Reduction of the neuroprotective transcription factor Npas4 results in increased neuronal necrosis, inflammation and brain lesion size following ischaemia
Reduction of the neuroprotective transcription factor Npas4 results in increased neuronal necrosis, inflammation and brain lesion size following ischaemia
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DOI：
10.1177/0271678x15606146
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发表时间：
2016-08-01
影响因子：
6.3
通讯作者：
Lewis, Martin D.
中科院分区：
文献类型：
--
作者：
Choy, Fong Chan;Klaric, Thomas S.;Lewis, Martin D.
中风是第二大致死原因，也是导致成人残疾的最常见原因。神经元Per-Arnt-Sim结构域蛋白4(Npas4)是一种活性依赖的转录因子，在包括脑缺血在内的多种脑损伤中均有表达。尽管先前的研究已经证明Npas4在保护神经元免受神经退行性损伤中发挥关键作用，但Npas4在缺血性脑损伤中的神经保护作用尚不清楚。在这项研究中，我们使用功能丧失的方法来检测Npas4在缺血性损伤背景下的神经保护潜力。利用缺氧和葡萄糖剥夺，我们证明了Npas4在小鼠皮质神经元中的敲除导致了细胞死亡的易感性增加。利用光化学诱导的小鼠中风模型，在体内进一步研究了Npas4的保护作用。我们发现，与野生型小鼠相比，Npas4基因敲除小鼠的病变面积明显更大，神经退行性变也更严重。此外，我们还发现，Npas4的消融导致激活的星形胶质细胞和小胶质细胞、促炎细胞因子IL-6和肿瘤坏死因子α水平增加，并从凋亡性细胞死亡转变为坏死性细胞死亡。综上所述，这些数据表明，Npas4通过限制进行性神经变性和神经炎症在缺血性中风中发挥神经保护作用。
Stroke is the second leading cause of death and the most frequent cause of adult disability. Neuronal Per-Arnt-Sim domain protein 4 (Npas4) is an activity-dependent transcription factor whose expression is induced in various brain insults, including cerebral ischaemia. Although previous studies have demonstrated that Npas4 plays a critical role in protecting neurons against neurodegenerative insults, the neuroprotective effect of Npas4 in response to ischaemic brain injury remains unknown. In this study, we used a loss-of-function approach to examine the neuroprotective potential of Npas4 in the context of ischaemic damage. Using oxygen and glucose deprivation, we demonstrated that the knockdown of Npas4 in mouse cortical neurons resulted in increased susceptibility to cell death. The protective effect of Npas4 was further investigated in vivo using a photochemically-induced stroke model in mice. We found a significantly larger lesion size and increased neurodegeneration in Npas4 knockout mice as compared to wild-type mice. Moreover, we also showed that ablation of Npas4 caused an increase in activated astrocytes and microglia, pro-inflammatory cytokines interleukin-6 and tumour necrosis factor alpha levels and a switch from apoptotic to necrotic cell death. Taken together, these data suggest that Npas4 plays a neuroprotective role in ischaemic stroke by limiting progressive neurodegeneration and neuroinflammation.