Temporal development of seizure threshold and spontaneous seizures after neonatal asphyxia and the effect of prophylactic treatment with midazolam in rats.

IF 4.6 2区 医学 Q1 NEUROSCIENCES Experimental Neurology Pub Date : 2024-11-04 DOI:10.1016/j.expneurol.2024.115042
Ricardo Schmidt, Björn Welzel, Annika Merten, Hannah Naundorf, Wolfgang Löscher
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Abstract

Birth asphyxia (BA) and subsequent hypoxic-ischemic encephalopathy (HIE) is one of the most serious birth complications affecting full-term infants and can result in severe disabilities including mental retardation, cerebral palsy, and epilepsy. Animal models of BA and HIE are important to characterize the functional and behavioral correlates of injury, explore cellular and molecular mechanisms, and assess the potential of novel therapeutic strategies. Here we used a non-invasive, physiologically validated rat model of BA and acute neonatal seizures that mimics many features of BA and HIE in human infants to study (i) the temporal development of epilepsy with spontaneous recurrent seizures (SRS) in the weeks and months after the initial brain injury, (ii) alterations in seizure threshold and hippocampal EEG that may precede the onset of SRS, and (iii) the effect of prophylactic treatment with midazolam. For this purpose, a total of 89 rat pups underwent asphyxia or sham asphyxia at postnatal day 11 and were examined over 8-10.5 months. In vehicle-treated animals, the incidence of electroclinical SRS progressively increased from 0 % at 2.5 months to 50 % at 6.5 months, 75 % at 8.5 months, and > 80 % at 10.5 months after asphyxia. Unexpectedly, post-asphyxial rats did not differ from sham-exposed rats in seizure threshold or interictal epileptiform discharges in the EEG. Treatment with midazolam (1 mg/kg i.p.) after asphyxia, which suppressed acute symptomatic neonatal seizures in about 60 % of the rat pups, significantly reduced the incidence of SRS regardless of its effect on neonatal seizures. This antiepileptogenic effect of midazolam adds to the recently reported prophylactic effects of this drug on BA-induced neuroinflammation, brain damage, behavioral alterations, and cognitive impairment in the rat asphyxia model of HIE.

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新生儿窒息后大鼠癫痫阈值和自发性癫痫发作的时间发展以及咪达唑仑预防性治疗的影响
出生窒息(BA)和随后的缺氧缺血性脑病(HIE)是影响足月婴儿的最严重出生并发症之一,可导致严重残疾,包括智力低下、脑瘫和癫痫。BA 和 HIE 的动物模型对于描述损伤的功能和行为相关性、探索细胞和分子机制以及评估新型治疗策略的潜力非常重要。在这里,我们使用了一种非侵入性、生理验证的大鼠 BA 和新生儿急性癫痫发作模型,该模型模拟了人类婴儿 BA 和 HIE 的许多特征,以研究:(i) 初始脑损伤后数周和数月内癫痫与自发性复发性癫痫发作(SRS)的时间发展;(ii) SRS 开始前癫痫发作阈值和海马脑电图的改变;(iii) 咪达唑仑预防性治疗的效果。为此,共对89只幼鼠在出生后第11天进行了窒息或假窒息,并在8-10.5个月内进行了检查。在接受过药物治疗的动物中,电临床 SRS 的发生率从窒息后 2.5 个月时的 0% 逐步上升到 6.5 个月时的 50%、8.5 个月时的 75%,以及 10.5 个月时的 80%。意想不到的是,窒息后的大鼠与假暴露的大鼠在癫痫发作阈值或脑电图中发作间期癫痫样放电方面没有区别。窒息后使用咪达唑仑(1 毫克/千克,静脉注射)治疗可抑制约 60% 的幼鼠的新生儿急性症状性癫痫发作,无论其对新生儿癫痫发作的影响如何,都能显著降低 SRS 的发生率。除了咪达唑仑的这种抗致痫作用外,最近还报道了这种药物对BA诱导的神经炎症、脑损伤、行为改变和HIE窒息模型大鼠认知障碍的预防作用。
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来源期刊
Experimental Neurology
Experimental Neurology 医学-神经科学
CiteScore
10.10
自引率
3.80%
发文量
258
审稿时长
42 days
期刊介绍: Experimental Neurology, a Journal of Neuroscience Research, publishes original research in neuroscience with a particular emphasis on novel findings in neural development, regeneration, plasticity and transplantation. The journal has focused on research concerning basic mechanisms underlying neurological disorders.
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