Rehabilitation Strategies for Memory Dysfunction after Traumatic Brain Injury

脑外伤后记忆障碍的康复策略

• 批准号: 9026810
• 负责人: COLEEN M. ATKINS
• 金额: $ 46.05万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 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/9026810
• 关键词: Acetylcholine; Acute; Affect; Agonist; Alzheimer' 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; 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; Nicotinic Receptors; Operative Surgical Procedures; Outcome; 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; awake; base; cholinergic; cognitive function; cognitive task; controlled cortical impact; desensitization; disability; improved; mind control; multi-electrode arrays; novel therapeutics; pre-clinical research; preclinical study; public health relevance; receptor; rehabilitation strategy; response; sham surgery; success; white matter

 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%的创伤性脑损伤（TBI）患者在最初脑创伤后的数月至数年内报告轻度至中度学习和记忆障碍。虽然有一些理解的变化，发生在脑外伤后海马，脑外伤后学习障碍的基础仍然没有完全理解。因此，没有FDA批准的药物治疗可用于改善TBI后的学习和记忆缺陷。该提案的总体目标是了解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。这种治疗方法有很强的理由。胆碱能受体在空间学习过程中对调节海马长时程增强（LTP）和θ节律很重要，并且TBI后胆碱能信号减少。然而，用胆碱酯酶抑制剂或胆碱能受体激动剂治疗具有有限的临床成功。一个令人兴奋的突破是α7烟碱AChR（nAChR）的正变构调节剂的开发。正变构调节剂仅在受体与激动剂结合时增强电流。这维持了胆碱能信号传导的自然空间和时间完整性。使用AVL-3288（一种α7 nAChR的正变构调节剂），中度液压脑损伤后3个月，海马LTP和认知缺陷均得到挽救。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将足以挽救LTP，改善θ振荡，并促进TBI慢性恢复期的认知功能。为了检验这一假设，提出了以下目标：1）确定α7 nAChR的正向别构调节是否足以恢复TBI后海马LTP和θ节律，2）确定α7 nAChR的正向别构调节是否改善TBI后的慢性认知缺陷，和3）从机制上确定α7 nAChRs的正向变构调节是否改善海马突触可塑性并减少慢性认知缺陷α7 nAChR的表达。使用TBI的两种临床前模型，液体冲击脑损伤和受控皮质撞击，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TBI后α7 nAChR如何促进海马回路变化。鉴于AVL-3288已处于I期，这些研究的临床潜力非常高 精神分裂症相关认知障碍的临床试验该提案得到了一个具有TBI，电生理学，认知和药理学专业知识的跨学科团队的支持。这项研究提案的结果有可能迅速转化为临床试验，并将为慢性TBI幸存者开发一种新的治疗方法，以改善认知和生活质量。