Seizure Activity and Hypoxia Differentially Regulate Endogenous Neurotrophic Activin A and Neuroglobin Expression in the Immature Mouse Brain

IF 1.6 4区医学 Q3 DEVELOPMENTAL BIOLOGY

International Journal of Developmental Neuroscience Pub Date : 2025-08-24 DOI:10.1002/jdn.70048

Clara Becker, Susan Jung, Regina Trollmann

{"title":"Seizure Activity and Hypoxia Differentially Regulate Endogenous Neurotrophic Activin A and Neuroglobin Expression in the Immature Mouse Brain","authors":"Clara Becker, Susan Jung, Regina Trollmann","doi":"10.1002/jdn.70048","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> Objectives</h3>\n \n <p>Activin A, a multifunctional growth and differentiation factor and neuroglobin (Ngb), an oxygen-dependent heme protein, have been proposed as novel oxygen-dependent neuroprotectants. Both these endogenous cytoprotective factors are partially controlled by hypoxia-inducible transcription factors (HIFs) and are strongly upregulated in various forms of acute brain injury, including traumatic, hypoxic and ischaemic lesions. Considering their potential role as biomarkers of neonatal brain injury, we investigated the regulatory effects of seizure-induced excitotoxicity and acute hypoxia on the activin A and Ngb systems in the developing mouse brain.</p>\n </section>\n \n <section>\n \n <h3> Methods</h3>\n \n <p>We analysed the effects of acute pilocarpine-induced seizures in the brains of neonatal C57BL/6 WT mice (P10) on the age –and region-specific mRNA (real-rime-PCR) and protein expression (IHC) of Ngb and activin A (and activin A's receptors—activin A receptor Type IB, ActRIB; activin A receptor type IIA, ActRIIA; and activin A receptor Type IIB, ActRIIB) after 0–72 h of regeneration. Using the established mouse model of acute neonatal hypoxic brain injury, the same analyses were performed on the brains of another group of mouse pups (P7) subjected to acute hypoxia (FiO<sub>2</sub> 8% for 6 h) and the prolyl hydroxylase inhibitor (PHI) FG-4497, which stabilizes cerebral HIF accumulation.</p>\n </section>\n \n <section>\n \n <h3> <b>Results</b> (Mean ± SEM)</h3>\n \n <p>Seizures induced significant changes in the regulation of both Ngb and activin A. Cerebral Ngb mRNA expression increased over time in response to acute seizure activity (Ngb mRNA ratio: 6 h: 4.75 ± 0.79, 72 h: 10.53 ± 1.71; vs. controls 6 h: 6.23 ± 1.15, 72 h: 8.12 ± 0.56, <i>p</i> < 0.01), exceeding the expected age-related increase. Activin A mRNA expression significantly decreased within 6 h of regeneration in response to seizures compared to controls (<i>p</i> < 0.01), while mRNA levels of specific receptors were unaffected. In response to acute hypoxia and FG-4497, a marked upregulation of cerebral Ngb mRNA concentrations was observed compared to controls (Ngb mRNA ratio: 1.99 ± 0.73 vs. 0.82 ± 0.09, <i>p</i> < 0.05). Contrary to the findings in the seizure-exposed brains, a significant upregulation of activin A, ActRIB and ActRIIB was detected in response to hypoxia and high-dose FG-4497 compared to controls.</p>\n </section>\n \n <section>\n \n <h3> Conclusions</h3>\n \n <p>The present results demonstrate the differential regulation of Ngb and activin A in relation to time and type of injury and indicate their potential roles as biomarkers of excitotoxic and hypoxic injury in the developing brain.</p>\n </section>\n </div>","PeriodicalId":13914,"journal":{"name":"International Journal of Developmental Neuroscience","volume":"85 5","pages":""},"PeriodicalIF":1.6000,"publicationDate":"2025-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"International Journal of Developmental Neuroscience","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/jdn.70048","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"DEVELOPMENTAL BIOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Objectives

Activin A, a multifunctional growth and differentiation factor and neuroglobin (Ngb), an oxygen-dependent heme protein, have been proposed as novel oxygen-dependent neuroprotectants. Both these endogenous cytoprotective factors are partially controlled by hypoxia-inducible transcription factors (HIFs) and are strongly upregulated in various forms of acute brain injury, including traumatic, hypoxic and ischaemic lesions. Considering their potential role as biomarkers of neonatal brain injury, we investigated the regulatory effects of seizure-induced excitotoxicity and acute hypoxia on the activin A and Ngb systems in the developing mouse brain.

Methods

We analysed the effects of acute pilocarpine-induced seizures in the brains of neonatal C57BL/6 WT mice (P10) on the age –and region-specific mRNA (real-rime-PCR) and protein expression (IHC) of Ngb and activin A (and activin A's receptors—activin A receptor Type IB, ActRIB; activin A receptor type IIA, ActRIIA; and activin A receptor Type IIB, ActRIIB) after 0–72 h of regeneration. Using the established mouse model of acute neonatal hypoxic brain injury, the same analyses were performed on the brains of another group of mouse pups (P7) subjected to acute hypoxia (FiO₂ 8% for 6 h) and the prolyl hydroxylase inhibitor (PHI) FG-4497, which stabilizes cerebral HIF accumulation.

Results (Mean ± SEM)

Seizures induced significant changes in the regulation of both Ngb and activin A. Cerebral Ngb mRNA expression increased over time in response to acute seizure activity (Ngb mRNA ratio: 6 h: 4.75 ± 0.79, 72 h: 10.53 ± 1.71; vs. controls 6 h: 6.23 ± 1.15, 72 h: 8.12 ± 0.56, p < 0.01), exceeding the expected age-related increase. Activin A mRNA expression significantly decreased within 6 h of regeneration in response to seizures compared to controls (p < 0.01), while mRNA levels of specific receptors were unaffected. In response to acute hypoxia and FG-4497, a marked upregulation of cerebral Ngb mRNA concentrations was observed compared to controls (Ngb mRNA ratio: 1.99 ± 0.73 vs. 0.82 ± 0.09, p < 0.05). Contrary to the findings in the seizure-exposed brains, a significant upregulation of activin A, ActRIB and ActRIIB was detected in response to hypoxia and high-dose FG-4497 compared to controls.

Conclusions

The present results demonstrate the differential regulation of Ngb and activin A in relation to time and type of injury and indicate their potential roles as biomarkers of excitotoxic and hypoxic injury in the developing brain.

Abstract Image

查看原文本刊更多论文

癫痫活动和缺氧对未成熟小鼠脑内源性神经营养激活素A和神经球蛋白表达的差异调节

激活素A是一种多功能生长和分化因子，神经球蛋白（Ngb）是一种氧依赖性血红素蛋白，被认为是新型的氧依赖性神经保护剂。这两种内源性细胞保护因子都部分受缺氧诱导的转录因子（hif）控制，并在各种形式的急性脑损伤中强烈上调，包括创伤性、缺氧性和缺血性损伤。考虑到它们作为新生儿脑损伤生物标志物的潜在作用，我们研究了癫痫诱发的兴奋性毒性和急性缺氧对发育中的小鼠大脑中激活素A和Ngb系统的调节作用。方法分析新生儿C57BL/6 WT小鼠（P10）急性匹罗卡平诱发癫痫对新生0-72 h后Ngb和激活素A（以及激活素A受体-激活素A受体IB型、ActRIB型、激活素A受体IIA型、ActRIIA型和激活素A受体IIB型、ActRIIB型）的年龄和区域特异性mRNA （real- real- real- pcr）和蛋白表达（IHC）的影响。利用建立的小鼠急性新生儿缺氧脑损伤模型，对另一组小鼠幼崽（P7）的大脑进行了相同的分析，这些小鼠幼崽在急性缺氧（FiO2 8%，持续6小时）和稳定大脑HIF积累的脯氨酰羟化酶抑制剂（PHI） FG-4497下进行了大脑分析。结果（Mean±SEM）癫痫发作引起Ngb和激活素a的调节发生显著变化，随着时间的推移，大脑Ngb mRNA表达随急性发作活动而增加（Ngb mRNA比值：6小时：4.75±0.79,72小时：10.53±1.71；与对照组相比，6小时：6.23±1.15,72小时：8.12±0.56,p < 0.01），超过预期的年龄相关增加。与对照组相比，激活素A mRNA的表达在癫痫发作后6小时内显著降低（p < 0.01），而特异性受体的mRNA水平未受影响。在急性缺氧和FG-4497的作用下，与对照组相比，脑Ngb mRNA浓度显著上调（Ngb mRNA比值：1.99±0.73比0.82±0.09,p < 0.05）。与癫痫发作暴露的大脑结果相反，与对照组相比，在缺氧和高剂量FG-4497的反应中检测到激活素a、ActRIB和ActRIIB的显著上调。结论Ngb和激活素A在损伤时间和损伤类型上存在差异，并可能作为发育中脑兴奋性毒性和缺氧损伤的生物标志物。

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

International Journal of Developmental Neuroscience 医学-发育生物学

CiteScore

3.30

自引率

5.60%

发文量

审稿时长

6-12 weeks

期刊介绍： International Journal of Developmental Neuroscience publishes original research articles and critical review papers on all fundamental and clinical aspects of nervous system development, renewal and regeneration, as well as on the effects of genetic and environmental perturbations of brain development and homeostasis leading to neurodevelopmental disorders and neurological conditions. Studies describing the involvement of stem cells in nervous system maintenance and disease (including brain tumours), stem cell-based approaches for the investigation of neurodegenerative diseases, roles of neuroinflammation in development and disease, and neuroevolution are also encouraged. Investigations using molecular, cellular, physiological, genetic and epigenetic approaches in model systems ranging from simple invertebrates to human iPSC-based 2D and 3D models are encouraged, as are studies using experimental models that provide behavioural or evolutionary insights. The journal also publishes Special Issues dealing with topics at the cutting edge of research edited by Guest Editors appointed by the Editor in Chief. A major aim of the journal is to facilitate the transfer of fundamental studies of nervous system development, maintenance, and disease to clinical applications. The journal thus intends to disseminate valuable information for both biologists and physicians. International Journal of Developmental Neuroscience is owned and supported by The International Society for Developmental Neuroscience (ISDN), an organization of scientists interested in advancing developmental neuroscience research in the broadest sense.