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尿苷治疗对新生儿缺氧缺血性脑病大鼠模型的长期认知影响。

Long-term cognitive effects of uridine treatment in a neonatal rat model of hypoxic-ischemic encephalopathy.

作者信息

Goren Bulent, Cakir Aysen, Ocalan Busra, Serter Kocoglu Sema, Alkan Tulin, Cansev Mehmet, Kahveci Nevzat

机构信息

Uludag University School of Medicine, Department of Physiology, Bursa, Turkey.

Uludag University School of Medicine, Department of Physiology, Bursa, Turkey.

出版信息

Brain Res. 2017 Mar 15;1659:81-87. doi: 10.1016/j.brainres.2017.01.026. Epub 2017 Jan 23.

DOI:10.1016/j.brainres.2017.01.026
PMID:28126402
Abstract

Hypoxic-ischemic encephalopathy (HIE), is the most common brain disorder in neonates during the perinatal period, which, to date, can only be managed to some extent by hypothermia. Uridine is the principal circulating pyrimidine in humans which is utilized as a precursor for membrane phospholipid biosynthesis. Uridine has recently been shown to provide clinical benefit in treatment of Alzheimer's disease due to its involvement in increasing number of brain synapses along with other phospholipid precursors. We previously showed that uridine treatment ameliorated brain damage by reducing apoptosis in a rat model of neonatal HIE. The aim of the present study was to investigate the effects of uridine administration on cognitive functions during periadolescent period in rats subjected to hypoxic-ischemic (HI) brain damage in neonatal period. Male newborn rats were subjected to HI insult on postnatal day 7 (P7) and were injected intraperitoneally with either saline or uridine (500mg/kg) for three consecutive days. Part of pups in each group were sacrificed on P10 to collect brain samples for active Caspase-3 analyses and the remaining pups were raised through P40 to evaluate early reflexes, sensorimotor coordination and learning and memory functions by Negative Geotaxis (NG), Beam Walking (BW) and Morris Water Maze (MWM) tasks, respectively. Confirming our previous findings, we showed that uridine administration reduced apoptotic cell damage on P10. No significant difference was observed between uridine and saline groups in early reflexes or sensorimotor coordination. On the other hand, rats receiving uridine displayed improved learning and memory in MWM during periadolescent period. We conclude that uridine treatment improves learning and memory in the long term by, probably, reducing apoptotic cell death in early newborn period. This is the first study to show beneficial cognitive effects of uridine in rats with brain damage.

摘要

缺氧缺血性脑病(HIE)是围产期新生儿最常见的脑部疾病,迄今为止,只能通过低温治疗在一定程度上进行处理。尿苷是人体中主要的循环嘧啶,用作膜磷脂生物合成的前体。最近研究表明,尿苷由于参与增加脑突触数量以及其他磷脂前体,在治疗阿尔茨海默病方面具有临床益处。我们之前的研究表明,在新生大鼠缺氧缺血性脑病模型中,尿苷治疗可通过减少细胞凋亡来减轻脑损伤。本研究的目的是探讨在新生期遭受缺氧缺血(HI)性脑损伤的大鼠围青春期给予尿苷对认知功能的影响。雄性新生大鼠在出生后第7天(P7)遭受HI损伤,并连续三天腹腔注射生理盐水或尿苷(500mg/kg)。每组部分幼崽在P10处死,收集脑样本进行活性Caspase-3分析,其余幼崽饲养至P40,分别通过负趋地性(NG)、横梁行走(BW)和莫里斯水迷宫(MWM)任务评估早期反射、感觉运动协调以及学习和记忆功能。与我们之前的研究结果一致,我们发现给予尿苷可减少P10时的凋亡细胞损伤。在早期反射或感觉运动协调方面,尿苷组和生理盐水组之间未观察到显著差异。另一方面,接受尿苷治疗的大鼠在围青春期的MWM中表现出学习和记忆能力的改善。我们得出结论,尿苷治疗可能通过减少新生早期的凋亡细胞死亡,长期改善学习和记忆。这是第一项显示尿苷对脑损伤大鼠具有有益认知作用的研究。

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