Reducing Neuronal Loss After Traumatic Brain Injury

 描述(申请人提供)：中-重度创伤性脑损伤(TBI)通常会导致神经元死亡和神经认知障碍，未成熟和成熟的神经元都容易受到损伤。内质网(ER)在膜和分泌蛋白的折叠、钙储存和细胞内钙稳态中起着重要作用。它的功能可以被扰乱，因为它对许多刺激的反应减少，包括血糖水平下降，缺氧，以及钙水平的变化，所有这些都在脑损伤后观察到。内质网功能紊乱(通常被称为内质网应激)会导致错误折叠的蛋白质积累。内质网激活的信号通路之一是双链RNA激活的蛋白激酶样内质网蛋白激酶(Perk)。一旦激活，PERK将翻译起始因子eIF2a磷酸化，该因子作用于减少全球蛋白质合成，同时允许合成参与蛋白质折叠的伴侣。如果内质网功能不能恢复，PERK会导致细胞死亡的中介CCAAT/增强子结合蛋白同源蛋白(CHOP)的表达增加。我们观察到，TBI增加了eIF2a的磷酸化，并增强了CHOP的表达。为了研究靶向PERK-eIF2a-CHOP通路的翻译潜力，我们已经获得了初步的实验结果，表明损伤后给予Ganabenz(一种FDA批准的抑制eIF2a磷酸酶的药物)可以减少神经元丢失并改善神经认知结果。此外，损伤后给予化学伴侣(FDA批准的药物4-苯基丁酸(4-PBA))也能改善结果。基于这些和其他观察结果，我们建议检验这样一种假设，即脑损伤后给予Ganabenz、4-PBA以及它们的组合将有效地减少成熟和未成熟神经元的损失，并改善神经认知功能。目的1：确定愈创安慰剂的疗效及其治疗时间窗。目的2：确定4-PBA的最佳剂量和治疗时间窗。目的：评价愈创木酚与4-PBA联合应用是否更有效。这些研究的结果为未来的临床研究提供了基础，以确定单独或联合使用药物是否可以改善脑外伤后的预后。

 DESCRIPTION (provided by applicant): Moderate-severe traumatic brain injury (TBI) often causes neuronal death and neurocognitive impairments, with both immature and mature neurons being vulnerable to the injury. The endoplasmic reticulum (ER) plays a major role in the folding of membrane and secreted proteins and in calcium storage and intracellular calcium homeostasis. Its function can disrupted in response to decreased in response to a number of stimuli including reduced glucose levels, hypoxia, and altered calcium levels, all of which have been observed after TBI. Disrupted ER function (often referred to as ER stress) can result in the accumulation of misfolded proteins. One of the signaling pathways activated in response to ER stress is double-stranded RNA-activated protein kinase-like endoplasmic reticulum kinase (Perk). Once activated, Perk phosphorylates the translation initiation factor eIF2a, which acts to reduce global protein synthesis while permitting the synthesis of chaperones involved in protein folding. If ER function cannot be restored, Perk leads to the increased expression of CCAAT/enhancer-binding protein homologous protein (CHOP), a mediator of cell death. We have observed that TBI increases eIF2a phosphorylation and enhances CHOP expression. In order to examine the translational potential of targeting Perk-eIF2a-CHOP pathway, we have obtained preliminary experimental results to indicate that post injury administration of guanabenz (a FDA-approved drug that acts to inhibit eIF2a phosphatase) reduces neuronal loss and improves neurocognitive outcome. Furthermore, post-injury administration a chemical chaperone (4-phenylbuteric acid (4-PBA), an FDA-approved drug) also improved outcome. Based on these and other observations, we propose to test the hypothesis that post-TBI administration of guanabenz, 4-PBA, and their combination will effectively reduce loss of both mature and immature neurons and improve neurocognitive function. Aim 1: To determine efficacy of guanabenz and its therapeutic time window. Aim 2: To define the optimal dose and therapeutic time window for 4-PBA. Aim 3: To evaluate if the combination of guanabenz and 4-PBA is more efficacious. The results from these studies provide the basis for future clinical studies to determine if individual drugs alone or in combination can be used to improve outcome after TBI.