Tropomyosin-related kinase B (TrkB) has emerged as a key mediator in the pathophysiology of traumatic brain injury (TBI). However, it is not known whether TrkB's agonist N-acetyl serotonin (NAS) involves in neuronal damage and brain dysfunction caused by TBI that is known as one of the most important causes of disability and death worldwide. Here, we investigated the effects of NAS on brain edema, blood-brain barrier (BBB), apoptosis activation and autophagy dysfunction after experimental TBI. A mouse TBI model was applied, NAS and ANA-12 (an antagonist of TrkB) were administered. Here, we first found that NAS administration ameliorated TBI-induced brain edema, blood-brain barrier (BBB) disruption, increase of matrix metalloproteinase-9 (MMP-9) expression and decrease of claudin-5 expression. NAS treatment decreased TBI-induced cell death and apoptosis activation (detected by propidium iodide labeling, TUNEL staining, blots for Bcl-2, Bax and caspase-3). In addition, NAS treatment decreased the expression of Beclin-1 and LC3, along with ratio of Beclin-1/Bcl-2, but increased p62 expression following TBI. NAS also enhanced the activation of the TrkB/Akt pathway following TBI. Whereas, the above protective effect of NAS following TBI was blocked by ANA-12 addition. Thus, we conclude that NAS-initiating the TrkB/Akt signaling cascade provides neuroprotection after experimental TBI in mice, which at least in part through inhibiting apoptosis activation and autophagic dysfunction.

中文翻译：

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TrkB受体激动剂N-乙酰5-羟色胺通过减轻细胞凋亡激活和自噬功能障碍，在颅脑损伤后提供大脑保护。

Tropomyosin相关激酶B（TrkB）已成为创伤性脑损伤（TBI）病理生理学中的关键介体。但是，尚不知道TrkB的激动剂N-乙酰5-羟色胺（NAS）是否参与由TBI引起的神经元损伤和脑功能障碍，而TBI被认为是全世界致残和死亡的最重要原因之一。在这里，我们调查了NAS对实验性TBI后脑水肿，血脑屏障（BBB），细胞凋亡激活和自噬功能障碍的影响。应用小鼠TBI模型，施用NAS和ANA-12（TrkB的拮抗剂）。在这里，我们首先发现NAS给药可改善TBI诱导的脑水肿，血脑屏障（BBB）破坏，基质金属蛋白酶9（MMP-9）表达增加和claudin-5表达减少。NAS治疗可减少TBI诱导的细胞死亡和凋亡激活（通过碘化丙啶标记，TUNEL染色，Bcl-2，Bax和caspase-3印迹检测）。此外，NAS处理降低了Beclin-1和LC3的表达以及Beclin-1 / Bcl-2的比例，但在TBI后增加了p62的表达。NAS还增强了TBI后TrkB / Akt途径的激活。然而，ANA的加入阻止了TBI后NAS的上述保护作用。因此，我们得出结论，NAS启动TrkB / Akt信号级联反应在小鼠进行实验性TBI后提供了神经保护作用，这至少部分是通过抑制细胞凋亡激活和自噬功能障碍来实现的。NAS处理降低了Beclin-1和LC3的表达以及Beclin-1 / Bcl-2的比例，但在TBI后增加了p62的表达。NAS还增强了TBI后TrkB / Akt途径的激活。然而，ANA的加入阻止了TBI后NAS的上述保护作用。因此，我们得出结论，NAS启动TrkB / Akt信号级联反应在小鼠进行实验性TBI后提供了神经保护作用，这至少部分是通过抑制细胞凋亡激活和自噬功能障碍来实现的。NAS处理降低了Beclin-1和LC3的表达以及Beclin-1 / Bcl-2的比例，但在TBI后增加了p62的表达。NAS还增强了TBI后TrkB / Akt途径的激活。然而，ANA的加入阻止了TBI后NAS的上述保护作用。因此，我们得出结论，NAS启动TrkB / Akt信号级联反应在小鼠进行实验性TBI后提供了神经保护作用，这至少部分是通过抑制细胞凋亡激活和自噬功能障碍来实现的。