Berbamine alleviates neuropathic pain via suppressing spinal TMEM34/SGK1/FOXO3 axis

IF 6.7 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine Pub Date : 2025-03-07 DOI:10.1016/j.phymed.2025.156619

Chang-Heng Yao , Zi-Meng Zhang , Shen Zhang , Han Jiang , Rui Wang , Ji-Hua Liu , Hao Xie , Wen-Ling Dai

{"title":"Berbamine alleviates neuropathic pain via suppressing spinal TMEM34/SGK1/FOXO3 axis","authors":"Chang-Heng Yao , Zi-Meng Zhang , Shen Zhang , Han Jiang , Rui Wang , Ji-Hua Liu , Hao Xie , Wen-Ling Dai","doi":"10.1016/j.phymed.2025.156619","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><div>The pathologic mechanism of neuropathic pain (NP) is still not fully understood, and efficient and safe therapeutic options are limited.</div></div><div><h3>Purpose</h3><div>Seeking new treatment options for neuropathic pain.</div></div><div><h3>Study Design</h3><div>Exploring new therapeutic target for NP and finding analgesic medications derived from traditional Chinese medicines against the target is urgent.</div></div><div><h3>Methods</h3><div>Chronic constriction injury (CCI) model was used for behavioral assays. <em>In vitro</em> assay was conducted by using primary neurons, glial cells, as well as PC12, C6, and BV2 cells. The mechanical and thermal withdrawal threshold was assessed using Von Frey filaments and Hargreaves method. RNA sequencing (RNA-Seq), immunofluorescence, western blot, and quantitative RT-PCR were also used.</div></div><div><h3>Results</h3><div>Spinal transmembrane34 (TMEM34) was firstly found to be elevated in CCI induced NP. Knocking-down spinal TMEM34 obviously alleviated NP, while overexpressing TMEM34 promoted NP and induced allodynia in naïve rats. Furthermore, TMEM34 was expressed in spinal neurons and astrocytes but not in microglia to activate them in CCI rats. Serum and glucocorticoid inducible kinase-1 (SGK1) was similarly expressed in astrocytes and neurons, and its expression trend is compatible with that of TMEM34. p-SGK1 expression was also suppressed by blocking TMEM34 in CCI rats. In addition, TMEM34/SGK1 was found to prevent Forkhead box O3 (FOXO3) from activating neurons and astrocytes and promoting NP. Berbamine (BBM), an active compound in <em>Stephania epigaea</em> H. S. Lo, was screened to block the TMEM34/SGK1/FOXO3 axis, hence relieving NP.</div></div><div><h3>Conclusions</h3><div>Our findings highlighted the significance of TMEM34 as a critical factor in NP and found a prospective medication that inhibited TMEM34 to reduce NP.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"140 ","pages":"Article 156619"},"PeriodicalIF":6.7000,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Phytomedicine","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0944711325002594","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}

引用次数: 0

Abstract

Background

The pathologic mechanism of neuropathic pain (NP) is still not fully understood, and efficient and safe therapeutic options are limited.

Purpose

Seeking new treatment options for neuropathic pain.

Study Design

Exploring new therapeutic target for NP and finding analgesic medications derived from traditional Chinese medicines against the target is urgent.

Methods

Chronic constriction injury (CCI) model was used for behavioral assays. In vitro assay was conducted by using primary neurons, glial cells, as well as PC12, C6, and BV2 cells. The mechanical and thermal withdrawal threshold was assessed using Von Frey filaments and Hargreaves method. RNA sequencing (RNA-Seq), immunofluorescence, western blot, and quantitative RT-PCR were also used.

Results

Spinal transmembrane34 (TMEM34) was firstly found to be elevated in CCI induced NP. Knocking-down spinal TMEM34 obviously alleviated NP, while overexpressing TMEM34 promoted NP and induced allodynia in naïve rats. Furthermore, TMEM34 was expressed in spinal neurons and astrocytes but not in microglia to activate them in CCI rats. Serum and glucocorticoid inducible kinase-1 (SGK1) was similarly expressed in astrocytes and neurons, and its expression trend is compatible with that of TMEM34. p-SGK1 expression was also suppressed by blocking TMEM34 in CCI rats. In addition, TMEM34/SGK1 was found to prevent Forkhead box O3 (FOXO3) from activating neurons and astrocytes and promoting NP. Berbamine (BBM), an active compound in Stephania epigaea H. S. Lo, was screened to block the TMEM34/SGK1/FOXO3 axis, hence relieving NP.

Conclusions

Our findings highlighted the significance of TMEM34 as a critical factor in NP and found a prospective medication that inhibited TMEM34 to reduce NP.

查看原文本刊更多论文

求助全文

约1分钟内获得全文求助全文

来源期刊

Phytomedicine 医学-药学

CiteScore

10.30

自引率

5.10%

发文量

670

审稿时长

91 days

期刊介绍： Phytomedicine is a therapy-oriented journal that publishes innovative studies on the efficacy, safety, quality, and mechanisms of action of specified plant extracts, phytopharmaceuticals, and their isolated constituents. This includes clinical, pharmacological, pharmacokinetic, and toxicological studies of herbal medicinal products, preparations, and purified compounds with defined and consistent quality, ensuring reproducible pharmacological activity. Founded in 1994, Phytomedicine aims to focus and stimulate research in this field and establish internationally accepted scientific standards for pharmacological studies, proof of clinical efficacy, and safety of phytomedicines.