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 re...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-κB)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-κB p65,Beclin-1,microtubule-associated protein l light chain 3,tumor necrosis factor-α,and interleukin-1βin 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-κB 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.展开更多
目的探讨Toll样受体4(TLR4)抑制剂TAK-242对糖尿病周围神经痛(DPN)模型大鼠的治疗效果及其可能的作用机制。方法 SPF级雄性SD大鼠60只,随机均分为3组,分别为正常对照组(NC组)、DPN模型组(DPN组)、TAK-242治疗组(TAK组)。采用链脲佐菌素(...目的探讨Toll样受体4(TLR4)抑制剂TAK-242对糖尿病周围神经痛(DPN)模型大鼠的治疗效果及其可能的作用机制。方法 SPF级雄性SD大鼠60只,随机均分为3组,分别为正常对照组(NC组)、DPN模型组(DPN组)、TAK-242治疗组(TAK组)。采用链脲佐菌素(STZ)方法建立DPN大鼠模型,采用ELISA及RT-PCR方法检测DPN模型大鼠腰膨大脊髓组织的高迁移率族蛋白B1(HMGB1)-TLR4轴上下游基因(HMGB1、TLR4、MAPK、NF-κB、IL-6)的变化,分析上述细胞因子表达水平与大鼠疼痛行为的相关性。使用TLR4抑制剂TAK-242对DPN模型大鼠进行药物干预,观察其治疗效果及对HMGB1-TLR4轴基因表达的影响。结果 ELISA检测显示,DPN组大鼠的血清HMGB1、TLR4、IL-6表达水平均较NC组升高(P<0.05);TAK组大鼠的TLR4及IL-6表达水平较DPN组下降(P<0.05)。RT-PCR检测显示,DPN组大鼠的HMGB1、TLR4、NF-κB、IL-6 m RNA表达水平较NC组升高(P<0.05);TAK组大鼠的TLR4、NF-κB、IL-6 m RNA表达水平较DPN组下降(P<0.05)。结论 TLR4抑制剂TAK-242通过阻断HMGB1-TLR4轴对DPN模型动物起治疗作用。展开更多
基金financially supported by the National Natural Science Foundation of China,No.81771625(to XF)the Jiangsu Provincial Key Medical Discipline of China,No.ZDXKA2016013(to XF)the Pediatric Clinical Center of Suzhou City of China,No.Szzx201504(to XF)
文摘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-κB)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-κB p65,Beclin-1,microtubule-associated protein l light chain 3,tumor necrosis factor-α,and interleukin-1βin 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-κB 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.
文摘目的探讨Toll样受体4(TLR4)抑制剂TAK-242对糖尿病周围神经痛(DPN)模型大鼠的治疗效果及其可能的作用机制。方法 SPF级雄性SD大鼠60只,随机均分为3组,分别为正常对照组(NC组)、DPN模型组(DPN组)、TAK-242治疗组(TAK组)。采用链脲佐菌素(STZ)方法建立DPN大鼠模型,采用ELISA及RT-PCR方法检测DPN模型大鼠腰膨大脊髓组织的高迁移率族蛋白B1(HMGB1)-TLR4轴上下游基因(HMGB1、TLR4、MAPK、NF-κB、IL-6)的变化,分析上述细胞因子表达水平与大鼠疼痛行为的相关性。使用TLR4抑制剂TAK-242对DPN模型大鼠进行药物干预,观察其治疗效果及对HMGB1-TLR4轴基因表达的影响。结果 ELISA检测显示,DPN组大鼠的血清HMGB1、TLR4、IL-6表达水平均较NC组升高(P<0.05);TAK组大鼠的TLR4及IL-6表达水平较DPN组下降(P<0.05)。RT-PCR检测显示,DPN组大鼠的HMGB1、TLR4、NF-κB、IL-6 m RNA表达水平较NC组升高(P<0.05);TAK组大鼠的TLR4、NF-κB、IL-6 m RNA表达水平较DPN组下降(P<0.05)。结论 TLR4抑制剂TAK-242通过阻断HMGB1-TLR4轴对DPN模型动物起治疗作用。
