Neuroprotective effect and mechanism of celastrol and its derivatives <italic style="font-style: italic">in vitro</italic>

CHEN Peipei; YUAN Xiaoxuan; ZHANG Xin; XU Wei; XU Shaohua

doi:10.6039/j.issn.1001-0408.2024.05.05

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Neuroprotective effect and mechanism of celastrol and its derivatives in vitro

更新时间：2024-03-08

- Neuroprotective effect and mechanism of celastrol and its derivatives in vitro
- ZHONGGUO YAOFANG Vol. 35, Issue 5, Pages: 536-541(2024)
- 作者机构：
  
  1.福建中医药大学药学院，福州　350122
  2.中国中医科学院道地药材国家重点实验室，北京　100700
- 作者简介：
- 基金信息：
- DOI：10.6039/j.issn.1001-0408.2024.05.05
  CLC： R965;R285
- Published：15 March 2024，
  
  Received：20 September 2023，
  
  Revised：28 December 2023，
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陈佩佩,袁晓煊,张鑫等.雷公藤红素及其衍生物的体外神经保护作用与机制研究 ^Δ[J].中国药房,2024,35(05):536-541.

CHEN Peipei,YUAN Xiaoxuan,ZHANG Xin,et al.Neuroprotective effect and mechanism of celastrol and its derivatives in vitro[J].ZHONGGUO YAOFANG,2024,35(05):536-541.
陈佩佩,袁晓煊,张鑫等.雷公藤红素及其衍生物的体外神经保护作用与机制研究 ^Δ[J].中国药房,2024,35(05):536-541. DOI： 10.6039/j.issn.1001-0408.2024.05.05.

CHEN Peipei,YUAN Xiaoxuan,ZHANG Xin,et al.Neuroprotective effect and mechanism of celastrol and its derivatives in vitro[J].ZHONGGUO YAOFANG,2024,35(05):536-541. DOI： 10.6039/j.issn.1001-0408.2024.05.05.

摘要

目的

从神经炎症和氧化损伤2个方面探究雷公藤红素（Cel）及其衍生物Cel-1、Cel-2的神经保护作用及可能机制。

方法

利用1 μg/mL脂多糖（LPS）诱导建立小胶质BV2细胞神经炎症模型、200 μmol/L过氧化氢（H

）诱导建立人神经母细胞瘤SH-SY5Y细胞氧化损伤模型，考察不同浓度（0.625～20 μmol/L）Cel、Cel-1、Cel-2对2种细胞的毒性；并在安全浓度（0.039～0.625 μmol/L）范围内检测LPS诱导BV2细胞培养液中一氧化氮（NO）、肿瘤坏死因子α（TNF-α）、白细胞介素1β（IL-1β）、IL-6含量，检测H

诱导SH-SY5Y细胞的存活率。检测0.156、0.313、0.625 μmol/L活性化合物Cel-2作用后H

诱导SH-SY5Y细胞中磷脂酰肌醇3激酶（PI3K）、磷酸化PI3K（p-PI3K）、蛋白激酶B（Akt）、磷酸化Akt（p-Akt）、胱天蛋白酶3（caspase-3）、B淋巴细胞瘤2（Bcl-2）和Bcl-2相关X蛋白（Bax）表达水平。

结果

在0.039～0.625 μmol/L浓度梯度区间，神经炎症模型实验显示，Cel、Cel-1、Cel-2均可降低BV2细胞培养液中NO、TNF-α、IL-1β、IL-6的含量（

＜0.05或

＜0.01），其对神经炎症的半数抑制浓度分别为（0.25±0.04）、（0.61±0.14）、（0.11±0.02） μmol/L；氧化损伤模型实验显示，Cel、Cel-1、Cel-2在一定浓度下可逆转H

处理后SH-SY5Y细胞存活率降低的现象（

＜0.05或

＜0.01），其神经保护的半数效应浓度分别为（0.43±0.08）、（0.45±0.04）、（0.28±0.03） μmol/L。经H

诱导，Cel-2干预后SH-SY5Y细胞中PI3K、Akt蛋白的磷酸化水平和Bcl-2蛋白表达水平、Bcl-2/Bax比值均显著升高（

＜0.05或

＜0.01），caspase-3、Bax蛋白表达水平均显著降低（

＜0.05或

＜0.01）。

结论

Cel、Cel-1、Cel-2在一定浓度下均具有显著的神经保护活性，且以Cel-2的活性最强；Cel-2的作用机制可能与调控PI3K/Akt、caspase-3/Bcl-2/Bax信号通路，减轻炎症反应、氧化应激损伤，抑制神经细胞凋亡有关。

Abstract

OBJECTIVE

To explore the neuroprotective effect and possible mechanism of celastrol （Cel） and its derivatives （Cel-1， Cel-2） in terms of neuroinflammation and oxidative damage.

METHODS

Neuroinflammation model of microglial BV2 cells was induced by 1 μg/mL lipopolysaccharide （LPS）； oxidative damage model of human neuroblastoma SH-SY5Y cells was induced by 200 μmol/L hydrogen peroxide （H

）. The toxicity of different concentrations of Cel， Cel-1 and Cel-2 （0.625-20 μmol/L） to the two types of cells was investigated. The levels of nitric oxide （NO）， tumor necrosis factor α （TNF-α）， interleukin 1β （IL-1β）， and IL-6 in BV2 cells induced by LPS at safe concentrations （0.039-0.625 μmol/L） were all detected. The survival rate of SH-SY5Y cells induced by H

was also determined. The expression levels of phosphoinositide 3-kinase （PI3K）， p-PI3K， protein kinase B （Akt）， p-Akt， cystatinase 3 （caspase-3）， B-cell lymphoma 2 （Bcl-2） and Bcl-2-related X protein （Bax） in SH-SY5Y cells induced by H

at 0.156， 0.313， 0.625 μmol/L of active compound 2 were all detected.

RESULTS

In the concentration gradient range between 0.039 and 0.625 μmol/L， the results of neuroinflammation model experiments showed that Cel， Cel-1 and Cel-2 could reduce the contents of NO， TNF-α， IL-1β， and IL-6 in culture medium of BV2 cells （

＜0.05 or

＜0.01）； their IC

values for neuroinflammation were （0.25±0.04），（0.61±0.14） and （0.11±0.02） μmol/L respectively. Meanwhile， all of them could reverse the phenomenon of decreased cell survival rate after H

treatment in the oxidative damage experiments at a certain concentration （

＜0.05 or

＜0.01）， with neuroprotective EC

values of （0.43±0.08），（0.45±0.04） and （0.28±0.03） μmol/L， respectively. Induced by H

， the phosphorylation of PI3K and Akt protein， protein expressions of Bcl-2 and Bcl-2/Bax ratio were all increased significantly （

＜0.05 or

＜0.01）， while the protein expressions of caspase-3 and Bax were decreased significantly （

＜0.05 or

＜0.01）.

CONCLUSIONS

Cel， Cel-1， and Cel-2 all have significant neuroprotective activities at certain concentrations， and Cel-2 shows the most significant protective effect. The mechanism of action of Cel-2 may be related to regulating the PI3K/Akt and caspase-3/Bcl-2/Bax signaling pathways， reducing the inflammatory response， oxidative stress damage and inhibiting neuronal apoptosis.

关键词

雷公藤红素衍生物神经保护作用神经炎症氧化应激

Keywords

derivativesneuroprotectiveneuroinflammationoxidative stress

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Neuroprotective effect and mechanism of celastrol and its derivatives in vitro

DOI：10.6039/j.issn.1001-0408.2024.05.05

摘要

Abstract

关键词

Keywords

references