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: 8825927
• 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/8825927
• 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; Health; 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; mild traumatic brain injury; morphometry; mouse model; neurogenesis; novel; 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）： 爆炸相关的创伤性脑损伤（TBI）一直是伊拉克战争和战争中受伤的主要原因。 阿富汗。轻度 TBI 病例的一个显着特征是与创伤后应激障碍 (PTSD) 显着相关。然而，由于症状重叠，区分这两种疾病一直很困难。我们中心的合作者已经建立了 mTBI 大鼠模型，其中成年雄性大鼠在全身麻醉下遭受重复性爆炸损伤。爆炸暴露诱发了多种与创伤后应激障碍相关的行为特征。 在初步研究中，我们已经证明 BCI-632/MGS0039 在体外和体内具有降低 A¿42 的作用以及在体内的促认知作用。根据这些结果，我们预测 II 类 mGluR 抑制剂 BCI-632/MGS0039（或优化的前药 BCI-838/MGS0210）会减弱“积累”。为了准备转移到大鼠模型，我们研究了一种转基因小鼠模型，在该模型中，我们不仅表现出强大的脑Aβ还原活性，而且表现出令人惊讶的强大抗焦虑活性（通过张开手臂的时间测量，下左图）、促认知活性（时间探索新物体，下中图）和促神经发生活性（Ki67阳性细胞，下右图）。我们现在建议进入爆炸暴露大鼠模型，在该模型中我们将测试该药物通过其促认知、抗焦虑和海马促神经原活性减轻爆炸暴露大鼠焦虑表型的能力。 我们提出以下具体目标： 具体目标 1. 使用原代神经元培养物评估临床上有前景的 II 族 mGluR 抑制剂 (BCI-632/MGS0039) 对 APP/¿ 代谢的影响，以建立药物在完整神经元中的作用机制；具体目标 2a。评估优化的 BCI-838/MGS0210 前药在与急变相关的 mTBI/PTSD 啮齿动物模型中的体内作用，该前药代谢为活性药物 BCI-632/MGS0039（一种 II 组 mGluR 抑制剂）。行为概况将包括标准 Kawarabayashi 等人的 A¿ 方案，包括 A¿ 寡聚物和免疫沉淀质谱法、长期治疗后、结构病理学的形态测量、以及海马神经发生的 BrdU 和抗双皮质素分析。将在大鼠暴露于爆炸性 TBI 之前或之后采用预防和治疗药物方案对非转基因 Long-Evans 大鼠进行研究。具体目标 2b。将进行试点实验以评估可行性 小鼠作为爆炸相关 mTBI/PTSD 模型中的测试动物。将使用野生型和 3xTg 小鼠，为未来的项目做准备，其中基因操纵小鼠将暴露于 TBI。