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（由申请人提供）：创伤性脑损伤 (TBI) 每年给国家造成超过 765 亿美元的损失，估计有 530 万美国居民患有与 TBI 相关的残疾（CDC 2009 年数据）。 TBI 发生时发生的直接神经元损伤，有可能减轻 TBI 后数小时甚至数周发生的继发性损伤，从而改善患者的脑功能和生活质量然而，目前尚无临床有效的药物疗法来治疗继发于 TBI 的神经元损伤。大脑胆碱能机制对于学习和记忆至关重要，而这些机制在人类 TBI 患者和 TBI 动物中都受到严重和长期的影响。使用乙酰胆碱酯酶 (AChE) 抑制剂作为治疗策略已取得一定的临床成功；然而，最近，AChE 抑制的不良毒性作用限制了剂量的增加。随着胆碱能受体的正变构调节剂（PAM）的开发，一项前所未有的工作已经展开，PAM 与变构位点结合，它们单独没有作用，但在当前的提议中增加了内源性乙酰胆碱的亲和力和/或功效。 ，我们检查了苄基喹诺酮羧酸 (BQCA) 的功效，BQCA 是 M1 毒蕈碱受体的 PAM，已知其发生率较低由其他胆碱能受体亚型 M2-M5 介导的不良副作用 在目标 1 中，我们利用学习和记忆的功能结果，检查了 BQCA 给药 3 周对局灶性单侧运动感觉皮层挫伤损伤 (CCI) 小鼠模型的影响。对损伤后 3 天（亚急性）或 3 周（亚慢性）开始的治疗进行比较，目标 2 适用于功能性大脑。目的 3 检查 BQCA 对受损大脑影响的性别差异，我们的研究将首次探讨毒蕈碱 PAM 在 TBI 模型中的作用。还将首次提供 CCI 后急性期和亚急性期服用胆碱能 PAM 后认知和运动恢复方面性别差异的数据。这项转化研究与国家医学中心的结果一致。康复研究 (NCMRR) 2006 报告强调需要进行临床前研究来促进神经康复，结果将为了解 M1 受体 PAM 对 TBI 后功能恢复的作用奠定必要的基础。