Rehab Therapy Adjunct with a Neurogenic, Mnemoactive, A-Beta-Lowering Compound

含有神经源性、记忆活性、A-β 降低化合物的康复治疗辅助剂

• 批准号: 8596270
• 负责人: SAMUEL E. GANDY
• 金额: --
• 依托单位: JAMES J PETERS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-01 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8596270
• 关键词: Adult; Afghanistan; Animal Testing; Anti-Anxiety Agents; Anxiety; Attenuated; Behavioral; Blast Cell; Blast Injuries; Brain; Bromodeoxyuridine; Cells; Chronic; Cognition; Cognitive; Disease; Drug effect disorder; Employee Strikes; Future; General Anesthesia; Hippocampus (Brain); Immunoprecipitation; In Vitro; Injury; Iraq; Left; Long-Evans Rats; Mass Spectrum Analysis; Measures; Metabolism; Modeling; Moods; Mus; Neurons; Pathology; Pharmaceutical Preparations; Phenotype; Post-Traumatic Stress Disorders; Preparation; Prodrugs; Prophylactic treatment; Protocols documentation; Rattus; Rodent Model; Study models; Symptoms; Testing; Time; Transgenic Mice; Traumatic Brain Injury; War; arm; base; in vivo; inhibitor/antagonist; male; morphometry; mouse model; neurogenesis; novel; public health relevance; research study; trait

DESCRIPTION (provided by applicant): Blast related traumatic brain injury (TBI) has been a major cause of injury in the wars in Iraq and Afghanistan. A striking feature of the mild TBI cases has been the prominent association with post- traumatic stress disorder (PTSD). However, due to the overlapping symptoms distinction between the two disorders has been difficult. Collaborators at our center have characterized a rat model of mTBI in which adult male rats were exposed to repetitive blast injury while under general anesthesia. Blast exposure induced a variety of PTSD-related behavioral traits. In preliminary studies, we have demonstrated that BCI-632/MGS0039 has A¿42-lowering effects in vitro and in vivo as well as pro-cognitive effects in vivo. Based on these results, we predicted that the group II mGluR inhibitor BCI-632/MGS0039 (or the optimized pro-drug, BCI-838/MGS0210) would attenuate ¿¿ accumulation. In preparation for moving to the rat model, we studied a transgenic mouse model in which we demonstrated not only robust brain A¿-reduction activity, but surprisingly robust anxiolytic activity (as measured by Time in Open Arm, left panel below), pro-cognitive activity (Time Exploring Novel Object, center panel below), and pro-neurogenesis activity (Ki67-positive cells, right panel below). We now propose to move into the blast exposed rat model where we will test the ability of the drug to mitigate the anxiety phenotype in our blast exposed rats through its pro-cognitive, anxiolytic, and hippocampal pro-neurogenic activities. We propose the following specific aims: Specific Aim 1. To evaluate effects of a clinically promising group II mGluR inhibitor (BCI-632/MGS0039) on APP/¿¿ metabolism in vitro using primary neuronal culture in order to establish the mechanism of action of the drug in intact neurons; Specific Aim 2a. To evaluate the in vivo effects in a rodent model of blast-related mTBI/PTSD of the optimized BCI- 838/MGS0210 pro-drug that is metabolized to the active drug BCI-632/MGS0039, a group II mGluR inhibitor. The behavioral profile will include standard Kawarabayashi et al A¿ protocol, including A¿ oligomers and immunoprecipitation-mass spectrometry, following chronic treatment, morphometry of structural pathology, and BrdU and anti-doublecortin analysis for hippocampal neurogenesis. Nontransgenic Long-Evans rats will be studied employing prophylactic and treatment drug protocols before or after exposure of rats to blast TBI. Specific Aim 2b. Pilot experiments will be performed to evaluate the feasibility of mice as test animals in this model of blast-related mTBI/PTSD. Wildtype and 3xTg mice will be used, in preparation for future projects in which genetically manipulated mice will be exposed to TBI.

描述（由申请人提供）： 与爆炸相关的脑损伤（TBI）一直是伊拉克战争中受伤的主要原因 阿富汗。轻度TBI病例的一个惊人特征是与创伤后应激障碍（PTSD）的显着关联。但是，由于这两种疾病之间的重叠症状疾病一直很困难。我们中心的合作者表征了MTBI的大鼠模型，其中成年雄性大鼠在全身麻醉下暴露于重复性爆炸损伤。爆炸暴露引起了各种与PTSD相关的行为特征。在初步研究中，我们已经证明BCI-632/MGS0039在体外和体内具有42个降低效应，以及体内的促值效应。基于这些结果，我们预测了 II组MGLUR抑制剂BCI-632/MGS0039（或优化的Pro-Drug，BCI-838/MGS0210）会衰减。 In preparation for moving to the rat model, we studied a transgenic mouse model in which we demonstrated not only robust brain A¿ -reduction activity, but surprisingly robust anxiolytic activity (as measured by Time in Open Arm, left panel below), pro-cognitive activity (Time Exploring Novel Object, center panel below), and pro-neurogenesis activity (Ki67-positive cells, right panel below).现在，我们建议进入爆炸暴露的大鼠模型，在那里我们将通过其促进，抗焦虑性和海马促促促性神经生成活性来测试药物在爆炸暴露大鼠中减轻焦虑表型的能力。我们提出以下具体目的：特定目的1。评估临床上有希望的II组MGLUR抑制剂（BCI-632/MGS0039）对APP/»»体外神经元培养的代谢，以建立完整神经元药物的作用机制；特定目标2a。为了评估优化BCI-838/MGS0210 Pro-Drug的啮齿动物相关MTBI/PTSD的体内效应，该模型已代谢为活性药物BCI-632/MGS0039，这是II组MGLUR抑制剂。行为曲线将包括标准的Kawarabayashi等人的方案，包括慢性治疗，结构病理学的形态学以及BRDU和抗双生素分析以进行海马神经发生后，包括A检测和免疫沉淀 - 质谱法。在暴露于大鼠爆炸TBI之前或之后，非转基因长evans大鼠将使用预防性和治疗药物方案进行研究。特定目标2B。将进行试验实验以评估可行性 在这种与爆炸相关的MTBI/PTSD模型中，小鼠作为测试动物。将使用WildType和3XTG小鼠，为将来的项目做准备，其中一般操纵的小鼠将暴露于TBI。