Combination of Aconiti Lateralis Radix Praeparata (FZ) and
Paeoniae Radix Alba (BS) shows a significant effect in
rheumatoid arthritis (RA). This study aimed to investigate the efficacy enhancing and toxicity reducing mechanism of combination of them in adjuvant-induced
arthritis (AIA) rats by metabolomics. Rats were randomly divided into seven groups, including A (healthy control), B (model control), C1 (therapy group), C2 (efficacy enhancing group), D1 (toxicity group), and D2 (toxicity reducing group), and
dexamethasone group was used as positive control. The plasma biochemical indexes showed that therapeutic dose of
lipid-soluble
alkaloids of FZ could significantly inhibit the concentrations of IL-1β, TNF-α, and IFN-γ in AIA rats, and combination with total
glucosides of peony could further reduce the concentration of IL-1β. Then, UPLC-LTQ/Orbitrap MS with untargeted metabolomics was performed to identify the possible metabolites and pathways. Through multivariate data analysis of therapeutic dose groups (A vs. B vs. C1 vs. C2) and multivariate data analysis of toxic dose groups (A vs. B vs. D1 vs. D2), 10 and 7
biomarkers were identified based on
biomarker analysis, respectively. After inducing AIA model, the plasma contents of
spermidine,
vanillylmandelic acid,
catechol, and
linoleate were increased significantly, and the contents of
citric acid,
L-tyrosine,
L-phenylalanine,
leucine,
L-tryptophan, and
uridine 5'-monophosphate (
UMP) were decreased significantly. High dose of
lipid-soluble
alkaloids of FZ could increase the plasma contents of
L-lysine,
L-arginine, and
deoxycholic acid, while the plasma contents of
UMP,
carnitine,
N-formylanthranilic acid, and
adenosine were decreased significantly. The pathway analysis indicated that therapeutic dose of
lipid-soluble
alkaloids of FZ could regulate energy and
amino acid metabolic disorders in AIA rats. However, toxic dose could cause
bile acid, fat,
amino acid, and energy metabolic disorders. And combination with total
glucosides of peony could enhance the
therapeutic effects and attenuate the toxicity induced by
lipid-soluble
alkaloids of FZ.