Positive allosteric modulation of cholinergic receptors in recovery after brain trauma

脑外伤后恢复过程中胆碱能受体的正变构调节

• 批准号: 9093336
• 负责人: DANIEL PHILIPP HOLSCHNEIDER
• 金额: $ 24.95万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9093336
• 关键词: 3-Dimensional; Accelerometer; Acetylcholine; Acetylcholinesterase; Acetylcholinesterase Inhibitors; Acute; Adverse effects; Affect; Affinity; Allosteric Site; Animal Model; Animals; Autoradiography; Basal Ganglia; Behavioral; Binding; Brain; Brain Injuries; Brain imaging; Carboxylic Acids; Centers for Disease Control and Prevention (U.S.); Cerebrovascular Circulation; Cerebrum; Cholinergic Receptors; Cholinomimetics; Chronic; Clinical; Clinical Data; Cognition; Cognitive deficits; Contusions; Core-Binding Factor; Cortical Contusions; Country; Data; Development; Dose; Drug Combinations; Environment; Equilibrium; Female; Functional disorder; Future; Gait; Hippocampus (Brain); Hour; Human; Image; Incidence; Injury; Intervention; Learning; Length; Life; Ligands; Limb structure; Maps; Mediating; Memory; Modeling; Modification; Motor; Motor Activity; Mus; Muscarinic Acetylcholine Receptor; Muscarinic Antagonists; Muscarinic M1 Receptor; Muscarinics; Neurocognitive Deficit; Neuronal Plasticity; Neurons; Neurorehabilitation; Outcome; Pathway interactions; Patients; Pattern; Pharmacotherapy; Prognostic Marker; Quality of life; Recovery; Recovery of Function; Rehabilitation Research; Rehabilitation therapy; Reporting; Review Literature; Rodent Model; Role; Scopolamine; Secondary to; Sex Characteristics; Signal Transduction; Survivors; System; Therapeutic; Time; Toxic effect; Translations; Traumatic Brain Injury; Traumatic Brain Injury recovery; Treatment Effectiveness; Visuospatial; Water; Work; acute toxicity; awake; basal forebrain; cholinergic; cognitive recovery; cost; disability; dosage; field study; functional outcomes; functional restoration; gait examination; improved; improved outcome; innovation; interest; male; meetings; motor deficit; motor learning; motor recovery; mouse model; novel; novel therapeutics; positive allosteric modulator; pre-clinical; preclinical study; public health relevance; receptor; sedative; sex; success; therapeutic target; translational study; transmission process; treadmill; treatment strategy

 DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) costs the country more than $76.5 billion a year, with an estimated 5.3 million U.S. residents living with TBI-related disabilities (CDC 2009 data). Although it is not possible to eliminate the immediate neuronal damage that occurs at the moment of TBI, it may be possible to alleviate the secondary damage that occurs hours or even weeks post-TBI, and thereby improve the brain function and quality of life of TBI survivors. However, there are currently no clinically efficacious drug therapies to tret neuronal damage secondary to TBI. Brain cholinergic mechanisms are essential to learning and memory, and these are severely impacted, both acutely and chronically, in human TBI patients and in TBI animal models. Use of acetylcholinesterase (AChE) inhibitors as a treatment strategy has met with modest clinical success; however, undesirable toxic effects of AChE inhibition have limited dosage increases. Recently, an unprecedented line of work has been opened with the development of positive allosteric modulators (PAMs) of cholinergic receptors. PAMs bind to allosteric sites where they have no effect alone, but increase the affinity and/or efficacy of endogenous acetylcholine. In the current proposal, we examine the efficacy of benzylquinolone carboxylic acid (BQCA), a PAM of the M1 muscarinic receptor which is known to have a lower incidence of undesirable side effects mediated by other cholinergic receptors subtypes M2-M5. In Aim 1, we examine the effects of 3 weeks of BQCA administration in a mouse model of focal, unilateral motorsensory cortical contusion injury (CCI) using functional outcomes of learning and memory, as well as motor function. Comparison is made for treatments initiated 3 days (subacute) or 3 weeks (subchronic) after injury. Aim 2 applies functional brain imaging to examine what cerebral circuits are affected during functional restoration following BQCA administration. Aim 3 examines sex differences in the effects of BQCA on the injured brain. Our study will be the first to explore the role of a muscarinic PAM in a TBI model. It will also for th first time present data on sex differences in cognitive and motor recovery following administration of cholinergic PAMs in the acute and subacute period after CCI. This translational study is consistent with the National Center for Medical Rehabilitation Research (NCMRR) 2006 report emphasizing the need for preclinical studies to advance neurorehabilitation. Results will lay the much needed groundwork for understanding the role of PAMs of the M1 receptor on functional recovery after TBI.

 描述（由适用提供）：脑外伤（TBI）每年损失超过765亿美元的损失，估计有530万与TBI相关疾病的美国居民（CDC 2009数据）。尽管不可能消除在TBI时发生的直接神经元损害，但可能会减轻TBI后数小时甚至数周发生的次要损害，从而改善TBI生存的大脑功能和生活质量。但是，目前尚无临床上有效的药物疗法来继发于TBI的TRET神经元损伤。脑胆碱能机制对于学习和记忆至关重要，在人类TBI患者和TBI动物模型中，这些机制在急性和慢性上都受到严重影响。使用乙酰胆碱酯酶（ACHE）抑制剂作为治疗策略已取得了适度的临床成功；但是，抑制ACHE的前所未有的毒性作用的剂量有限。最近，随着胆碱能受体的阳性变构调节剂（PAM）的发展，已经开设了前所未有的工作。 PAM与无单独效果的变构位点结合，但会增加内源性乙酰胆碱的亲和力和/或有效性。在目前的提案中，我们研究了M1毒蕈碱受体的PAM苄基喹诺酮羧酸（BQCA）的有效性，该毒蕈碱受体的PAM众所周知，该胆碱能受体亚型亚型M2-M5介导的不良副作用较低。在AIM 1中，我们使用学习和记忆的功能结果以及运动功能，检查了BQCA给药3周的bQCA给药的影响。对启动3天（亚急性）或3周（亚基）的治疗进行比较。 AIM 2应用功能性脑成像来检查BQCA给药后功能恢复期间受影响的脑回路。 AIM 3考试在BQCA对受伤大脑的影响中的性别差异。我们的研究将是第一个探索毒蕈碱PAM在TBI模型中的作用的研究。在CCI之后的急性和亚急性期间，它也将在第一次介绍有关认知和运动恢复性别的性别差异的数据。这项翻译研究与2006年国家医学康复研究中心（NCMRR）的报告一致，该报告强调了临床前研究的需求，以推动神经康复。结果将为理解M1受体在TBI后功能恢复的作用提供急需的基础。