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Early TLR4 inhibition reduces hippocampal injury at puberty in a rat model of neonatal hypoxic-ischemic brain damage via regulation of neuroimmunity and synaptic plasticity

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收录情况： ◇ SCIE

作者：
Zhen Tang[a] * ; Shaowu Cheng[b] ; Yanyan Sun[a] ; Yunqiao Zhang[c] ; Xiying Xiang[d] ; Zhicui Ouyang[a] ; Xing Zhu[a] ; Bo Wang[d] ; Mingyan Hei[d,*1] ;
机构： [a]Department of Pediatrics, the Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, China [b]The Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China [c]Neuropsychological Center, Sixth Affiliated Hospital, Kunming Medical University, Yunnan, 653100, China [d]Neonatal Center, Beijing Children's Hospital, Capital Medical University, Beijing, 100045, China
出处：
DOI： 10.1016/j.expneurol.2019.113039
ISSN：

关键词： Brain injuries Hippocampus Hypoxia-ischemia(HI) Neuroprotection Rat model Toll-like receptor 4

摘要：
Neonatal hypoxic-ischemic brain damage (HIBD) survivors present with long-term neurological disorders affecting their quality of life, and there remains a lack of effective treatment. Toll-like receptor 4 (TLR4) is widely distributed in nerve cells and its inhibition has a neuroprotective effect against brain injury. The present study aimed to evaluate the long-term neuroprotective effects of early inhibition of TLR4 during HIBD. Seven-day-old rat pups were subjected to left carotid artery ligation followed by 2 h of hypoxia (8.0% O2). A single dose of TAK-242 (0.5 mg/kg), a TLR4-specific antagonist, was intraperitoneally injected half an hour prior to hypoxic ischemia (HI). The long-term effects of TAK-242 inhibition on the induced hippocampal injury were investigated by assessing behaviour at P28, and then using a variety of methods to exploring the mechanism, including immunofluorescence, Golgi silver staining, Western blotting and real-time polymerase chain reaction (RT-PCR). TAK-242 treatment significantly reduced the expression levels of TLR4 and its downstream signalling molecules in the ipsilateral lesion of the hippocampus 24 h after HIBD. The Morris water maze (MWM) test demonstrated that TAK-242 treatment reduced the loss of HI-induced learning and memory functions. Immunofluorescence experiments showed that TAK-242 administration attenuated HI-induced loss of neurons, prevented the activation of microglia and astrocytes, and increased the expression of the glutamate receptor subtype, N-methyl D-aspartate 2A (NR2A) in the ipsilateral hippocampus region. Golgi silver staining revealed that TAK-242 prevented an HI-induced decline in spine density in the ipsilateral hippocampus. Western blot and RT-PCR results indicated that the expression of NR2A protein and mRNA in the ipsilateral hippocampi of adolescent rats decreased after neonatal HIBD; early TAK-242 administration may reverse these effects. In conclusion, our findings indicate that early inhibition of TLR4 signalling may improve the long-term prognosis of neonatal HIBD. The mechanisms contributing to this improvement involve reductions in neuronal loss, a decrease in glial cell activation, and an improvement in synaptic plasticity. © 2019

基金：
This work is supported by the National Natural Science Foundation of China (No. 81671505 ).
语种：
外文
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WOS：
PubmedID：
中科院(CAS)分区：
出版当年[2018]版：
大类 | 2 区 医学
小类 | 2 区 神经科学
最新[2023]版：
大类 | 2 区 医学
小类 | 2 区 神经科学
JCR分区：
出版当年[2017]版：
Q1 NEUROSCIENCES
最新[2023]版：
Q1 NEUROSCIENCES

影响因子： 最新[2023版] 最新五年平均 出版当年[2017版] 出版当年五年平均 出版前一年[2016版] 出版后一年[2018版]

第一作者：
第一作者机构： [a]Department of Pediatrics, the Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, China
通讯作者：
通讯机构： [d]Neonatal Center, Beijing Children's Hospital, Capital Medical University, Beijing, 100045, China [*1]Neonatal Center, Beijing Children's Hospital, Capital Medical University, Nanlishi Road 56, Xicheng District, Beijing 100045, China.
推荐引用方式(GB/T 7714)：
Zhen Tang,Shaowu Cheng,Yanyan Sun,et al.Early TLR4 inhibition reduces hippocampal injury at puberty in a rat model of neonatal hypoxic-ischemic brain damage via regulation of neuroimmunity and synaptic plasticity[J].EXPERIMENTAL NEUROLOGY.2019,321:113039.doi:10.1016/j.expneurol.2019.113039.
APA：
Zhen Tang,Shaowu Cheng,Yanyan Sun,Yunqiao Zhang,Xiying Xiang...&Mingyan Hei.(2019).Early TLR4 inhibition reduces hippocampal injury at puberty in a rat model of neonatal hypoxic-ischemic brain damage via regulation of neuroimmunity and synaptic plasticity.EXPERIMENTAL NEUROLOGY,321,
MLA：
Zhen Tang,et al."Early TLR4 inhibition reduces hippocampal injury at puberty in a rat model of neonatal hypoxic-ischemic brain damage via regulation of neuroimmunity and synaptic plasticity".EXPERIMENTAL NEUROLOGY 321.(2019):113039

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