Unveiling the 'Eating Poison' of Polygala tenuifolia xylem: Mood changes and myocardial injury

The precise processing methods of traditional Chinese herbal medicines are paramount to ensuring their safety and efficacy. Leigong PaoZhi Lun, the seminal work on the processing of Chinese herbal medicine, documents that the ingestion of xylem in the root of Polygala tenuifolia (PTX) induces a state referred to as "MEN". However, the biological phenotypic effects of PTX-induced "MEN" and its underlying mechanisms remain largely unexplored. This study employs a comprehensive approach, integrating behavioral observations related to the central nervous system (CNS) and cardiovascular system (CVS), electrocardiogram analysis, myocardial enzyme detection, ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-Q/TOF-MS)-based metabolomics, plasma exosomal microRNA (miRNA) sequencing, intracerebral cannulation of the lateral habenula (LHb) with administration of the N-Methyl-D-Aspartate receptor (NMDAR) antagonist 2-amino-5-phosphonopentanoic acid (AP5), molecular docking, and a combination of in silico and wet lab experiments. This multifaceted methodology unveiled the chemical phenotype of PTX, identifying 245 chemical constituents, including 7 specific metabolites. Two key findings emerged: PTX disrupts the glutamate (Glu)-gamma-aminobutyric acid (GABA) balance within the LHb, leading to CNS-related depressive-like mood alterations. Additionally, tenuifolin and sibiricose A5 in PTX mediate aldehyde dehydrogenase 2 (ALDH2) inactivation, resulting in CVS-related myocardial cell damage, subsequently causing increased heart rate and hypoxia. These findings provide a novel research perspective on the "safety" quality control and evaluation of P. tenuifolia. Additionally, they offer new evidence to elucidate the modern scientific implications of the theories of "same origin with different effects" and "co-existence of opposite properties" in traditional Chinese medicine.