氯胺酮通过抑制神经毒性代谢产物犬尿氨酸途径的产生,防止炎症诱导的人类海马神经发生减少。

IF 4.5 2区 医学 Q1 CLINICAL NEUROLOGY
Gargi Mandal, Madeline Kirkpatrick, Silvia Alboni, Nicole Mariani, Carmine M Pariante, Alessandra Borsini
{"title":"氯胺酮通过抑制神经毒性代谢产物犬尿氨酸途径的产生,防止炎症诱导的人类海马神经发生减少。","authors":"Gargi Mandal, Madeline Kirkpatrick, Silvia Alboni, Nicole Mariani, Carmine M Pariante, Alessandra Borsini","doi":"10.1093/ijnp/pyae041","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Understanding the precise mechanisms of ketamine is crucial for replicating its rapid antidepressant effects without inducing psychomimetic changes. Here, we explore whether the antidepressant-like effects of ketamine enantiomers are underscored by protection against cytokine-induced reductions in hippocampal neurogenesis and activation of the neurotoxic kynurenine pathway in our well-established in vitro model of depression in a dish.</p><p><strong>Methods: </strong>We used the fetal hippocampal progenitor cell line (HPC0A07/03C) to investigate ketamine's impact on cytokine-induced reductions in neurogenesis in vitro. Cells were treated with interleukin- 1beta (IL-1b) (10 ng/mL) or IL-6 (50 pg/mL), alone or in combination with ketamine enantiomers arketamine (R-ketamine, 400 nM) or esketamine (S-ketamine, 400 nM) or antidepressants sertraline (1 mM) or venlafaxine (1 mM).</p><p><strong>Results: </strong>Resembling the effect of antidepressants, both ketamine enantiomers prevented IL-1b- and IL-6-induced reduction in neurogenesis and increase in apoptosis. This was mediated by inhibition of IL-1b-induced production of IL-2 and IL-13 by R-ketamine and of IL-1b-induced tumor necrosis factor-alpha by S-ketamine. Likewise, R-ketamine inhibited IL-6-induced production of IL-13, whereas S-ketamine inhibited IL-6-induced IL-1b and IL-8. Moreover, both R- and S-ketamine prevented IL-1b-induced increases in indoleamine 2,3-dioxygenase expression as well as kynurenine production, which in turn was shown to mediate the detrimental effects of IL-1b on neurogenesis and apoptosis. In contrast, neither R- nor S-ketamine prevented IL-6-induced kynurenine pathway activation.</p><p><strong>Conclusions: </strong>Results suggest that R- and S-ketamine have pro-neurogenic and anti-inflammatory properties; however, this is mediated by inhibition of the kynurenine pathway only in the context of IL-1b. Overall, this study enhances our understanding of the mechanisms underlying ketamine's antidepressant effects in the context of different inflammatory phenotypes, ultimately leading to the development of more effective, personalized therapeutic approaches for patients suffering from depression.</p>","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":null,"pages":null},"PeriodicalIF":4.5000,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11450635/pdf/","citationCount":"0","resultStr":"{\"title\":\"Ketamine Prevents Inflammation-Induced Reduction of Human Hippocampal Neurogenesis via Inhibiting the Production of Neurotoxic Metabolites of the Kynurenine Pathway.\",\"authors\":\"Gargi Mandal, Madeline Kirkpatrick, Silvia Alboni, Nicole Mariani, Carmine M Pariante, Alessandra Borsini\",\"doi\":\"10.1093/ijnp/pyae041\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Understanding the precise mechanisms of ketamine is crucial for replicating its rapid antidepressant effects without inducing psychomimetic changes. Here, we explore whether the antidepressant-like effects of ketamine enantiomers are underscored by protection against cytokine-induced reductions in hippocampal neurogenesis and activation of the neurotoxic kynurenine pathway in our well-established in vitro model of depression in a dish.</p><p><strong>Methods: </strong>We used the fetal hippocampal progenitor cell line (HPC0A07/03C) to investigate ketamine's impact on cytokine-induced reductions in neurogenesis in vitro. Cells were treated with interleukin- 1beta (IL-1b) (10 ng/mL) or IL-6 (50 pg/mL), alone or in combination with ketamine enantiomers arketamine (R-ketamine, 400 nM) or esketamine (S-ketamine, 400 nM) or antidepressants sertraline (1 mM) or venlafaxine (1 mM).</p><p><strong>Results: </strong>Resembling the effect of antidepressants, both ketamine enantiomers prevented IL-1b- and IL-6-induced reduction in neurogenesis and increase in apoptosis. This was mediated by inhibition of IL-1b-induced production of IL-2 and IL-13 by R-ketamine and of IL-1b-induced tumor necrosis factor-alpha by S-ketamine. Likewise, R-ketamine inhibited IL-6-induced production of IL-13, whereas S-ketamine inhibited IL-6-induced IL-1b and IL-8. Moreover, both R- and S-ketamine prevented IL-1b-induced increases in indoleamine 2,3-dioxygenase expression as well as kynurenine production, which in turn was shown to mediate the detrimental effects of IL-1b on neurogenesis and apoptosis. In contrast, neither R- nor S-ketamine prevented IL-6-induced kynurenine pathway activation.</p><p><strong>Conclusions: </strong>Results suggest that R- and S-ketamine have pro-neurogenic and anti-inflammatory properties; however, this is mediated by inhibition of the kynurenine pathway only in the context of IL-1b. Overall, this study enhances our understanding of the mechanisms underlying ketamine's antidepressant effects in the context of different inflammatory phenotypes, ultimately leading to the development of more effective, personalized therapeutic approaches for patients suffering from depression.</p>\",\"PeriodicalId\":14134,\"journal\":{\"name\":\"International Journal of Neuropsychopharmacology\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":4.5000,\"publicationDate\":\"2024-10-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11450635/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"International Journal of Neuropsychopharmacology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1093/ijnp/pyae041\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CLINICAL NEUROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"International Journal of Neuropsychopharmacology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1093/ijnp/pyae041","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
引用次数: 0

摘要

背景:了解氯胺酮的确切机制对于复制其快速抗抑郁效果而不诱发精神拟态变化至关重要。在此,我们将在已建立的体外抑郁模型中,探讨氯胺酮对映体的抗抑郁样作用是否通过防止细胞因子诱导的海马神经发生减少和神经毒性犬尿氨酸通路的激活而得到强调:我们使用胎儿海马祖细胞系(HPC0A07/03C)来研究氯胺酮对细胞因子诱导的体外神经发生减少的影响。用白细胞介素1β(IL-1b)(10纳克/毫升)或IL-6(50皮克/毫升)处理细胞,单独或与氯胺酮对映体、氯胺酮(R-氯胺酮,400毫微克)或氯胺酮(S-氯胺酮,400毫微克)或抗抑郁药舍曲林(1毫摩尔)或文拉法辛(1毫摩尔)联合使用:与抗抑郁药的作用相似,两种氯胺酮对映体都能防止IL-1b和IL-6诱导的神经发生减少和细胞凋亡增加。R-氯胺酮抑制了IL-1b诱导的IL-2和IL-13的产生,S-氯胺酮抑制了IL-1b诱导的肿瘤坏死因子-α(TNF-a)的产生。同样,R-氯胺酮能抑制 IL-6 诱导的 IL-13 的产生,而 S-氯胺酮则能抑制 IL-6 诱导的 IL-1b 和 IL-8。此外,R-和S-氯胺酮都能阻止IL-1b诱导的吲哚胺2,3-二氧化酶(IDO)表达的增加以及犬尿氨酸的产生,而犬尿氨酸反过来又能介导IL-1b对神经发生和细胞凋亡的不利影响。相比之下,R-和S-氯胺酮都不能阻止IL-6诱导的犬尿氨酸通路激活:结论:研究结果表明,R-和S-氯胺酮具有促进神经发生和抗炎的特性,但这仅在IL-1b的情况下通过抑制犬尿氨酸通路来实现。总之,这项研究加深了我们对氯胺酮在不同炎症表型下的抗抑郁作用机制的了解,最终将为抑郁症患者开发出更有效的个性化治疗方法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Ketamine Prevents Inflammation-Induced Reduction of Human Hippocampal Neurogenesis via Inhibiting the Production of Neurotoxic Metabolites of the Kynurenine Pathway.

Background: Understanding the precise mechanisms of ketamine is crucial for replicating its rapid antidepressant effects without inducing psychomimetic changes. Here, we explore whether the antidepressant-like effects of ketamine enantiomers are underscored by protection against cytokine-induced reductions in hippocampal neurogenesis and activation of the neurotoxic kynurenine pathway in our well-established in vitro model of depression in a dish.

Methods: We used the fetal hippocampal progenitor cell line (HPC0A07/03C) to investigate ketamine's impact on cytokine-induced reductions in neurogenesis in vitro. Cells were treated with interleukin- 1beta (IL-1b) (10 ng/mL) or IL-6 (50 pg/mL), alone or in combination with ketamine enantiomers arketamine (R-ketamine, 400 nM) or esketamine (S-ketamine, 400 nM) or antidepressants sertraline (1 mM) or venlafaxine (1 mM).

Results: Resembling the effect of antidepressants, both ketamine enantiomers prevented IL-1b- and IL-6-induced reduction in neurogenesis and increase in apoptosis. This was mediated by inhibition of IL-1b-induced production of IL-2 and IL-13 by R-ketamine and of IL-1b-induced tumor necrosis factor-alpha by S-ketamine. Likewise, R-ketamine inhibited IL-6-induced production of IL-13, whereas S-ketamine inhibited IL-6-induced IL-1b and IL-8. Moreover, both R- and S-ketamine prevented IL-1b-induced increases in indoleamine 2,3-dioxygenase expression as well as kynurenine production, which in turn was shown to mediate the detrimental effects of IL-1b on neurogenesis and apoptosis. In contrast, neither R- nor S-ketamine prevented IL-6-induced kynurenine pathway activation.

Conclusions: Results suggest that R- and S-ketamine have pro-neurogenic and anti-inflammatory properties; however, this is mediated by inhibition of the kynurenine pathway only in the context of IL-1b. Overall, this study enhances our understanding of the mechanisms underlying ketamine's antidepressant effects in the context of different inflammatory phenotypes, ultimately leading to the development of more effective, personalized therapeutic approaches for patients suffering from depression.

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
CiteScore
8.40
自引率
2.10%
发文量
230
审稿时长
4-8 weeks
期刊介绍: The central focus of the journal is on research that advances understanding of existing and new neuropsychopharmacological agents including their mode of action and clinical application or provides insights into the biological basis of psychiatric disorders and thereby advances their pharmacological treatment. Such research may derive from the full spectrum of biological and psychological fields of inquiry encompassing classical and novel techniques in neuropsychopharmacology as well as strategies such as neuroimaging, genetics, psychoneuroendocrinology and neuropsychology.
×
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