Zhang Rui, Yang Yongkai, Lin Yijun
Department of Digestive and Nutrition, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, Fujian, China.
Fujian Children's Hospital (Fujian Branch of Shanghai children's Medical Center), Fuzhou, Fujian, China.
Int J Dev Neurosci. 2025 Feb;85(1):e10413. doi: 10.1002/jdn.10413.
Neonatal hypoxic-ischemic encephalopathy (HIE) is a severe neurological injury during infancy, often resulting in long-term cognitive deficits. This study aimed to investigate the neuroprotective effects of Edaravone (EDA), a free radical scavenger, and elucidate the potential role of brain-derived neurotrophic factor (BDNF) in mediating these effects in neonatal HIE rats. Using the Rice-Vannucci model, HIE was induced in neonatal rats, followed by immediate administration of EDA after the hypoxic-ischemic insult. To examine the role of BDNF, a separate group of rats received intrahippocampal injections of a lentiviral vector for BDNF knockdown prior to the induction of HIE and subsequent EDA treatment. Neuronal survival and apoptosis in the hippocampal region were assessed by immunofluorescence and TUNEL staining, respectively. BDNF expression levels in the hippocampus were analysed using enzyme-linked immunosorbent assay (ELISA). Cognitive function was evaluated using the Morris water maze (MWM) and Y maze tests. Results demonstrated that EDA significantly reduced hippocampal neuronal apoptosis and death, increased neuronal survival, and enhanced BDNF expression compared to the control group. However, the therapeutic effects of EDA were mitigated in the BDNF knockdown group, indicating a crucial role of BDNF in mediating the neuroprotective effects of EDA. Behavioural testing confirmed that EDA treatment significantly improved spatial learning and memory abilities in HIE rats, but these improvements were not observed in rats with BDNF knockdown. In conclusion, our study suggests that EDA treatment mitigates hippocampal neuronal death and improves cognitive dysfunction in HIE rats primarily by upregulating BDNF expression. These findings provide experimental support for the potential application of EDA in the treatment of HIE and highlight the essential role of BDNF in neuroprotection and cognitive recovery post-HIE.
新生儿缺氧缺血性脑病（HIE）是婴儿期一种严重的神经损伤，常导致长期认知缺陷。本研究旨在探讨自由基清除剂依达拉奉（EDA）的神经保护作用，并阐明脑源性神经营养因子（BDNF）在介导EDA对新生HIE大鼠这些作用中的潜在作用。采用Rice-Vannucci模型在新生大鼠中诱导HIE，缺氧缺血损伤后立即给予EDA。为了研究BDNF的作用，另一组大鼠在诱导HIE及随后的EDA治疗前，接受海马内注射用于敲低BDNF的慢病毒载体。分别通过免疫荧光和TUNEL染色评估海马区神经元的存活和凋亡。采用酶联免疫吸附测定（ELISA）分析海马中BDNF的表达水平。使用Morris水迷宫（MWM）和Y迷宫试验评估认知功能。结果表明，与对照组相比，EDA显著减少海马神经元凋亡和死亡，增加神经元存活，并增强BDNF表达。然而，在BDNF敲低组中，EDA的治疗效果减弱，表明BDNF在介导EDA的神经保护作用中起关键作用。行为测试证实，EDA治疗显著改善了HIE大鼠的空间学习和记忆能力，但在BDNF敲低的大鼠中未观察到这些改善。总之，我们的研究表明，EDA治疗主要通过上调BDNF表达减轻HIE大鼠海马神经元死亡并改善认知功能障碍。这些发现为EDA在HIE治疗中的潜在应用提供了实验支持，并突出了BDNF在HIE后神经保护和认知恢复中的重要作用。
