Rehabilitation Strategies for Memory Dysfunction after Traumatic Brain Injury

 描述(申请人提供)：近80%的遭受创伤性脑损伤(TBI)的人报告说，在最初的脑损伤后的几个月到几年里，他们的学习和记忆能力出现了轻微到中度的损害。尽管对脑损伤后海马区的变化有一些了解，但脑损伤后学习障碍的潜在基础仍不完全清楚。因此，目前还没有FDA批准的药物疗法来改善脑损伤后的学习和记忆障碍。这项建议的首要目标是了解脑外伤后学习和记忆功能障碍的慢性分子机制，并开发新的治疗策略来帮助我们的慢性脑损伤幸存者。临床前和临床研究的一个活跃领域是使用胆碱能药物来增强脑外伤后的认知。这种治疗方法有很强的理由。在空间学习过程中，胆碱能受体对调节海马长时程增强(LTP)和theta节律起重要作用，脑损伤后胆碱能信号转导功能减弱。然而，胆碱酯酶抑制剂或胆碱能受体激动剂的治疗临床成功有限。一个令人兴奋的突破是开发了α7尼古丁乙酰胆碱受体(NAChR)的正变构调节剂。正变构调节剂只有在受体与激动剂结合时才能增强电流。这维持了胆碱能信号的自然空间和时间完整性。使用α7nAChR的正变构调节剂AVL-3288，在中度液压脑损伤后3个月挽救了动物的海马长时程增强和认知障碍。基于这些初步数据，本建议的主要假设是，在脑损伤的慢性恢复期，以α7nAChR为靶点的正变构调节剂将足以挽救长时程增强，改善theta振荡，并促进认知功能。为了验证这一假说，提出了以下目标：1)确定α7 nAChRs的正变构调制是否足以恢复脑损伤后海马长时程和theta节律；2)确定α7 nAChRs的正变构调制是否改善脑损伤后的慢性认知障碍；3)从机械上确定α7 nAChRs的正变构调制是否通过α7 nAChR改善脑损伤后海马区突触的可塑性和减轻慢性认知障碍。使用两种临床前脑损伤模型，液压冲击性脑损伤和受控皮质撞击，以及两种动物物种，大鼠和小鼠，AVL-3288将得到彻底和严格的评估，以确定这种治疗方法是否有效。此外，多电极阵列记录 将被用来确定α7nAChRs如何在脑损伤后海马区电路的变化中做出贡献。鉴于AVL-3288已经处于I期，这些研究的临床潜力非常高 与精神分裂症相关的认知障碍的临床试验。这项提议得到了一个在脑损伤、电生理学、认知和药理学方面拥有专业知识的跨学科团队的支持。这项研究提案的发现有可能迅速转化为临床试验，并将为慢性脑损伤幸存者开发一种新的治疗方法，以改善认知和生活质量。

 DESCRIPTION (provided by applicant): Nearly 80% of people who have sustained a traumatic brain injury (TBI) report mild to moderate learning and memory impairments in the months to years following the initial brain trauma. Although there is some understanding of the changes that occur within the hippocampus after TBI, the underlying basis for learning deficits after TBI is still not completely understood. As a result, no FDA-approved pharmacological therapies are available to improve learning and memory deficits after TBI. The overarching objective of this proposal is to understand the chronic molecular mechanisms of learning and memory dysfunction after TBI and develop novel therapeutic strategies to translate to our chronic TBI survivors. An active area of both preclinical and clinical research is the use of cholinergic drugs to enhance cognition after TBI. Strong rationale exists for this therapeutic approach. Cholinergic receptors are important for modulating hippocampal long-term potentiation (LTP) and theta rhythm during spatial learning and cholinergic signaling is decreased after TBI. However, treatment with cholinesterase inhibitors or cholinergic receptor agonists have had limited clinical success. An exciting breakthrough has been the development of positive allosteric modulators of the α7 nicotinic AChR (nAChR). Positive allosteric modulators enhance current only when the receptor is bound to agonist. This maintains the natural spatial and temporal integrity of cholinergic signaling. Using AVL-3288, a positive allosteric modulator of the α7 nAChR, both hippocampal LTP and cognitive deficits were rescued in animals at 3 months after moderate fluid-percussion brain injury. Based on these preliminary data, the main hypothesis of this proposal is that targeting the α7 nAChR with a positive allosteric modulator will be sufficient to rescue LTP, improve theta oscillations, and promote cognitive functioning in the chronic recovery period of TBI. To test this hypothesis, the following aims are proposed: 1) To determine if positive allosteric modulation of α7 nAChRs is sufficient to restore hippocampal LTP and theta rhythms after TBI, 2) To determine if positive allosteric modulation of α7 nAChRs improves chronic cognitive deficits after TBI, and 3) To mechanistically determine if positive allosteric modulation of α7 nAChRs improves hippocampal synaptic plasticity and reduces chronic cognitive deficits after TBI through the α7 nAChR. Using two preclinical models of TBI, fluid-percussion brain injury and controlled cortical impact, and two animal species, rats and mice, AVL-3288 will be thoroughly and critically evaluated to determine if this therapeutic approach is efficacious. In addition, multielectrode array recordings will be utilized to determine how α7 nAChRs contribute to hippocampal circuitry changes after TBI. The clinical potential of these studies is very high given that AVL-3288 is already in Phase I clinical trials for cognitive impairment associated with schizophrenia. This proposal is supported by an interdisciplinary team with expertise in TBI, electrophysiology, cognition and pharmacology. Findings from this research proposal have the potential to be rapidly translated to clinical trials and will develop a new therapeutic for chronic TBI survivors to improve cognitio and quality of life.