and verify the control effects of HGWD on PIPN from animal level,organization level,protein level and mRNA level.Furthermore,the conclusion that HGWD would not diminish antitumor effect of paclitaxel was also confirmed through a tumor-burdened CFPAC-1 nude mice and two tumor cell experiments.The fourth part is the mechanism research by the prediction of common targets of HGWD and PIPN,PPI network,C-T nerwork,T-P network and the implementation of KEGG pathway enrichment and GO function analysis,found that HGWD have a bigger relevance inflammation and oxidative stress path on the treatment of PIPN.In this study,the mechanism of TLR4/Nf-?B pathway associated with inflammation and PI3K/Akt-Nrf2 associated with oxidative stress were studied,and it was found that HGWD could inhibit the prevention and treatment of PIPN by down-regulating TLR4/Nf-?B and simultaneously activating PI3K/Akt-Nrf2 signaling pathway.The fifth part is the study about the influence of intestinal flora.By the methods of DNA extraction,amplification,16 s rDNA sequencing and data analysis of gut microbiota from rat,which found that HGWD can reduce the changes of intestinal flora of alpha,beta,and the flora abundance changes of prevotellaceae,bifidobacteriaceae,desulfovibrionaceae and bacteroidaceae caused by paclitaxel.Function prediction found that main influence of intestinal flora mediated taxol amino acid metabolism,phenylalanine,isoleucine,tryptophan,histidine metabolism pathways of the most significant change,HGWD has significant inhibitory effect to metabolic abnormalities of these amino acids.In conclusion,this study found that HGWD is a potential effective therapeutic measure prevention and treatment of PIPN,mainly through the down-regulation of TLR4/Nf-?B and the activation of PI3K/Akt-Nrf2 pathways which play roles of anti-inflammatory and antioxidant,and can improve the amino acid metabolism mediated by the intestinal flora caused by the paclitaxel as well.In addition,in vivo and in vitro material basis of HGWD were also studied.These results may provide a basis for further mechanism research and clinical promotion of this treatment strategy.