Multimodal analysis of Aconitum pendulum N.Busch processed by soaking in Terminalia chebula Retz. decoction: aggregation-associated alkaloid partitioning and toxicity attenuation.

ETHNOPHARMACOLOGICAL RELEVANCE: Aconitum pendulum N.Busch (Ap) is a Tibetan medicinal plant traditionally used for rheumatic disorders and inflammatory pain. Its clinical use is limited by aconitine-type cardiotoxicity, and processing with Terminalia chebula Retz. (C) decoction is traditionally applied for detoxification, although the mechanism remains unclear. AIM OF THE STUDY: To investigate aggregation-related alkaloid partitioning, as well as the chemical and biological impacts of C-processing. MATERIALS AND METHODS: Ap and C-processed Ap (Ap-C) were compared using UPLC-Orbitrap-MS profiling, AFADESI-MSI, and triple-quadrupole LC-MS/MS quantification. Aqueous aggregation, washed precipitate composition, and alkaloid-C co-incubation were examined. Anti-arthritic and cardiac effects were assessed in CIA-S rats, and acute toxicity in zebrafish larvae. Tissue distribution was assessed at four time points after a single dose using signals normalized to an internal standard. RESULTS: The contents of all eight quantified alkaloids were lower in Ap-C than in Ap. Experiments supported alkaloid partitioning into washed precipitates containing C-derived constituents. Signals assigned to lipo-diterpenoid alkaloids were detected in aconitine-C precipitates, although their origin remained unresolved. Both preparations alleviated joint damage and inflammation in CIA-S rats. Ap-C attenuated reductions in connexin 43-positive area and increases in serum creatine kinase and lactate dehydrogenase relative to Ap. Cardiac diester-type diterpenoid alkaloid signals were lower at all four times, whereas the integrated renal response for this class was higher. Ap-C also caused less acute toxicity than Ap in zebrafish larvae. CONCLUSIONS: C processing reduced alkaloid contents and attenuated adverse cardiac changes while retaining anti-arthritic activity. We propose that alkaloid partitioning into precipitates during aqueous aggregation may contribute to toxicity attenuation.