Departments of Neurology and Neurosurgery, Brain Trauma Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, and Veterans Affairs Pittsburgh Health Care System, Geriatric Research, Educational and Clinical Center, Pittsburgh, Pennsylvania 15213.
J Neurosci. 2014 Mar 5;34(10):3743-55. doi: 10.1523/JNEUROSCI.2872-13.2014.
In this study, we investigated the development of endoplasmic reticulum (ER) stress after traumatic brain injury (TBI) and the efficacy of post-TBI administration of docosahexaenoic acid (DHA) in reducing ER stress. TBI was induced by cortical contusion injury in Sprague-Dawley rats. Either DHA (16 mg/kg in DMSO) or vehicle DMSO (1 ml/kg) was administered intraperitoneally at 5 min after TBI, followed by a daily dose for 3-21 d. TBI triggered sustained expression of the ER stress marker proteins including phosphorylated eukaryotic initiation factor-2α, activating transcription factor 4, inositol requiring kinase 1, and C/EBP homologous protein in the ipsilateral cortex at 3-21 d after TBI. The prolonged ER stress was accompanied with an accumulation of abnormal ubiquitin aggregates and increased expression of amyloid precursor protein (APP) and phosphorylated tau (p-Tau) in the frontal cortex after TBI. The ER stress marker proteins were colocalized with APP accumulation in the soma. Interestingly, administration of DHA attenuated all ER stress marker proteins and reduced the accumulation of both ubiquitinated proteins and APP/p-Tau proteins. In addition, the DHA-treated animals exhibited early recovery of their sensorimotor function after TBI. In summary, our study demonstrated that TBI induces a prolonged ER stress, which is positively correlated with abnormal APP accumulation. The sustained ER stress may play a role in chronic neuronal damage after TBI. Our findings illustrate that post-TBI administration of DHA has therapeutic potentials in reducing ER stress, abnormal protein accumulation, and neurological deficits.
在这项研究中，我们调查了创伤性脑损伤 (TBI) 后内质网 (ER) 应激的发展，以及 TBI 后给予二十二碳六烯酸 (DHA) 以减轻 ER 应激的疗效。TBI 通过 Sprague-Dawley 大鼠皮质挫伤伤诱导。DHA（DMSO 中的 16mg/kg）或载体 DMSO（1ml/kg）在 TBI 后 5 分钟腹腔内给药，随后每天给药 3-21 天。TBI 触发了 ER 应激标志物蛋白的持续表达，包括磷酸化真核起始因子-2α、激活转录因子 4、肌醇需求激酶 1 和 C/EBP 同源蛋白，在 TBI 后 3-21 天对侧皮质。长期的 ER 应激伴随着异常泛素聚集物的积累，以及 APP 和磷酸化 tau（p-Tau）在额皮质中的表达增加。ER 应激标志物蛋白与 APP 聚集在体部共定位。有趣的是，DHA 的给药减弱了所有 ER 应激标志物蛋白，并减少了泛素化蛋白和 APP/p-Tau 蛋白的积累。此外，DHA 治疗的动物在 TBI 后表现出传感器运动功能的早期恢复。总之，我们的研究表明，TBI 诱导了持久的 ER 应激，这与异常的 APP 积累呈正相关。持续的 ER 应激可能在 TBI 后慢性神经元损伤中起作用。我们的研究结果表明，TBI 后给予 DHA 具有减轻 ER 应激、异常蛋白积累和神经功能缺损的治疗潜力。
