Positive allosteric modulation of cholinergic receptors in recovery after brain trauma

 描述(申请人提供)：创伤性脑损伤(TBI)每年给美国造成的损失超过765亿美元，估计有530万美国居民患有与脑损伤相关的残疾(CDC 2009年的数据)。虽然不可能完全消除脑损伤后即刻的神经元损伤，但有可能减轻脑损伤后数小时甚至数周的继发性损伤，从而改善脑损伤幸存者的脑功能和生活质量。然而，目前还没有临床上有效的药物治疗脑外伤后继发的神经元损伤。脑胆碱能机制对学习和记忆是必不可少的，在人类脑损伤患者和脑损伤动物模型中，这些机制都受到严重的急性和慢性影响。使用乙酰胆碱酯酶(AChE)抑制剂作为一种治疗策略在临床上取得了一定的成功；然而，AChE抑制的不良毒性作用限制了剂量的增加。最近，随着胆碱能受体的正变构调节剂(PAM)的开发，一条前所未有的工作线已经打开。PAM结合到变构部位，在那里它们单独不起作用，但增加内源性乙酰胆碱的亲和力和/或有效性。在目前的建议中，我们检查了苄基喹诺酮羧酸(BQCA)的疗效，BQCA是M1 M受体的一种PAM，已知由其他胆碱能受体亚型M2-M5介导的不良副作用发生率较低。在目标1中，我们利用学习和记忆的功能结果，以及运动功能，在局灶性单侧运动感觉性皮质挫伤(CCI)小鼠模型上检测了BQCA给药3周的效果。比较的是伤后3天(亚急性)或3周(亚慢性)开始的治疗。目的2应用脑功能成像技术研究BQCA给药后功能恢复过程中大脑回路的变化。目的3研究BQCA对脑损伤影响的性别差异。我们的研究将是第一次探索毒扁豆碱类PAM在脑损伤模型中的作用。它还将首次公布在CCI后急性和亚急性期应用胆碱能PAM后认知和运动恢复方面的性别差异数据。这项翻译研究与国家医疗康复研究中心(NCMRR)2006年的报告一致，该报告强调了临床前研究的必要性，以促进神经康复。这些结果将为理解M1受体PAM在脑外伤后功能恢复中的作用奠定必要的基础。

 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.