Rehabilitation Strategies for Memory Dysfunction after Traumatic Brain Injury

脑外伤后记忆障碍的康复策略

基本信息

批准号：
9130297
负责人：
COLEEN M. ATKINS
金额：
$ 44.37万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9130297
关键词：
Acetylcholine Acute Affect Agonist Alzheimer&apos s Disease Aminobutyric Acids Animals Area Atrophic Binding Brain Injuries Cholinergic Agents Cholinergic Receptors Cholinesterase Inhibitors Chronic Clinical Clinical Research Clinical Trials Cognition Cognitive deficits Data Depressed mood Development Diagonal Band of Broca Dose Drug Kinetics Electrophysiology (science)FDA approved Fimbria of hippocampus Health Hippocampus (Brain)Impaired cognition Implant Injury Kinetics Knock-out Knockout Mice Learning Life Ligands Liquid substance Long-Term Potentiation Medial Memory Memory impairment Microglia Modeling Molecular Mus Neurons Operative Surgical Procedures Pathology Percussion Pharmacodynamics Pharmacological Treatment Pharmacology Phase Phase I Clinical Trials Phenotype Pre-Clinical Model Quality of life Rattus Recovery Reporting Research Proposals Schizophrenia Signal Transduction Slice Specificity Survivors Synapses Synaptic Transmission Synaptic plasticity Testing Therapeutic Theta Rhythm Time Translating Traumatic Brain Injury Wild Type Mouse alpha-bungarotoxin receptor awake base cholinergic cognitive function cognitive task controlled cortical impact desensitization disability improved improved outcome mind control multi-electrode arrays novel therapeutics positive allosteric modulator pre-clinical research preclinical study receptor rehabilitation strategy response sham surgery success white matter

项目摘要

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.

描述（由申请人提供）：近 80% 遭受创伤性脑损伤 (TBI) 的人在最初的脑外伤后数月至数年内报告有轻度至中度的学习和记忆障碍，尽管对这些变化有一些了解。 TBI 后海马内发生的学习障碍的根本原因尚不完全清楚，因此，尚无 FDA 批准的药物疗法可用于改善 TBI 后的学习和记忆障碍。该提案旨在了解 TBI 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以转化为我们的慢性 TBI 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 TBI 后的认知能力。 TBI。这种治疗方法存在强有力的理由。胆碱能受体对于调节空间学习过程中的海马长时程增强 (LTP) 和 θ 节律很重要，但 TBI 治疗后胆碱能信号减弱。胆碱酯酶抑制剂或胆碱能受体激动剂的临床成功有限，α7 烟碱 AChR (nAChR) 的正变构调节剂的开发仅在受体与激动剂结合时增强电流。使用 AVL-3288（α7 的正变构调节剂）实现胆碱能信号的空间和时间完整性。中度液体冲击脑损伤后 3 个月，动物的 nAChR、海马 LTP 和认知缺陷均得到恢复。基于这些初步数据，该提议的主要假设是，用正变构调节剂靶向 α7 nAChR 将足以拯救LTP，改善θ振荡，促进TBI慢性恢复期的认知功能为了检验这一假设，提出以下目标：1）确定是否存在正向变构调节。 α7 nAChRs 足以在 TBI 后恢复海马 LTP 和 θ 节律，2) 确定 α7 nAChRs 的正变构调节是否可改善 TBI 后的慢性认知缺陷，以及 3) 从机械角度确定 α7 nAChRs 的正变构调节是否可改善海马突触可塑性并通过 α7 nAChR 使用两种临床前模型减少 TBI 后的慢性认知缺陷。 TBI、液体冲击脑损伤和受控皮质冲击以及两种动物物种（大鼠和小鼠）将对 AVL-3288 进行彻底和严格的评估，以确定这种治疗方法是否有效。此外，多电极阵列记录。将用于确定 α7 nAChR 如何影响 TBI 后海马回路的变化。鉴于 AVL-3288 已处于 I 期，这些研究的临床潜力非常高。该提案得到了具有 TBI、电生理学、认知和药理学专业知识的跨学科团队的支持，该研究提案的结果有可能迅速转化为临床试验，并将开发一种新的治疗方法。慢性 TBI 幸存者改善认知和生活质量。