IDO-1 inhibition improves outcome after fluid percussion injury in adult male rats

IF 2.9 3区 医学 Q2 NEUROSCIENCES
Marawan Sadek, Kurt R. Stover, Xiaojing Liu, Mark A. Reed, Donald F. Weaver, Aylin Y. Reid
{"title":"IDO-1 inhibition improves outcome after fluid percussion injury in adult male rats","authors":"Marawan Sadek,&nbsp;Kurt R. Stover,&nbsp;Xiaojing Liu,&nbsp;Mark A. Reed,&nbsp;Donald F. Weaver,&nbsp;Aylin Y. Reid","doi":"10.1002/jnr.25338","DOIUrl":null,"url":null,"abstract":"<p>The enzyme indoleamine 2,3 dioxygenase 1 (IDO1) catalyzes the rate-limiting step in the kynurenine pathway (KP) which produces both neuroprotective and neurotoxic metabolites. Neuroinflammatory signals produced as a result of pathological conditions can increase production of IDO1 and boost its enzymatic capacity. IDO1 and the KP have been implicated in behavioral recovery after human traumatic brain injury (TBI), but their roles in experimental models of TBI are for the most part unknown. We hypothesized there is an increase in KP activity in the fluid percussion injury (FPI) model of TBI, and that administration of an IDO1 inhibitor will improve neurological recovery. In this study, adult male Sprague Dawley rats were subjected to FPI or sham injury and received twice-daily oral administration of the IDO1 inhibitor PF-06840003 (100 mg/kg) or vehicle control. FPI resulted in a significant increase in KP activity, as demonstrated by an increased ratio of kynurenine: tryptophan, in the perilesional neocortex and ipsilateral hippocampus 3 days postinjury (DPI), which normalized by 7 DPI. The increase in KP activity was prevented by PF-06840003. IDO1 inhibition also improved memory performance as assessed in the Barnes maze and anxiety behaviors as assessed in open field testing in the first 28 DPI. These results suggest increased KP activity after FPI may mediate neurological dysfunction, and IDO1 inhibition should be further investigated as a potential therapeutic target to improve recovery.</p>","PeriodicalId":16490,"journal":{"name":"Journal of Neuroscience Research","volume":"102 5","pages":""},"PeriodicalIF":2.9000,"publicationDate":"2024-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jnr.25338","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Neuroscience Research","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/jnr.25338","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
引用次数: 0

Abstract

The enzyme indoleamine 2,3 dioxygenase 1 (IDO1) catalyzes the rate-limiting step in the kynurenine pathway (KP) which produces both neuroprotective and neurotoxic metabolites. Neuroinflammatory signals produced as a result of pathological conditions can increase production of IDO1 and boost its enzymatic capacity. IDO1 and the KP have been implicated in behavioral recovery after human traumatic brain injury (TBI), but their roles in experimental models of TBI are for the most part unknown. We hypothesized there is an increase in KP activity in the fluid percussion injury (FPI) model of TBI, and that administration of an IDO1 inhibitor will improve neurological recovery. In this study, adult male Sprague Dawley rats were subjected to FPI or sham injury and received twice-daily oral administration of the IDO1 inhibitor PF-06840003 (100 mg/kg) or vehicle control. FPI resulted in a significant increase in KP activity, as demonstrated by an increased ratio of kynurenine: tryptophan, in the perilesional neocortex and ipsilateral hippocampus 3 days postinjury (DPI), which normalized by 7 DPI. The increase in KP activity was prevented by PF-06840003. IDO1 inhibition also improved memory performance as assessed in the Barnes maze and anxiety behaviors as assessed in open field testing in the first 28 DPI. These results suggest increased KP activity after FPI may mediate neurological dysfunction, and IDO1 inhibition should be further investigated as a potential therapeutic target to improve recovery.

Abstract Image

抑制 IDO-1 可改善成年雄性大鼠体液冲击损伤后的疗效
吲哚胺 2,3-二氧化酶 1(IDO1)催化犬尿氨酸途径(KP)中的限速步骤,该途径可产生具有神经保护作用和神经毒性的代谢物。病理情况下产生的神经炎症信号会增加 IDO1 的产生并提高其酶解能力。IDO1 和 KP 与人类创伤性脑损伤(TBI)后的行为恢复有关,但它们在创伤性脑损伤实验模型中的作用大多尚不清楚。我们假设,在脑外伤的体液叩击伤(FPI)模型中,KP活性会增加,而服用IDO1抑制剂会改善神经系统的恢复。在这项研究中,成年雄性 Sprague Dawley 大鼠接受了 FPI 或假性损伤,每天两次口服 IDO1 抑制剂 PF-06840003 (100 毫克/千克)或药物对照。损伤后 3 天(DPI),新皮质周围和同侧海马中的犬尿氨酸与色氨酸之比增加,表明 FPI 导致 KP 活性显著增加,到 7 天后恢复正常。PF-06840003 阻止了 KP 活性的增加。IDO1 抑制还能改善巴恩斯迷宫中的记忆表现,并改善开放场地测试中的焦虑行为。这些结果表明,FPI后KP活性的增加可能介导了神经功能紊乱,而IDO1抑制作为一种潜在的治疗靶点应得到进一步研究,以改善恢复情况。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
Journal of Neuroscience Research
Journal of Neuroscience Research 医学-神经科学
CiteScore
9.50
自引率
2.40%
发文量
145
审稿时长
1 months
期刊介绍: The Journal of Neuroscience Research (JNR) publishes novel research results that will advance our understanding of the development, function and pathophysiology of the nervous system, using molecular, cellular, systems, and translational approaches. JNR covers both basic research and clinical aspects of neurology, neuropathology, psychiatry or psychology. The journal focuses on uncovering the intricacies of brain structure and function. Research published in JNR covers all species from invertebrates to humans, and the reports inform the readers about the function and organization of the nervous system, with emphasis on how disease modifies the function and organization.
×
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