组胺 H3 和 Sigma-2 双受体配体 KSK-94 对肥胖大鼠模型中脂肪组织的影响

Pharmaceuticals Pub Date : 2024-07-01 DOI:10.3390/ph17070858
Magdalena Kotańska, M. Zadrożna, M. Kubacka, Kamil Mika, Katarzyna Szczepańska, Barbara Nowak, Alessio Alesci, Anthea Miller, E. R. Lauriano, Katarzyna Kieć-Kononowicz
{"title":"组胺 H3 和 Sigma-2 双受体配体 KSK-94 对肥胖大鼠模型中脂肪组织的影响","authors":"Magdalena Kotańska, M. Zadrożna, M. Kubacka, Kamil Mika, Katarzyna Szczepańska, Barbara Nowak, Alessio Alesci, Anthea Miller, E. R. Lauriano, Katarzyna Kieć-Kononowicz","doi":"10.3390/ph17070858","DOIUrl":null,"url":null,"abstract":"Background: Numerous studies highlight the critical role that neural histamine plays in feeding behavior, which is controlled by central histamine H3 and H1 receptors. This is the fundamental motivation for the increased interest in creating histamine H3 receptor antagonists as anti-obesity medications. On the other hand, multiple other neurotransmitter systems have been identified as pharmacotherapeutic targets for obesity, including sigma-2 receptor systems. Interestingly, in our previous studies in the rat excessive eating model, we demonstrated a significant reduction in the development of obesity using dual histamine H3/sigma-2 receptor ligands. Moreover, we showed that compound KSK-94 (structural analog of Abbott’s A-331440) reduced the number of calories consumed, and thus acted as an anorectic compound. Therefore, in this study, we extended the previous research and studied the influence of KSK-94 on adipose tissue collected from animals from our previous experiment. Methods: Visceral adipose tissue was collected from four groups of rats (standard diet + vehicle, palatable diet + vehicle, palatable diet + KSK-94, and palatable diet + bupropion/naltrexone) and subjected to biochemical, histopathological, and immunohistochemical studies. Results: The obtained results clearly indicate that compound KSK-94 prevented the hypertrophy and inflammation of visceral adipose tissue, normalized the levels of leptin, resistin and saved the total reduction capacity of adipose tissue, being more effective than bupropion/naltrexon in these aspects. Moreover, KSK-94 may induce browning of visceral white adipose tissue. Conclusion: Our study suggests that dual compounds with a receptor profile like KSK-94, i.e., targeting histamine H3 receptor and, to a lesser extent, sigma-2 receptor, could be attractive therapeutic options for patients at risk of developing obesity or with obesity and some metabolic disorders. However, more studies are required to determine its safety profile and the exact mechanism of action of KSK-94.","PeriodicalId":509865,"journal":{"name":"Pharmaceuticals","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"The Effect of KSK-94, a Dual Histamine H3 and Sigma-2 Receptor Ligand, on Adipose Tissue in a Rat Model of Developing Obesity\",\"authors\":\"Magdalena Kotańska, M. Zadrożna, M. Kubacka, Kamil Mika, Katarzyna Szczepańska, Barbara Nowak, Alessio Alesci, Anthea Miller, E. R. Lauriano, Katarzyna Kieć-Kononowicz\",\"doi\":\"10.3390/ph17070858\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Background: Numerous studies highlight the critical role that neural histamine plays in feeding behavior, which is controlled by central histamine H3 and H1 receptors. This is the fundamental motivation for the increased interest in creating histamine H3 receptor antagonists as anti-obesity medications. On the other hand, multiple other neurotransmitter systems have been identified as pharmacotherapeutic targets for obesity, including sigma-2 receptor systems. Interestingly, in our previous studies in the rat excessive eating model, we demonstrated a significant reduction in the development of obesity using dual histamine H3/sigma-2 receptor ligands. Moreover, we showed that compound KSK-94 (structural analog of Abbott’s A-331440) reduced the number of calories consumed, and thus acted as an anorectic compound. Therefore, in this study, we extended the previous research and studied the influence of KSK-94 on adipose tissue collected from animals from our previous experiment. Methods: Visceral adipose tissue was collected from four groups of rats (standard diet + vehicle, palatable diet + vehicle, palatable diet + KSK-94, and palatable diet + bupropion/naltrexone) and subjected to biochemical, histopathological, and immunohistochemical studies. Results: The obtained results clearly indicate that compound KSK-94 prevented the hypertrophy and inflammation of visceral adipose tissue, normalized the levels of leptin, resistin and saved the total reduction capacity of adipose tissue, being more effective than bupropion/naltrexon in these aspects. Moreover, KSK-94 may induce browning of visceral white adipose tissue. Conclusion: Our study suggests that dual compounds with a receptor profile like KSK-94, i.e., targeting histamine H3 receptor and, to a lesser extent, sigma-2 receptor, could be attractive therapeutic options for patients at risk of developing obesity or with obesity and some metabolic disorders. However, more studies are required to determine its safety profile and the exact mechanism of action of KSK-94.\",\"PeriodicalId\":509865,\"journal\":{\"name\":\"Pharmaceuticals\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2024-07-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Pharmaceuticals\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.3390/ph17070858\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Pharmaceuticals","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.3390/ph17070858","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0

摘要

背景:大量研究强调了神经组胺在摄食行为中的关键作用,而摄食行为是由中枢组胺 H3 和 H1 受体控制的。这也是越来越多的人关注组胺 H3 受体拮抗剂作为抗肥胖药物的根本原因。另一方面,其他多种神经递质系统也被确定为肥胖症的药物治疗靶点,包括 sigma-2 受体系统。有趣的是,我们之前在大鼠过量进食模型中进行的研究表明,使用组胺 H3/σ-2受体双配体能显著减少肥胖的发生。此外,我们还发现化合物 KSK-94(雅培 A-331440 的结构类似物)能减少卡路里的摄入量,从而起到厌食化合物的作用。因此,在本研究中,我们扩展了之前的研究,研究了 KSK-94 对之前实验中收集的动物脂肪组织的影响。研究方法收集四组大鼠(标准饮食+载体、适口饮食+载体、适口饮食+KSK-94、适口饮食+安非他酮/纳曲酮)的内脏脂肪组织,并对其进行生化、组织病理学和免疫组化研究。研究结果结果表明,复方 KSK-94 能防止内脏脂肪组织的肥大和炎症,使瘦素和抵抗素水平正常化,并提高脂肪组织的总还原能力,在这些方面比安非他酮/纳曲酮更有效。此外,KSK-94 还能诱导内脏白色脂肪组织褐变。结论我们的研究表明,像 KSK-94 这样具有受体特征的双重化合物,即以组胺 H3 受体为靶点,其次是以 sigma-2 受体为靶点,对于有肥胖风险或患有肥胖症和某些代谢紊乱的患者来说,可能是具有吸引力的治疗选择。不过,要确定 KSK-94 的安全性和确切作用机制,还需要进行更多的研究。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
The Effect of KSK-94, a Dual Histamine H3 and Sigma-2 Receptor Ligand, on Adipose Tissue in a Rat Model of Developing Obesity
Background: Numerous studies highlight the critical role that neural histamine plays in feeding behavior, which is controlled by central histamine H3 and H1 receptors. This is the fundamental motivation for the increased interest in creating histamine H3 receptor antagonists as anti-obesity medications. On the other hand, multiple other neurotransmitter systems have been identified as pharmacotherapeutic targets for obesity, including sigma-2 receptor systems. Interestingly, in our previous studies in the rat excessive eating model, we demonstrated a significant reduction in the development of obesity using dual histamine H3/sigma-2 receptor ligands. Moreover, we showed that compound KSK-94 (structural analog of Abbott’s A-331440) reduced the number of calories consumed, and thus acted as an anorectic compound. Therefore, in this study, we extended the previous research and studied the influence of KSK-94 on adipose tissue collected from animals from our previous experiment. Methods: Visceral adipose tissue was collected from four groups of rats (standard diet + vehicle, palatable diet + vehicle, palatable diet + KSK-94, and palatable diet + bupropion/naltrexone) and subjected to biochemical, histopathological, and immunohistochemical studies. Results: The obtained results clearly indicate that compound KSK-94 prevented the hypertrophy and inflammation of visceral adipose tissue, normalized the levels of leptin, resistin and saved the total reduction capacity of adipose tissue, being more effective than bupropion/naltrexon in these aspects. Moreover, KSK-94 may induce browning of visceral white adipose tissue. Conclusion: Our study suggests that dual compounds with a receptor profile like KSK-94, i.e., targeting histamine H3 receptor and, to a lesser extent, sigma-2 receptor, could be attractive therapeutic options for patients at risk of developing obesity or with obesity and some metabolic disorders. However, more studies are required to determine its safety profile and the exact mechanism of action of KSK-94.
求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
自引率
0.00%
发文量
0
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信