Russell G Wells, Azzam F Azzam, Amie L Hiller, Michael F Sardinia
{"title":"血管紧张素 IV 类似物对 3-硝基丙酸诱导的大鼠亨廷顿症样症状的影响","authors":"Russell G Wells, Azzam F Azzam, Amie L Hiller, Michael F Sardinia","doi":"10.3233/JHD-231507","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Huntington's disease (HD) is a neurodegenerative disorder characterized by motor, cognitive, and psychiatric dysfunction caused by a mutant huntingtin protein. Compromised metabolic activity resulting from systemic administration of the mitochondrial toxin, 3-nitropropionic acid (3-NP), is known to mimic the pathology of HD and induce HD-like symptoms in rats. N-hexanoic-Tyr-Ile-(6)-amino hexanoic amide (PNB-0408), also known as Dihexa, has been shown to have neuroprotective and procognitive properties in animal models of Alzheimer's and Parkinson's diseases. Given the mechanism of action and success in other neurodegenerative diseases, we felt it an appropriate compound to investigate further for HD.</p><p><strong>Objective: </strong>The present study was designed to test if PNB-0408, an angiotensin IV analog, could attenuate 3-NP-induced HD-like symptoms in rats and serve as a potential therapeutic agent.</p><p><strong>Methods: </strong>Forty male Wistar rats were randomized into three groups consisting of a \"vehicle\" group, a \"3-NP\" group, and a \"3-NP + PNB-0408\" group. PNB-0408 was administered along with chronic exposure to 3-NP. Animal body weight, motor function, and cognitive abilities were measured for five weeks, before euthanasia and histopathological analysis.</p><p><strong>Results: </strong>Exposure to 3-NP decreased the amount of weight rats gained, impaired spatial learning and memory consolidation, and led to marked motor dysfunction. From our observations and analysis, PNB-0408 did not protect rats from the deficits induced by 3-NP neurotoxicity.</p><p><strong>Conclusions: </strong>Our findings suggest that PNB-0408 may not be an efficacious treatment strategy for preventing 3-NP-induced HD-like symptoms in a preclinical model. These data highlight the need for further research of this compound in alternate models and/or alternative approaches to managing this disorder.</p>","PeriodicalId":16042,"journal":{"name":"Journal of Huntington's disease","volume":null,"pages":null},"PeriodicalIF":2.1000,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Effects of an Angiotensin IV Analog on 3-Nitropropionic Acid-Induced Huntington's Disease-Like Symptoms in Rats.\",\"authors\":\"Russell G Wells, Azzam F Azzam, Amie L Hiller, Michael F Sardinia\",\"doi\":\"10.3233/JHD-231507\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Huntington's disease (HD) is a neurodegenerative disorder characterized by motor, cognitive, and psychiatric dysfunction caused by a mutant huntingtin protein. Compromised metabolic activity resulting from systemic administration of the mitochondrial toxin, 3-nitropropionic acid (3-NP), is known to mimic the pathology of HD and induce HD-like symptoms in rats. N-hexanoic-Tyr-Ile-(6)-amino hexanoic amide (PNB-0408), also known as Dihexa, has been shown to have neuroprotective and procognitive properties in animal models of Alzheimer's and Parkinson's diseases. Given the mechanism of action and success in other neurodegenerative diseases, we felt it an appropriate compound to investigate further for HD.</p><p><strong>Objective: </strong>The present study was designed to test if PNB-0408, an angiotensin IV analog, could attenuate 3-NP-induced HD-like symptoms in rats and serve as a potential therapeutic agent.</p><p><strong>Methods: </strong>Forty male Wistar rats were randomized into three groups consisting of a \\\"vehicle\\\" group, a \\\"3-NP\\\" group, and a \\\"3-NP + PNB-0408\\\" group. PNB-0408 was administered along with chronic exposure to 3-NP. Animal body weight, motor function, and cognitive abilities were measured for five weeks, before euthanasia and histopathological analysis.</p><p><strong>Results: </strong>Exposure to 3-NP decreased the amount of weight rats gained, impaired spatial learning and memory consolidation, and led to marked motor dysfunction. From our observations and analysis, PNB-0408 did not protect rats from the deficits induced by 3-NP neurotoxicity.</p><p><strong>Conclusions: </strong>Our findings suggest that PNB-0408 may not be an efficacious treatment strategy for preventing 3-NP-induced HD-like symptoms in a preclinical model. These data highlight the need for further research of this compound in alternate models and/or alternative approaches to managing this disorder.</p>\",\"PeriodicalId\":16042,\"journal\":{\"name\":\"Journal of Huntington's disease\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":2.1000,\"publicationDate\":\"2024-01-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Huntington's disease\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.3233/JHD-231507\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"NEUROSCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Huntington's disease","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.3233/JHD-231507","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
引用次数: 0
摘要
背景:亨廷顿氏病(Huntington's disease,HD)是一种神经退行性疾病,其特征是由突变亨廷蛋白引起的运动、认知和精神功能障碍。众所周知,全身服用线粒体毒素 3-硝基丙酸(3-NP)会导致新陈代谢活动紊乱,从而模拟 HD 的病理过程并诱发大鼠出现类似 HD 的症状。N-hexanoic-Tyr-Ile-(6)-amino hexanoic amide (PNB-0408),又称 Dihexa,已被证明在阿尔茨海默氏症和帕金森氏症动物模型中具有神经保护和促进认知的特性。鉴于其作用机制以及在其他神经退行性疾病中的成功应用,我们认为这是一种适合进一步研究 HD 的化合物:本研究旨在测试血管紧张素 IV 类似物 PNB-0408 能否减轻 3-NP 诱导的大鼠 HD 类症状,并作为一种潜在的治疗药物:将 40 只雄性 Wistar 大鼠随机分为三组,包括 "载体 "组、"3-NP "组和 "3-NP + PNB-0408" 组。PNB-0408 与 3-NP 的慢性暴露同时给药。在安乐死和组织病理学分析之前,对动物的体重、运动功能和认知能力进行了为期五周的测量:结果:暴露于 3-NP 会降低大鼠的体重增加量,损害空间学习和记忆巩固,并导致明显的运动功能障碍。根据我们的观察和分析,PNB-0408 不能保护大鼠免受 3-NP 神经毒性引起的缺陷的影响:我们的研究结果表明,在临床前模型中,PNB-0408 可能不是预防 3-NP 引起的类似 HD 症状的有效治疗策略。这些数据突出表明,有必要在替代模型和/或替代方法中进一步研究这种化合物,以治疗这种疾病。
Effects of an Angiotensin IV Analog on 3-Nitropropionic Acid-Induced Huntington's Disease-Like Symptoms in Rats.
Background: Huntington's disease (HD) is a neurodegenerative disorder characterized by motor, cognitive, and psychiatric dysfunction caused by a mutant huntingtin protein. Compromised metabolic activity resulting from systemic administration of the mitochondrial toxin, 3-nitropropionic acid (3-NP), is known to mimic the pathology of HD and induce HD-like symptoms in rats. N-hexanoic-Tyr-Ile-(6)-amino hexanoic amide (PNB-0408), also known as Dihexa, has been shown to have neuroprotective and procognitive properties in animal models of Alzheimer's and Parkinson's diseases. Given the mechanism of action and success in other neurodegenerative diseases, we felt it an appropriate compound to investigate further for HD.
Objective: The present study was designed to test if PNB-0408, an angiotensin IV analog, could attenuate 3-NP-induced HD-like symptoms in rats and serve as a potential therapeutic agent.
Methods: Forty male Wistar rats were randomized into three groups consisting of a "vehicle" group, a "3-NP" group, and a "3-NP + PNB-0408" group. PNB-0408 was administered along with chronic exposure to 3-NP. Animal body weight, motor function, and cognitive abilities were measured for five weeks, before euthanasia and histopathological analysis.
Results: Exposure to 3-NP decreased the amount of weight rats gained, impaired spatial learning and memory consolidation, and led to marked motor dysfunction. From our observations and analysis, PNB-0408 did not protect rats from the deficits induced by 3-NP neurotoxicity.
Conclusions: Our findings suggest that PNB-0408 may not be an efficacious treatment strategy for preventing 3-NP-induced HD-like symptoms in a preclinical model. These data highlight the need for further research of this compound in alternate models and/or alternative approaches to managing this disorder.