Ligustrazine mitigates chronic venous disease-induced pain hyperalgesia through desensitization of inflammation-associated TRPA1 activity in DRG. (15th November 2022)

• Record Type: Journal Article
• Authors: Yu, Mei; Ye, Fan; Ma, Chao; Jin, Xiang; Ji, Haiwang; Wang, Dijun; Yang, Yan; Zhu, Chan; Tang, Zongxiang
• Is Part Of: Journal of ethnopharmacology. Volume 298(2022)
• Publication Date: 2022-11-15
• Subjects: Ligustrazine -- Chronic venous disease -- Chronic pain -- Inflammation -- TRPA1; APs Action potentials -- CVeD Chronic venous disease -- DRG Dorsal root ganglion -- IL-1β Interleukin-1β -- i.p. Intraperitoneal -- LZH Ligustrazine hydrochloride -- NLRP3 NOD-like receptor protein 3 -- P2X3 Purinergic P2X receptor 3 -- RMP Resting membrane potential -- TNF-α Tumor necrosis factor-α -- TRPA1 Transient receptor potential ankyrin 1 -- TRPV1 Transient receptor potential vanilloid 1; Ethnopharmacology -- Periodicals; Pharmacognosy -- Periodicals; Herbs -- Periodicals; Herbs -- Periodicals; Pharmacognosy -- Periodicals; Pharmacognosie -- Périodiques; Herbes -- Périodiques; 615.1
• DOI: 10.1016/j.jep.2022.115667
• Languages: English
• ISSNs: 0378-8741

Abstract

Abstract: Ethnopharmacological relevance: Ligustrazine, an important active ingredient extracted from Ligusticum chuanxiong hort, has been widely used to cure cardiovascular diseases and exerts an analgesic effect. Aims of this study: The aim of this study is to investigate whether ligustrazine mitigates chronic venous disease (CVeD)-induced pain and to explore its underlying mechanisms. Materials and methods: A mouse model of CVeD was established by vein ligature. Ligustrazine was administered intraperitoneally to CVeD mice for a single injection (20 mg/kg, 100 mg/kg, and 200 mg/kg) or once a day for three weeks (100 mg/kg and 200 mg/kg), and TRPA1 overexpressed HEK 293 cells were treated with ligustrazine (600 μM) in the presence of mustard oil (100 μM) for 2 min. Patch clamp and calcium imaging were used to measure the inhibitory response of ligustrazine on DRG neurons and TRPA1 transfected HEK293 cells. Results: The present results showed that mice receiving vein ligature surgery exhibited obvious pain hypersensitivity to mechanical, cold and thermal stimuli, whereas ligustrazine significantly reversed the pain hyperalgesia in CVeD mice. Furthermore, ligustrazine desensitized transient receptor potential ankyrin 1 (TRPA1) activity in the dorsal root ganglion (DRG) neurons, resulting in suppressing the DRG neuronal excitability in the CVeD mice. However, ligustrazine could not directly inhibit the response of TRPA1 transfected HEK293 cells to mustard oil. Strikingly, ligustrazine restricted the macrophage infiltration and decreased the mRNA levels of Interleukin-1β (IL-1β) and NOD-like receptor protein 3 (NLRP3) in the DRG neurons of the CVeD mice. Conclusions: The present study provided evidence that ligustrazine alleviated pain hypersensitivity to mechanical, cold and thermal stimuli in CVeD mice. Ligustrazine could weaken the activity of TRPA1 in the DRG to mitigate CVeD-induced pain hyperalgesia mainly through inhibition of inflammation. Our findings identify that ligustrazine may be a new therapeutic agent for the treatment of CVeD-induced pain. Graphical abstract: Image 1 Highlights: The mice receiving vein ligature surgery exhibited obvious pain hypersensitivity to mechanical, cold and thermal stimuli. Ligustrazine could dose dependently ameliorate the CVeD-induced pain hyperalgesia. Ligustrazine desensitized TRPA1 activity of the DRG neurons. Ligustrazine decreased the macrophage infiltration and the levels of inflammatory cytokines in the DRG neurons. Ligustrazine could weaken the activity of TRPA1 in the DRG mainly through inhibition of inflammation.