Long-term effect of indomethacin on a rat model of neonatal hypoxia ischemic encephalopathy through behavioral tests

IF 1.7 4区医学 Q3 DEVELOPMENTAL BIOLOGY

International Journal of Developmental Neuroscience Pub Date : 2023-10-16 DOI:10.1002/jdn.10305

Tugay Tepe, Mehmet Satar, Mustafa Ozdemir, Hacer Yapicioglu Yildizdas, Ferda Ozlü, Seyda Erdogan, Tugba Toyran, Kübra Akillioglu, Seda Köse, Cagri Avci

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Abstract

Background

Many medical experts prescribe indomethacin because of its anti-inflammatory, analgesic, tocolytic, and duct closure effects. This article presents an evaluation of the enduring impact of indomethacin on neonatal rats with hypoxic–ischemic (HI) insults, employing behavioral tests as a method of assessment.

Methods

The experiment was conducted on male Wistar-Albino rats weighing 10 to 15 g, aged between seven and 10 days. The rats were divided into three groups using a random allocation method as follows: hypoxic ischemic encephalopathy (HIE) group, HIE treated with indomethacin group (INDO), and Sham group. A left common carotid artery ligation and hypoxia model was applied in both the HIE and INDO groups. The INDO group was treated with 4 mg/kg intraperitoneal indomethacin every 24 h for 3 days, while the Sham and HIE groups were given dimethylsulfoxide (DMSO). After 72 h, five rats from each group were sacrificed and brain tissue samples were stained with 2,3,5-Triphenyltetrazolium chloride (TCC) for infarct-volume measurement. Seven rats from each group were taken to the behavioral laboratory in the sixth postnatal week (PND42) and six from each group were sacrificed for the Evans blue (EB) experiment for blood–brain barrier (BBB) integrity evaluation. The open field (OF) test and Morris water maze (MWM) tests were performed. After behavioral tests, brain tissue were obtained and stained with TCC to assess the infarct volume.

Results

The significant increase in the time spent in the central area and the frequency of crossing to the center in the INDO group compared with the HIE group indicated that indomethacin decreased anxiety-like behavior (p < 0.001, p < 0.05). However, the MWM test revealed that indomethacin did not positively affect learning and memory performance (p > 0.05). Additionally, indomethacin significantly reduced infarct volume and neuropathological grading in adolescence (p < 0.05), although not statistically significant in the early period. Moreover, the EB experiment demonstrated that indomethacin effectively increased BBB integrity (p < 0.05).

Conclusions

In this study, we have shown for the first time that indomethacin treatment can reduce levels of anxiety-like behavior and enhance levels of exploratory behavior in a neonatal rat model with HIE. It is necessary to determine whether nonsteroidal anti-inflammatory agents, such as indomethacin, should be used for adjuvant therapy in newborns with HIE.

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吲哚美辛对新生儿缺氧缺血性脑病大鼠模型的长期作用。

背景：许多医学专家开吲哚美辛处方，因为它具有抗炎、镇痛、分娩和导管闭合的作用。本文采用行为测试作为评估方法，评估吲哚美辛对新生大鼠缺氧缺血性损伤的持久影响。方法：采用10～15只雄性Wistar Albino大鼠进行实验 g、年龄在7岁到10岁之间天。采用随机分配法将大鼠分为三组：缺氧缺血性脑病（HIE）组、吲哚美辛治疗组（INDO）和Sham组。HIE组和INDO组均采用左颈总动脉结扎缺氧模型。INDO组每24小时腹腔注射消炎痛4mg/kg h持续3天，同时Sham和HIE组给予二甲基亚砜（DMSO）。72之后 h、每组处死5只大鼠，并用2，3，5-三苯基氯化四氮唑（TCC）对脑组织样品进行染色以测量梗死体积。每组7只大鼠在出生后第6周（PND42）被带到行为实验室，每组6只大鼠被处死用于血脑屏障（BBB）完整性评估的伊文思蓝（EB）实验。进行了开放场地（OF）试验和Morris水迷宫（MWM）试验。在行为测试后，获得脑组织并用TCC染色以评估梗死体积。结果：与HIE组相比，INDO组在中心区停留的时间和穿越中心的频率显著增加，表明吲哚美辛降低了焦虑样行为（p 此外，消炎痛显著降低了青春期的梗死体积和神经病理学分级（p 结论：在这项研究中，我们首次表明吲哚美辛治疗可以降低HIE新生大鼠模型的焦虑样行为水平，增强探索行为水平。有必要确定非甾体抗炎药，如吲哚美辛，是否应用于新生儿缺氧缺血性脑病的辅助治疗。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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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.