Reducing Memory Dysfunction Following Brain Injury

描述(申请人提供)：在大鼠、小鼠、非人类灵长类动物和人类患者身上进行的研究表明，海马体是颞叶内的一种结构，在学习和记忆中发挥关键作用，这种结构的破坏可能会导致严重的损害。由于这种基本的认知功能对日常活动至关重要，学习和记忆障碍会让人很难保住工作、管理财务和计划日常活动。这些问题严重损害了创伤性脑损伤患者的生活质量，可能会阻碍康复的有效性，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证明，创伤性脑损伤导致海马细胞死亡和功能障碍，而海马细胞是学习和记忆障碍的基础。通过一系列实验，我们已经鉴定出两种能够增加细胞保护基因表达的化合物，这些基因是包括神经元在内的多种细胞类型的内源性基因，并被转录因子Nrf2激活。我们的工作假设是，脑损伤后给予这些新发现的化合物将通过增加Nrf2驱动基因的表达来减少继发性病理并改善学习和记忆。我们将结合生化、分子、遗传和行为测试来检验损伤后服用这些化合物是否可以降低血脑屏障通透性，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结果可能会为对遭受创伤性脑损伤的患者进行临床测试铺平道路。

DESCRIPTION (provided by applicant): 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.