Reducing Neuronal Loss After Traumatic Brain Injury

 描述（由申请人提供）：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以及钙储存和细胞内钙稳态中起主要作用。它的功能可以响应于对许多刺激的响应降低而被破坏，包括葡萄糖水平降低、缺氧和钙水平改变，所有这些都在TBI后被观察到。ER功能的破坏（通常称为ER应激）可导致错误折叠蛋白质的积累。双链RNA激活的蛋白激酶样内质网激酶（Perk）是内质网应激激活的信号通路之一。一旦激活，Perk磷酸化翻译起始因子eIF 2a，其作用是减少整体蛋白质合成，同时允许参与蛋白质折叠的伴侣蛋白的合成。如果ER功能不能恢复，Perk导致CCAAT/增强子结合蛋白同源蛋白（CHOP）表达增加，这是细胞死亡的介导物。我们已经观察到TBI增加eIF 2a磷酸化并增强CHOP表达。为了检查靶向Perk-eIF 2a-CHOP途径的翻译潜力，我们获得了初步实验结果，表明损伤后给予guanabenz（一种FDA批准的抑制eIF 2a磷酸酶的药物）可减少神经元损失并改善神经认知结果。此外，损伤后给予化学伴侣（4-苯基丁酸（4-PBA），FDA批准的药物）也改善了结果。基于这些和其他观察结果，我们建议测试以下假设：TBI后给予胍那苄、4-PBA及其组合将有效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：确定胍那苄的疗效和治疗时间窗。目的2：确定4-PBA的最佳剂量和治疗时间窗。目的3：评价胍那苄和4-PBA联合用药是否更有效。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单个药物是否可以改善TBI后的结果。

 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.