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

描述（由申请人提供）： 爆炸相关的创伤性脑损伤（TBI）是伊拉克战争中受伤的主要原因， 阿富汗轻度TBI病例的一个显著特征是与创伤后应激障碍（PTSD）的显著关联。然而，由于两种疾病之间的重叠症状的区别一直很困难。我们中心的合作者描述了mTBI大鼠模型的特征，其中成年雄性大鼠在全身麻醉下暴露于重复性冲击伤。爆炸暴露诱发了多种PTSD相关的行为特征。 在初步研究中，我们已经证明了BCI-632/MGS 0039在体外和体内具有降低A42的作用，以及体内的促认知作用。根据这些结果，我们预测 第二组mGluR抑制剂BCI-632/MGS 0039（或优化的前药BCI-838/MGS 0210）将减弱蓄积。在准备转移到大鼠模型中，我们研究了转基因小鼠模型，其中我们不仅证明了稳健的脑A1-减少活性，而且还证明了令人惊讶的稳健的抗焦虑活性（如通过开放臂中的时间测量的，下左图）、促认知活性（时间探索新对象，下中图）和促神经发生活性（Ki 67阳性细胞，下右图）。我们现在建议进入冲击波暴露大鼠模型，在该模型中，我们将测试药物通过其促认知、抗焦虑和海马促神经原活性减轻冲击波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价具有临床前景的II组mGluR抑制剂（BCI-632/MGS 0039）对APP/β代谢的体外影响，以确定药物在完整神经元中的作用机制;具体目的2a。评价优化的BCI- 838/MGS 0210前体药物在啮齿类动物爆炸相关mTBI/PTSD模型中的体内作用，该前体药物代谢为活性药物BCI-632/MGS 0039（一种II组mGluR抑制剂）。行为特征将包括标准Kawarabayashi等人的A？方案，包括A？寡聚体和免疫沉淀-质谱法，慢性治疗后，结构病理学的形态测定，以及海马神经发生的BrdU和抗双皮质素分析。在大鼠暴露于冲击波TBI之前或之后，将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。将进行中试实验以评估可行性 在这个与爆炸相关的mTBI/PTSD模型中，将使用野生型和3xTg小鼠，为将来的项目做准备，其中遗传操作的小鼠将暴露于TBI。

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.