Maciag Monika, Plazinski Wojciech, Pulawski Wojciech, Kolinski Michal, Jozwiak Krzysztof, Plazinska Anita
Department of Biopharmacy, Medical University of Lublin, 4a Chodzki Street, 20-093 Lublin, Poland; Independent Laboratory of Behavioral Studies, Medical University of Lublin, 4a Chodzki Street, 20-093 Lublin, Poland.
Department of Biopharmacy, Medical University of Lublin, 4a Chodzki Street, 20-093 Lublin, Poland; Jerzy Haber Institute of Catalysis and Surface Chemistry, Polish Academy of Sciences, 8 Niezapominajek Street, 30-239 Cracow, Poland.
Biomed Pharmacother. 2023 Apr;160:114355. doi: 10.1016/j.biopha.2023.114355. Epub 2023 Feb 3.
β-adrenergic receptors (βARs) belong to a key molecular targets that regulate the most important processes occurring in the human organism. Although over the last decades a zebrafish model has been developed as a model complementary to rodents in biomedical research, the role of βAR in regulation of pathological and toxicological effects remains to elucidate. Therefore, the study aimed to clarify the role of βAR with a particular emphasis on the distinct role of subtypes A and B of zebrafish βAR. As model compounds selective βAR agonists - (R,R)-fenoterol ((R,R)-Fen) and its new derivatives: (R,R)-4'-methoxyfenoterol ((R,R)-MFen) and (R,R)-4'-methoxy-1-naphtylfenoterol ((R,R)-MNFen) - were tested. We described dose-dependent changes observed after fenoterols exposure in terms of general toxicity, cardiotoxicity and neurobehavioural responses. Subsequently, to better characterise the role of β-adrenergic stimulation in zebrafish, we have performed a series of molecular docking simulations. Our results indicate that (R,R)-Fen displays the highest affinity for subtype A of zebrafish βAR and βAR might be involved in pigment depletion. (R,R)-MFen shows the lowest affinity for zebrafish βARs out of the tested fenoterols and this might be associated with its cardiotoxic and anxiogenic effects. (R,R)-MNFen displays the highest affinity for subtype B of zebrafish βAR and modulation of this receptor might be associated with the development of malformations, increases locomotor activity and induces a negative chronotropic effect. Taken together, the presented data offer insights into the functional responses of the zebrafish βARs confirming their intraspecies conservation, and support the translation of the zebrafish model in pharmacological and toxicological research.
β-肾上腺素能受体（βARs）属于调节人体最重要生理过程的关键分子靶点。尽管在过去几十年中，斑马鱼模型已被开发为生物医学研究中与啮齿动物互补的模型，但βAR在调节病理和毒理效应中的作用仍有待阐明。因此，本研究旨在阐明βAR的作用，特别强调斑马鱼βAR A亚型和B亚型的独特作用。作为模型化合物，测试了选择性βAR激动剂——（R,R）-非诺特罗（（R,R）-Fen）及其新衍生物：（R,R）-4'-甲氧基非诺特罗（（R,R）-MFen）和（R,R）-4'-甲氧基-1-萘基非诺特罗（（R,R）-MNFen）。我们描述了非诺特罗暴露后在一般毒性、心脏毒性和神经行为反应方面观察到的剂量依赖性变化。随后，为了更好地表征β-肾上腺素能刺激在斑马鱼中的作用，我们进行了一系列分子对接模拟。我们的结果表明，（R,R）-Fen对斑马鱼βAR A亚型表现出最高亲和力，且βAR可能参与色素消耗。在测试的非诺特罗中，（R,R）-MFen对斑马鱼βARs的亲和力最低，这可能与其心脏毒性和致焦虑作用有关。（R,R）-MNFen对斑马鱼βAR B亚型表现出最高亲和力，该受体的调节可能与畸形发育、运动活性增加和负性变时效应诱导有关。综上所述，所呈现的数据为斑马鱼βARs的功能反应提供了见解，证实了它们在种内的保守性，并支持斑马鱼模型在药理学和毒理学研究中的转化。
