AM1241 缓解脑缺血再灌注损伤的作用和机制

IF 3.5 3区 医学 Q2 NEUROSCIENCES
Shipeng Li , Ping Yang , Zhenghan Wu , Wenqiang Huang , Xiaofeng Zhu , Lianmei Zhong
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引用次数: 0

摘要

目的:研究表明,脑缺血再灌注损伤(CIRI)涉及一系列生理和病理机制,包括炎症、氧化应激和细胞凋亡。研究发现,大麻素受体 2 激动剂 AM1241 具有抗炎和抗氧化应激作用。然而,AM1241 是否对脑缺血再灌注损伤有保护作用尚不清楚,其潜在机制也不明确:本研究探讨了 AM1241 在 H2O2 刺激的 BV2 细胞和 C57BL/6 CIRI 小鼠模型中的体外和体内抗炎、抗氧化应激和抗凋亡作用及其机制:结果:在体外,AM1241能明显抑制H2O2诱导的促炎细胞因子TNF-α和IL-6的释放、活性氧(ROS)以及Toll样受体4/髓系分化蛋白2(MD2/TLR4)复合物的增加。在 H2O2 刺激下,MD2 的过表达导致 MD2/TLR4 复合物、TNF-α、IL-6、NOX2、BAX 和裂解-Caspase3(C-Caspase3)水平的升高,以及 MAPK 通路和 NF-κB 的激活,而 AM1241 逆转了这些作用。此外,分子对接实验表明,AM1241 与 MD2 直接相互作用。表面等离子共振(SPR)实验进一步证实了 AM1241 与 MD2 的结合。在体内,AM1241能显著减轻过表达MD2的CIRI小鼠的神经功能损伤、脑水肿、梗死体积增大、氧化应激水平和神经细胞凋亡:我们的研究首次证明,AM1241通过抑制MD2/TLR4复合物,发挥抗炎、抗氧化应激和抗细胞凋亡作用,从而缓解小鼠CIRI。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

The effects and mechanisms of AM1241 in alleviating cerebral ischemia-reperfusion injury

The effects and mechanisms of AM1241 in alleviating cerebral ischemia-reperfusion injury

Objective

Research has shown that cerebral ischemia-reperfusion injury (CIRI) involves a series of physiological and pathological mechanisms, including inflammation, oxidative stress, and cell apoptosis. The cannabinoid receptor 2 agonist AM1241 has been found to have anti-inflammatory and anti-oxidative stress effects. However, it is unclear whether AM1241 has a protective effect against brain ischemia-reperfusion injury, and its underlying mechanisms are not yet known.

Methods

In this study, we investigated the anti-inflammatory, anti-oxidative stress, and anti-apoptotic effects of AM1241 and its mechanisms in BV2 cells stimulated with H2O2 and in a C57BL/6 mouse model of CIRI in vitro and in vivo, respectively.

Results

In vitro, AM1241 significantly inhibited the release of pro-inflammatory cytokines TNF-α and IL-6, reactive oxygen species (ROS), and the increase in Toll-like receptor 4/myeloid differentiation protein 2 (MD2/TLR4) complex induced by H2O2. Under H2O2 stimulation, MD2 overexpression resulted in increased levels of MD2/TLR4 complex, TNF-α, IL-6, NOX2, BAX, and Cleaved-Caspase3 (C-Caspase3), as well as the activation of the MAPK pathway and NF-κB, which were reversed by AM1241. In addition, molecular docking experiments showed that AM1241 directly interacted with MD2. Surface Plasmon Resonance (SPR) experiments further confirmed the binding of AM1241 to MD2. In vivo, AM1241 significantly attenuated neurofunctional impairment, brain edema, increased infarct volume, oxidative stress levels, and neuronal apoptosis in CIRI mice overexpressing MD2.

Conclusion

Our study demonstrates for the first time that AM1241 alleviates mouse CIRI by inhibiting the MD2/TLR4 complex, exerting anti-inflammatory, anti-oxidative stress and anti-apoptotic effects.

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来源期刊
Brain Research Bulletin
Brain Research Bulletin 医学-神经科学
CiteScore
6.90
自引率
2.60%
发文量
253
审稿时长
67 days
期刊介绍: The Brain Research Bulletin (BRB) aims to publish novel work that advances our knowledge of molecular and cellular mechanisms that underlie neural network properties associated with behavior, cognition and other brain functions during neurodevelopment and in the adult. Although clinical research is out of the Journal''s scope, the BRB also aims to publish translation research that provides insight into biological mechanisms and processes associated with neurodegeneration mechanisms, neurological diseases and neuropsychiatric disorders. The Journal is especially interested in research using novel methodologies, such as optogenetics, multielectrode array recordings and life imaging in wild-type and genetically-modified animal models, with the goal to advance our understanding of how neurons, glia and networks function in vivo.
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