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

描述(由申请人提供)： 冲击波相关的创伤性脑损伤(TBI)一直是伊拉克和伊拉克战争中造成伤害的主要原因 阿富汗。轻度创伤性脑损伤的一个显著特征是与创伤后应激障碍(PTSD)显著相关。然而，由于症状重叠，很难区分这两种疾病。我们中心的合作者描述了一种mTBI的大鼠模型，在该模型中，成年雄性大鼠在全身麻醉下暴露于重复冲击伤。冲击波暴露诱导了一系列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BCI632/MGS0039在体外和体内具有降低�42的作用以及在体内具有促进认知的作用。根据这些结果，我们预测 II组mGluR抑制剂BCI632/MGS0039(或优化的前体药物BCI838/MGS0210)将抑制��的积聚。为了准备转移到大鼠模型，我们研究了一个转基因小鼠模型，在该模型中，我们不仅展示了强大的脑A�还原活性，而且表现出令人惊讶的强大的抗焦虑活性(通过张开手臂的时间来衡量，下方的左面板)，促进认知的活动(探索新对象的时间，下方的中央面板)，以及促进神经发生的活动(Ki67阳性细胞，下方的右面板)。我们现在建议进入冲击波暴露的大鼠模型，在那里我们将测试该药物通过其前认知、抗焦虑和海马前神经发生活性来缓解冲击波暴露大鼠焦虑表型的能力。1.利用原代培养神经元的方法，评价临床上有应用前景的II型mGluR抑制剂(BCI-632/MGS0039)对APP/��代谢的影响，以确定该药在完整神经元中的作用机制；目的：评价优化的BCI-838/MGS0210前药代谢成活性药物BCI-632/MGS0039的体内效应。行为简介将包括标准的Kawa abayashi等人的�方案，包括A�寡聚体和免疫沉淀-质谱仪，用于慢性治疗后的免疫沉淀-质谱仪，结构病理学的形态计量学，以及用于海马神经发生的BrdU和抗双重皮质素分析。非转基因Long-Evans大鼠将在暴露于冲击性脑损伤之前或之后，采用预防和治疗药物方案进行研究。具体目标2b。将进行试点实验，以评估可行性 在这个与冲击性脑损伤/创伤后应激障碍相关的模型中，将小鼠作为实验动物。将使用野生型和3xTg小鼠，为未来的项目做准备，在这些项目中，基因操纵的小鼠将暴露在脑损伤中。

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.