Blockade of Nogo-A/Nogo-66 receptor 1 (NgR1) Inhibits Autophagic Activation and Prevents Secondary Neuronal Damage in the Thalamus after Focal Cerebral Infarction in Hypertensive Rats
Blockade of Nogo-A/Nogo-66 receptor 1 (NgR1) Inhibits Autophagic Activation and Prevents Secondary Neuronal Damage in the Thalamus after Focal Cerebral Infarction in Hypertensive Rats
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DOI：
10.1016/j.neuroscience.2020.02.010
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发表时间：
2020-02
期刊：
影响因子：
3.3
通讯作者：
Wei Xu;Peiying Xiao;Shuhan Fan;Yicong Chen;Weixian Huang;Xinran Chen;Gang Liu;C. Dang;J. Zeng;S. Xing
中科院分区：
文献类型：
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作者：
Wei Xu;Peiying Xiao;Shuhan Fan;Yicong Chen;Weixian Huang;Xinran Chen;Gang Liu;C. Dang;J. Zeng;S. Xing
局灶性脑梗死导致自噬激活，导致同侧丘脑继发性神经元损伤。虽然Nogo-A失活增强神经元可塑性，但其在缺血性卒中后丘脑自噬激活中的作用仍不清楚。本研究旨在探讨Nogo-A/Nogo-66受体1（NgR 1）在脑梗死后同侧丘脑自噬激活中的作用。采用大脑中动脉闭塞（MCAO）方法建立局灶性新皮质梗死。通过尼氏染色和免疫组化评估同侧丘脑的继发性损害。免疫荧光和免疫印迹法检测Nogo-A、NgR 1、Rho-A和Rho相关卷曲螺旋蛋白激酶1（ROCK 1）的表达以及自噬通量。Nogo-A-NgR 1信号转导在自噬激活中的作用通过在MCAO后24 h脑室内递送NgR 1拮抗剂肽NEP 1 -40来确定。结果显示，Nogo-A和NgR 1的过度表达与MCAO后7天和14天同侧丘脑中Beclin 1、LC 3-II和死骨小体1（SQSTM 1）/p62水平的显著增加在时间上一致。相比之下，NEP 1 -40处理显著降低Rho-A和ROCK 1的表达，伴随着LC 3-II转化以及Beclin 1和SQSTM 1/p62水平的显著降低。此外，NEP 1 -40治疗显著减少了同侧丘脑中的神经元损失和神经胶质增生，并在MCAO后观察到的时间点加速了体感恢复。这些结果表明，阻断Nogo-A-NgR 1信号传导抑制自噬激活，减弱同侧丘脑中的继发性神经元损伤，并促进局灶性脑皮质梗死后的功能恢复。
Focal cerebral infarction leads to autophagic activation, which contributes to secondary neuronal damage in the ipsilateral thalamus. Although Nogo-A deactivation enhances neuronal plasticity, its role in autophagic activation in the thalamus after ischemic stroke remains unclear. This study aimed to investigate the potential roles of Nogo-A/Nogo-66 receptor 1 (NgR1) in autophagic activation in the ipsilateral thalamus after cerebral infarction. Focal neocortical infarction was established using the middle cerebral artery occlusion (MCAO) method. Secondary damage in the ipsilateral thalamus was assessed by Nissl staining and immunostaining. The expression of Nogo-A, NgR1, Rho-A and Rho-associated coiled-coil containing protein kinase 1 (ROCK1) as well as autophagic flux were evaluated by immunofluorescence and immunoblotting. The roles of Nogo-A–NgR1 signaling in autophagic activation were determined by intraventricular delivery of an NgR1 antagonist peptide, NEP1–40, at 24 h after MCAO. The results showed that Nogo-A and NgR1 overexpression temporally coincided with marked increases in the levels of Beclin1, LC3-II and sequestosome 1 (SQSTM1)/p62 in the ipsilateral thalamus at seven and fourteen days after MCAO. In contrast, NEP1–40 treatment significantly reduced the expression of Rho-A and ROCK1 which was accompanied by marked reductions of LC3-II conversion as well as the levels of Beclin1 and SQSTM1/p62. Furthermore, NEP1–40 treatment significantly reduced neuronal loss and gliosis in the ipsilateral thalamus, and accelerated somatosensory recovery at the observed time-points after MCAO. These results suggest that blockade of Nogo-A–NgR1 signaling inhibits autophagic activation, attenuates secondary neuronal damage in the ipsilateral thalamus, and promotes functional recovery after focal cerebral cortical infarction.