Abstract
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.
Highlights
Rheumatoid arthritis (RA) is an unknown etiology, chronic and inflammatory synovitis-based autoimmune systemic disease, which is characterized by invasive joint inflammation and symmetric lesions of the hands and foot facet joints, accompanied by positive serum anticyclic citrullinated peptide antibody (Anti-CCP) and rheumatoid factor (RF), even involving extra-articular organs and leading to joint deformity and functional injury [1, 2].In recent years, drugs for the treatment of RA have been continuously put into clinical treatment, such as glucocorticoids, tumor necrosis factor-alpha (TNF-α) inhibitors, technetium [99Tc] methylene diphosphonate injection, nonsteroidal anti-inflammatory drugs (NSAIDs), biological targeting agents and disease-modifying antirheumatic drugsEvidence-Based Complementary and Alternative Medicine (DMARDs)
After immunization with Complete Freund’s adjuvant (CFA), swelling immediately appeared on the injected feet, on the 8th day after immunization, swelling and erythema gradually appeared on the left foot, and the model group all reached the peak of inflammation on the 28th day
The above results illustrated that dexamethasone had a strong anti-inflammatory effect, lipidsoluble alkaloids of FZ had a good effect on adjuvant-induced arthritis (AIA) rats, and combination with total glucosides of peony could enhance this effect
Summary
They bring many serious side effects during the treatment of RA, such as Cushing’s syndrome, diabetes, hepatotoxicity, and even malignant tumors [3]. Some studies reported that Aconitum alkaloids were the main bioactive components of FZ, which mainly consist of monoester-diterpenoid aconitines (MDAs) and diesterditerpenoid aconitines (DDAs). They were reported to induce toxic reactions such as gastrointestinal toxicity, neurotoxicity, and fatal cardiac toxicity [7, 8]; excessive use of FZ in the treatment of RA might have serious consequences
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