Administration of Tauroursodeoxycholic Acid Attenuates Early Brain Injury via Akt Pathway Activation.
Administration of Tauroursodeoxycholic Acid Attenuates Early Brain Injury via Akt Pathway Activation.
复制标题
牛磺熊去氧胆酸通过激活 Akt 通路减轻早期脑损伤
DOI：
10.3389/fncel.2017.00193
复制
发表时间：
2017
影响因子：
5.3
通讯作者：
Zhang J
中科院分区：
文献类型：
--
作者：
Sun D;Gu G;Wang J;Chai Y;Fan Y;Yang M;Xu X;Gao W;Li F;Yin D;Zhou S;Chen X;Zhang J
创伤性脑损伤（TBI）是创伤性死亡和残疾的主要原因之一，并且新兴的研究表明内质网（ER）应激在TBI的病理生理学中起重要作用。牛磺熊去氧胆酸（TUDCA），一种亲水性胆汁酸，已被报道作为ER应激抑制剂和化学伴侣，并具有减轻细胞凋亡和炎症的潜力。为了研究TUDCA对脑损伤的影响，我们用可控皮质撞击（CCI）装置对小鼠进行了TBI。使用蛋白质印迹法，我们首先检测了TBI诱导的ER应激标记物GRP 78、p-PERK、PERK、p-eIF 2a、eIF 2a、ATF 4、p-Akt、Akt、Pten、Bax、Bcl-2、Caspase-12和CHOP表达水平的变化，以及使用RT-PCR检测Akt、GRP 78、Caspase-12和CHOP mRNA水平的变化。通过末端脱氧核苷酸转移酶（TdT）介导的dUTP缺口末端标记（TUNEL）法评估神经细胞死亡，并通过免疫荧光双染色检测神经细胞中CHOP的表达。通过改良的神经系统严重程度评分（mNSS）和平衡木和平衡木行走试验评估神经和运动缺陷，并评估脑含水量。我们的结果表明，ER应激在TBI后72 h达到峰值，TUDCA消除ER应激并抑制p-PERK、p-eIF 2a、ATF 4、Pten、Caspase-12和CHOP表达水平。此外，我们的研究结果表明，TUDCA还改善神经功能，减轻脑水肿。此外，TUDCA增加p-Akt表达和Bcl-2/Bax比值。然而，Akt抑制剂MK2206或靶向Akt的siRNA的施用消除了TUDCA的有益作用。总之，我们的结果表明，TUDCA可能通过激活Akt通路减轻早期脑损伤。
Traumatic brain injury (TBI) is one of the leading causes of trauma-induced mortality and disability, and emerging studies have shown that endoplasmic reticulum (ER) stress plays an important role in the pathophysiology of TBI. Tauroursodeoxycholic acid (TUDCA), a hydrophilic bile acid, has been reported to act as an ER stress inhibitor and chemical chaperone and to have the potential to attenuate apoptosis and inflammation. To study the effects of TUDCA on brain injury, we subjected mice to TBI with a controlled cortical impact (CCI) device. Using western blotting, we first examined TBI-induced changes in the expression levels of GRP78, an ER stress marker, p-PERK, PERK, p-eIF2a, eIF2a, ATF4, p-Akt, Akt, Pten, Bax, Bcl-2, Caspase-12 and CHOP, as well as changes in the mRNA levels of Akt, GRP78, Caspase-12 and CHOP using RT-PCR. Neuronal cell death was assessed by a terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end-labeling (TUNEL) assay, and CHOP expression in neuronal cells was detected by double-immunofluorescence staining. Neurological and motor deficits were assessed by modified neurological severity scores (mNSS) and beam balance and beam walking tests, and brain water content was also assessed. Our results indicated that ER stress peaked at 72 h after TBI and that TUDCA abolished ER stress and inhibited p-PERK, p-eIF2a, ATF4, Pten, Caspase-12 and CHOP expression levels. Moreover, our results show that TUDCA also improved neurological function and alleviated brain oedema. Additionally, TUDCA increased p-Akt expression and the Bcl-2/Bax ratio. However, the administration of the Akt inhibitor MK2206 or siRNA targeting of Akt abolished the beneficial effects of TUDCA. Taken together, our results indicate that TUDCA may attenuate early brain injury via Akt pathway activation.