J147 Treatment for Traumatic Brain Injury in Brain Damage and Long-Term Functional Recovery

摘要 创伤性脑损伤（traumatic brain injury，TBI）是一个重要的临床问题，但成功的治疗方法很少 从实验室到诊所在这个提议中，我们假设J147的治疗性治疗 防止继发性脑损伤，促进TBI后的长期功能恢复。J147， 姜黄素衍生的小分子化合物，其可以容易地穿过BBB，已经显示具有多个 神经保护和神经营养特性，以对抗年龄相关的神经退行性疾病。此外，J147 显示对实验性缺血性中风和谷氨酸诱导的神经元死亡具有神经保护作用， 皮层神经元培养然而，J147在TBI中的作用尚未被研究。在一只老鼠的控制下， 我们的初步数据显示，J147治疗可防止神经元细胞变性， 并减弱TBI后病变周围区域中延长的ER应力。此外，J147治疗显著 在TBI后2周的观察期内促进神经功能的恢复， 改善神经元可塑性。这些令人兴奋的初步数据表明，J147治疗可能代表了 预防和/或减少继发性脑损伤的有希望的治疗方法， TBI后的结果。在本申请中，我们提出用J147治疗开发新的TBI疗法， 研究J147治疗介导的有益作用的分子机制。我们现建议 三个目的是研究这种新的TBI疗法。 目的1：探讨J147治疗TBI在功能恢复和损伤严重程度方面的最佳剂量。 35天后检查脑挫伤体积、海马神经元损失和白色物质损伤 脑损伤在35天存活期内将进行一系列神经行为测试。 在目标2中，我们将探索J147的治疗时间窗，及其对长期恢复的影响和影响 在不同的年龄。为了探索治疗时间窗，J147的最佳剂量将在1 - 10天开始。 12小时动物将被允许存活35天。用于测试J147的长期影响及其影响 在不同年龄组中，将两个不同年龄组进行TBI并用J147治疗。动物将 可以存活6个月。所有测量将按照与目标1相似的方式进行。 在目标3中，我们将探索J147治疗减轻脑损伤的潜在机制 并促进功能恢复，重点关注ER应激、凋亡和神经元可塑性。的空间和 评价ER应激和应激相关Sirt1激活的时间变化。神经元细胞 将确定病灶周围区域的变性和凋亡。RNAi实验将在 探讨J147在脑外伤后Sirt1激活与内质网应激及细胞凋亡关系中的作用。的作用 J147在损伤后神经元可塑性中的作用也将被探索。

ABSTRACT Traumatic brain injury (TBI) is a significant clinical problem with few therapeutic interventions successfully translated from the bench to the clinic. In this proposal, we hypothesize that the therapeutic treatment of J147 protects against secondary brain damage and promotes long-term functional recovery following TBI. J147, a curcumin-derived small molecule compound which can easily cross the BBB, has been shown to have multiple neuroprotective and neurotrophic properties against age-related neurodegenerative disorders. In addition, J147 is shown to be neuroprotective against experimental ischemic stroke and glutamate-induced neuronal death in cortical neuron culture. However, the effects of J147 in TBI has not yet been investigated. In a mouse controlled cortical impact model of TBI, our preliminary data show that J147 treatment prevents neuronal cell degeneration and attenuates prolonged ER stress in the perilesional area after TBI. Moreover, J147 treatment significantly promotes the recovery of neurological functions during the 2-week observation period after TBI, with a substantial improvement in neuronal plasticity. These exciting preliminary data suggest that J147 treatment may represent a promising therapeutic approach to prevent and/or reduce secondary brain damage, improving long-term outcomes following TBI. In this application, we propose to develop a new TBI therapy with J147 treatment and to investigate molecular mechanisms underlying J147 therapy-mediated beneficial effects. We now propose three aims to investigate this new TBI therapy. In aim 1, we will explore the optimal dose of J147 treatment for TBI in functional recovery and injury severity. Brain contusion volume, hippocampal neuronal loss and white matter damage will be examined 35 days after brain injury. A battery of neurobehavioral tests will be performed during the 35-day survival time. In aim 2, we will explore the therapeutic time-window of J147, and its effects on long-term recovery and impacts among different ages. For exploring the therapeutic time-window, the optimal dose of J147 will be initiated 1- 12h. The animals will be allowed to survive for 35 days. For testing long-term effects of J147 and its impacts among different ages, two different age groups will be subjected to TBI and treated with J147. Animals will be allowed to survive for 6 months. All measurements will be performed similarly to Aim 1. In aim 3, we will explore the potential mechanisms underlying the J147 treatment that attenuate brain damage and promote functional recovery, with a focus on ER stress, apoptosis, and neuronal plasticity. The spatial and temporal variation of ER stress and stress-related Sirt1 activation will be assessed. The neuronal cell degeneration and apoptosis in the perilesional area will be determined. The RNAi experiment will be performed to identify the actions of J147 in the relation of Sirt1 activation with ER stress and apoptosis after TBI. The role of J147 in post-injury neuronal plasticity will also be explored.