Resatorvid protects against hypoxic-ischemic brain damage in neonatal rats
Resatorvid protects against hypoxic-ischemic brain damage in neonatal rats
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DOI：
10.4103/1673-5374.272615
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发表时间：
2020-07-01
影响因子：
6.1
通讯作者：
Feng, Xing
中科院分区：
文献类型：
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作者：
Jiang, Li-Jun;Xu, Zhen-Xing;Feng, Xing
神经元自噬和炎症反应过度激活引起的继发性脑损伤在缺氧缺血性脑损伤（HIBD）中起重要作用。尽管以往的研究表明Toll样受体4（TLR 4）和核因子κ-B（NF-κ B B）参与了脑损伤引起的神经炎症反应，但TLR 4介导的自噬信号通路在新生儿HIBD中的作用和机制尚不清楚。我们推测该通路可能通过调节HIBD新生大鼠的神经元自噬和神经炎症来调节脑损伤。因此，我们使用Rice-Vannucci方法建立了新生HIBD大鼠模型，并在缺氧缺血后30分钟注射0.75、1.5或3 mg/kg的TLR 4抑制剂resatorvid（TAK-242）。我们的结果表明，HIBD后新生大鼠接受TAK-242给药可显著减少梗死体积和脑水肿程度，减轻神经元损伤和神经行为损害，并降低海马中TLR 4、磷酸化NF-κ B p65、Beclin-1、微管相关蛋白l轻链3、肿瘤坏死因子-α和白细胞介素-1 β的表达水平。因此，TAK-242似乎在HIBD后通过抑制TLR 4/NF-κ B信号通路抑制自噬激活和炎性细胞因子释放而发挥神经保护作用。本研究于2018年1月14日获得扬州大学附属医院实验动物伦理委员会批准（批件号：20180114-15）。
Secondary brain damage caused by hyperactivation of autophagy and inflammatory responses in neurons plays an important role in hypoxic-ischemic brain damage (HIBD). Although previous studies have implicated Toll-like receptor 4 (TLR4) and nuclear factor kappa-B (NF-kappa B) in the neuroinflammatory response elicited by brain injury, the role and mechanisms of the TLR4-mediated autophagy signaling pathway in neonatal HIBD are still unclear. We hypothesized that this pathway can regulate brain damage by modulating neuron autophagy and neuroinflammation in neonatal rats with HIBD. Hence, we established a neonatal HIBD rat model using the Rice-Vannucci method, and injected 0.75, 1.5, or 3 mg/kg of the TLR4 inhibitor resatorvid (TAK-242) 30 minutes after hypoxic ischemia. Our results indicate that administering TAK-242 to neonatal rats after HIBD could significantly reduce the infarct volume and the extent of cerebral edema, alleviate neuronal damage and neurobehavioral impairment, and decrease the expression levels of TLR4, phospho-NF-kappa B p65, Beclin-1, microtubule-associated protein l light chain 3, tumor necrosis factor-alpha, and interleukin-1 beta in the hippocampus. Thus, TAK-242 appears to exert a neuroprotective effect after HIBD by inhibiting activation of autophagy and the release of inflammatory cytokines via inhibition of the TLR4/NF-kappa B signaling pathway. This study was approved by the Laboratory Animal Ethics Committee of Affiliated Hospital of Yangzhou University, China (approval No. 20180114-15) on January 14, 2018.