IF 6.4 1区 生物学 Q1 BIOLOGY
eLife Pub Date : 2025-03-28 DOI:10.7554/eLife.100527
Lotfi Ferhat, Rabia Soussi, Maxime Masse, Grigorios Kyriatzis, Stéphane Girard, Fanny Gassiot, Nicolas Gaudin, Mathieu Laurencin, Anne Bernard, Angélique Bôle, Géraldine Ferracci, Maria Smirnova, François Roman, Vincent Dive, Salvatore Cisternino, Jamal Temsamani, Marion David, Pascaline Lécorché, Guillaume Jacquot, Michel Khrestchatisky
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引用次数: 0

摘要

临床前和临床研究表明,轻度至中度低体温对心脏骤停、缺血性中风、围产期缺氧/缺血、创伤性脑损伤和癫痫发作具有神经保护作用。诱导低体温主要涉及物理降温疗法,这种疗法会诱发多种临床并发症,而一些分子已被证明在药理诱导低体温(PIH)中有效。神经紧张素(NT)是一种 13 个氨基酸的神经肽,可调节体温,它与各种受体相互作用,介导其外周和中枢效应。脑内给药时,NT 会诱发 PIH。然而,由于 NT 降解快且不易通过血脑屏障(BBB),如果在外周给药,则无法观察到这些效应。我们将NT与结合低密度脂蛋白受体(LDLR)的多肽共轭,生成 "载体化 "的NT,增强了BBB的通透性。我们评估了外周给药后它们对癫痫的影响。其中一种共轭物 VH-N412 显示出更高的稳定性、与 LDLR 和 NTSR-1 的结合潜力、啮齿动物/人类交叉反应性以及更好的脑分布。在凯恩酸盐(KA)诱导的状态性癫痫(SE)小鼠模型中,VH-N412 可引起与抗惊厥效应相关的快速低体温、强效神经保护和减少海马炎症。VH-N412 还能减少齿状回苔藓纤维的萌发,并保护小鼠的学习和记忆能力。在培养的海马神经元中,VH-N412显示出与温度无关的神经保护特性。据我们所知,这是第一份用 PIH 成功治疗 SE 的报告。总之,我们的研究结果表明,载体化 NT 可通过低体温和/或内在神经保护特性引起不同的神经保护机制。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
A peptide-neurotensin conjugate that crosses the blood-brain barrier induces pharmacological hypothermia associated with anticonvulsant, neuroprotective, and anti-inflammatory properties following status epilepticus in mice.

Preclinical and clinical studies show that mild to moderate hypothermia is neuroprotective in sudden cardiac arrest, ischemic stroke, perinatal hypoxia/ischemia, traumatic brain injury, and seizures. Induction of hypothermia largely involves physical cooling therapies, which induce several clinical complications, while some molecules have shown to be efficient in pharmacologically induced hypothermia (PIH). Neurotensin (NT), a 13 amino acid neuropeptide that regulates body temperature, interacts with various receptors to mediate its peripheral and central effects. NT induces PIH when administered intracerebrally. However, these effects are not observed if NT is administered peripherally, due to its rapid degradation and poor passage of the blood-brain barrier (BBB). We conjugated NT to peptides that bind the low-density lipoprotein receptor (LDLR) to generate 'vectorized' forms of NT with enhanced BBB permeability. We evaluated their effects in epileptic conditions following peripheral administration. One of these conjugates, VH-N412, displayed improved stability, binding potential to both the LDLR and NTSR-1, rodent/human cross-reactivity and improved brain distribution. In a mouse model of kainate (KA)-induced status epilepticus (SE), VH-N412 elicited rapid hypothermia associated with anticonvulsant effects, potent neuroprotection, and reduced hippocampal inflammation. VH-N412 also reduced sprouting of the dentate gyrus mossy fibers and preserved learning and memory skills in the treated mice. In cultured hippocampal neurons, VH-N412 displayed temperature-independent neuroprotective properties. To the best of our knowledge, this is the first report describing the successful treatment of SE with PIH. In all, our results show that vectorized NT may elicit different neuroprotection mechanisms mediated by hypothermia and/or by intrinsic neuroprotective properties.

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来源期刊
eLife
eLife BIOLOGY-
CiteScore
12.90
自引率
3.90%
发文量
3122
审稿时长
17 weeks
期刊介绍: eLife is a distinguished, not-for-profit, peer-reviewed open access scientific journal that specializes in the fields of biomedical and life sciences. eLife is known for its selective publication process, which includes a variety of article types such as: Research Articles: Detailed reports of original research findings. Short Reports: Concise presentations of significant findings that do not warrant a full-length research article. Tools and Resources: Descriptions of new tools, technologies, or resources that facilitate scientific research. Research Advances: Brief reports on significant scientific advancements that have immediate implications for the field. Scientific Correspondence: Short communications that comment on or provide additional information related to published articles. Review Articles: Comprehensive overviews of a specific topic or field within the life sciences.
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