Exploring Effect of Levo-tetrahydropalmatine on Spinal Metabolic Profiles of Rats with Chronic Pain Based on Widely-targeted Metabolomics
10.13422/j.cnki.syfjx.20241516
- VernacularTitle:基于广泛靶向代谢组学技术探究延胡索乙素对慢性疼痛大鼠脊髓代谢谱的影响
- Author:
Dan WU
1
;
Junhong ZHANG
1
;
Lu FU
1
;
Yute ZHONG
1
;
Ping WANG
1
;
Haiyu XU
1
Author Information
1. Institute of Chinese Materia Medica， China Academy of Chinese Medical Sciences， Beijing 100700， China
- Publication Type:Journal Article
- Keywords:
levo-tetrahydropalmatine;
chronic pain;
widely-targeted metabolomics;
glutathione metabolism;
ferroptosis
- From:
Chinese Journal of Experimental Traditional Medical Formulae
2024;30(23):187-194
- CountryChina
- Language:Chinese
-
Abstract:
ObjectiveTo elucidate the underlying mechanism of the efficacy of Levo-tetrahydropalmatine （l-THP） in alleviating chronic pain and identify the key metabolites and metabolic pathways for l-THP regulation. MethodA classical chronic constrictive injury （CCI） model was built in rats’ bodies， and the pain intensity was evaluated by detecting the mechanical withdrawal threshold. On the sixth day after surgery， oral administration of l-THP （64 mg·kg-1） and positive control drug pregabalin （Pre， 30 mg·kg-1） was performed on rats. After the last administration following consecutive five times of administration， ipsilateral spinal cord tissues were collected for widely-targeted metabonomics， with eight rats in each group. Differential metabolites （DEMs） were identified according to the standard of VIP>1.0 and P<0.05， and functional enrichment and interaction analyses of the Kyoto Encyclopedia of Genes and Genomes （KEGG） were performed to obtain the key metabolites and metabolic pathways associated with the analgesic effects of l-THP. ResultIn behavioral science， administration of both l-THP and Pre significantly improved mechanical hyperalgesia in CCI rats （P<0.01）， thus mitigating pain. Metabonomic analysis results revealed that l-THP administration corrected the aberrant metabolic profile in the spinal cord of CCI rats. Meanwhile， 53 DEMs were called back， including several classical pain biomarkers such as sphingosine-1-phosphate （S1P）， cyclic adenosine monophosphate （cAMP）， acetylcholine， and glutamate. Functional enrichment analysis of the DEMs indicated the involvement of metabolic pathways such as ferroptosis， autophagy， neuroactive ligand-receptor interactions， phospholipase D and cAMP-related signaling pathways， glutathione metabolism， and cofactor biosynthesis in mediating the effects of l-THP on the metabolic profile of the spinal cord. Further analyses on the relative metabolite abundance and metabolic pathways indicated that by significantly decreasing the relative levels of glutamate （P<0.01） and glycine （P<0.01） in the spinal cord， l-THP can promote the synthesis of reduced glutathione （GSH） and increase the ratio of reduced/oxidized GSH （P<0.05）. Additionally， it can relieve oxidative stress in the spinal cord of CCI rats and significantly reduce the acetyl-CoA level （P<0.01） to finally inhibit ferroptosis occurrence. Conclusionl-THP may exert analgesic effects by regulating multiple metabolic pathways including GSH metabolism， ferroptosis， cofactor biosynthesis， and amino acid synthesis to correct the aberrant metabolic profile in the spinal cord of CCI rats. Ferroptosis and GSH metabolism may be the key pathways for l-THP regulation， with glutamate， glycine， glutathione， and acetyl-CoA as the key metabolites.
