基于网络和实验药理学分析松脂醇抗甲基苯丙胺成瘾的神经机制。

IF 6.7 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine Pub Date : 2025-01-01 DOI:10.1016/j.phymed.2024.156322

Shuyuan Fan , Yize Qi , Fukang Zhang , Yatong Shi , Kunfang Ma , Qihang Pan , Ai Jiang , Luanyue He , Junlong Zhang , Tengfei Ma , Li Zhou

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引用次数: 0

摘要

背景：成瘾是一种慢性脑部疾病，其潜在的神经元机制以药物寻求和使用为特征。荷叶花（FD）及其成分用于治疗成瘾。然而，FD与寻求行为的神经元机制相关的有效成分仍不清楚。目的：探讨FD单体成分对甲基苯丙胺成瘾的影响及其机制。方法：采用LC-MS/MS和生物信息学方法筛选FD的主要化学成分和潜在靶点。利用分子对接技术筛选与神经元亚型机制相关的FD成分。通过行为实验、免疫荧光和Western blot验证相关通路中靶点的有效性。采用电生理方法对D1-tdTomato和D2-eGFP转基因小鼠中FD成分的功能进行了鉴定。结果：FD有25种活性成分125个靶点，包括多巴胺1受体(D1R)/多巴胺2受体(D2R)/cAMP信号通路。此外，我们发现pinresinol （PINL）是FD靶向该信号通路的主要成分。此外，PINL能减弱甲基甲醚诱导的寻找行为，降低纹状体D1R神经元中c-Fos的表达，但对D2R神经元没有作用。因此，PINL在功能上减少了D1R神经元的过度兴奋，但对D2R神经元没有作用。最后，我们明确了D1R/PKA通路是介导PINL对甲基甲醚诱导的寻求行为影响的关键因素。结论：我们发现PINL特异性靶向D1R/PKA信号通路的D1R神经元，并减少冰毒诱导的寻求行为，为治疗成瘾疾病提供了新的策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

Dissecting the neuronal mechanisms of pinoresinol against methamphetamine addiction based on network and experimental pharmacology

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Dissecting the neuronal mechanisms of pinoresinol against methamphetamine addiction based on network and experimental pharmacology

Background

Addiction is a chronic brain disease in which the underlying neuronal mechanism is characterized by drug-seeking and use. Flos Daturae (FD) and its components are used to treat addiction. However, the effective ingredients of FD that are linked to the neuronal mechanisms of seeking behavior remain unclear.

Objective

We aimed to explore the effect and mechanism of the monomer ingredients of FD on methamphetamine (METH) addiction.

Methods

The main chemical constituents and potential targets of FD were screened using LC-MS/MS and bioinformatics method. Molecular docking was used to screen the component of FD associated with the neuronal subtype mechanism. The effectiveness of the targets in related pathways was verified by behavioral experiment, immunofluorescence and Western blot. Electrophysiology was used to identify the functions of the ingredients of FD in D1-tdTomato and D2-eGFP transgenic mice.

Results

There were 125 targets of 25 active components in FD, which included dopamine 1 receptor (D1R)/dopamine 2 receptor (D2R)/cAMP signaling pathway. Furthermore, we identified that pinoresinol (PINL) is a major component of FD targeting this signaling pathway. Moreover, PINL attenuated METH-induced seeking behavior and decreased expression of c-Fos in striatal D1R neurons, but not D2R neurons. Accordingly, PINL functionally reduced the over-excitation of D1R, but not D2R neurons. Finally, we clarified that D1R/PKA pathway is a critical factor mediating the effects of PINL on METH-induced seeking behavior.

Conclusion

We revealed that PINL specifically targeted D1R/PKA signaling in D1R neurons and decreased METH-induced seeking behavior, providing a new strategy to treat addictive diseases.

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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.