Reducing Memory Dysfunction Following Brain Injury

摘要 在大鼠、小鼠、非人类灵长类动物和人类患者中进行的研究表明， 海马体，颞叶内的一个结构，在学习中起着关键作用， 记忆，而对这一结构的损害可能导致严重的损害。作为这一基本 认知功能对日常活动至关重要，学习和记忆功能障碍使其 很难保住一份工作，管理一个人的财务，并计划日常活动。这些问题严重 损害创伤性脑损伤患者的生活质量， 康复的有效性，并阻碍恢复独立的生活方式。使用 脑损伤的实验模型，包括我们在内的许多研究人员已经表明， 创伤性脑损伤导致海马细胞死亡和学习功能障碍 和记忆缺陷通过一系列的实验，我们鉴定出两种化合物 能够增加细胞保护基因的表达，这些基因是内源性的， 包括神经元在内的许多细胞类型，并由转录因子Nrf2激活。我们 工作假设是TBI后给予这些新鉴定的化合物将 减少继发性病变并通过增加表达来改善学习和记忆 Nrf2驱动的基因。我们将使用生物化学、分子、遗传和 行为测试以检查损伤后给予这些化合物是否可以减少 血脑屏障通透性，提供神经保护，并改善学习和记忆。如果 成功，这项基于机制的研究的结果可能为临床试验铺平道路， 遭受创伤性脑损伤的患者。

Abstract Studies performed in rats, mice, non-human primates, and human patients have demonstrated that the hippocampus, a structure within the temporal lobe, plays a critical role in learning and memory, and damage to this structure can result in profound impairments. As this basic cognitive function is critical for day-to-day activities, learning and memory dysfunction makes it difficult to hold a job, manage one's finances, and plan daily activities. These problems severely compromise the quality of life for persons with traumatic brain injury, can hamper the effectiveness of rehabilitation, and hinder a return to an independent lifestyle. Using experimental models of brain injury, a number of investigators including us have shown that traumatic brain injury causes hippocampal cell death and dysfunction that underlies learning and memory deficits. Through a series of experimentats, we have identified two compounds that are capable of increasing the expression of cytoprotective genes, which are endogenous to a number of cell types including neurons and are activated by the transcription factor Nrf2. Our working hypothesis is that post-TBI administration of these newly identified compounds will reduce secondary pathologies and improve learning and memory by increasing the expression of Nrf2-driven genes. We will use a combination of biochemical, molecular, genetic and behavioral tests to examine if post-injury administration of these compounds can decrease blood-brain barrier permeability, offer neuroprotection, and improve learning and memory. If successful, the results from this mechanism-based study may pave the way for clinical testing in patients who have sustained a traumatic brain injury.