A traditional Chinese formula-Lingjiao Gouteng decoction protects dopaminergic neurons from Parkinson's disease via systematic modulation of phospholipid redox metabolism.

Abstract

BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disorder marked by dopaminergic neuron loss. Current treatments fail to halt progression and often cause long-term side effects. Traditional Chinese medicine (TCM), recognized for its holistic therapeutic approach, has potential in alleviating symptoms associated with PD. Lingjiao Gouteng decoction (LJGT), a TCM used for tremor symptoms, requires further investigation to clarify its neuroprotective mechanisms and pharmacological basis. PURPOSE: This study aims to explore the potential mechanisms underlying the neuroprotective effects of LJGT in the treatment of PD and to identify the key bioactive components contributing to its therapeutic efficacy. METHODS: The chemical components of the LJGT compound were characterized by LC-MS/MS technology. PD-like mouse models were established through 6-hydroxydopamine or adeno-associated virus carrying human SNCA, followed by LJGT administration. The effects of LJGT on PD-like motor deficits were assessed by rotarod test, pole test, and gait analysis. Dopaminergic neuron loss was evaluated by immunohistochemistry, LC-MS/MS, and Western blotting. To investigate the underlying mechanisms of LJGT in PD treatment, RNA-seq, lipidomics, and oxidized phospholipidomics analysis were conducted. Furthermore, the key bioactive components of LJGT were identified by molecular docking, cellular thermal shift assay, and C11-Bodipy staining. RESULTS: LJGT significantly ameliorated behavioral impairments and attenuated neuronal damage in PD mouse models. Multi-omics further revealed that the neuroprotective effects of LJGT are mediated through the regulation of phospholipid redox metabolism and inhibition of phospholipid peroxidation. Notably, treatment with LJGT significantly downregulated the expression of ALOX15 in this pathway, while upregulating the expression levels of GPX4 and FTH1. Additionally, the bioactive compounds 3,5-di-caffeoylquinic acid, hesperidin, and isoacteoside were identified as key modulators targeting ALOX15/PEBP1 complex, GPX4/NEDD4 complex, and FTH1, respectively, thereby regulating the phospholipid redox metabolism homeostasis and synergistically contributing to the overall anti-phospholipid peroxidation effect of LJGT. CONCLUSION: LJGT exerts neuroprotective effects in PD by modulating the phospholipid redox metabolism, reflecting the holistic therapeutic characteristics of TCM. These findings provide a scientific basis for the clinical application of LJGT and its potential as a multi-component and multi-target therapeutic agent for PD.