Broadly Neuroprotective Drug for TBI

描述（由申请人提供）：本申请涉及广泛的挑战领域（15）转化科学，以及特定的挑战主题15- ns -103，因为我们的提案是神经系统疾病新治疗方法的“概念验证”的“演示”。该申请也可以适用于广泛的挑战领域（03）生物标志物的发现和验证，以及特定的挑战主题：神经生物标志物的标准化和验证，因为我们正在检查BDNF和突触可塑性标志物的水平，可以作为创伤性脑损伤的生物标志物，因为我们的建议与识别和验证敏感和预测性生物标志物有关，以评估特定营养素（姜黄素衍生物）的状态。创伤性脑损伤（TBI）每年影响超过150万美国人，使其成为普通人群中最常见的致残原因之一。创伤性脑损伤的治疗异常复杂，因为创伤性脑损伤可由多种损伤和机制引起，损害神经功能并具有长期认知影响。因此，创伤性脑损伤的适当治疗需要能够适当解决多种弱点的治疗方法，特别是那些与认知和行为障碍背后的长期神经元功能和可塑性相关的弱点。为了满足对广泛的神经保护药物的需求，我们已经确定了姜黄素的一种强效合成衍生物，即CNB-001，它可以全面正常化脑损伤后中断的几种神经元过程。天然产物姜黄素是CNB-001的前体，在多种神经退行性疾病模型中，如阿尔茨海默病、脑缺血，促进成人海马神经发生，以及在我们的手中，对抗TBI后的学习障碍，显示出优异的功能障碍。CNB-001的优势是其效力是姜黄素的几倍，口服有效，可迅速被血液和大脑吸收。CNB-001具有神经保护和神经元功能增强的特性，表明CNB-001是治疗TBI和其他神经退行性疾病的独特候选药物。为了检测我们的化合物CNB-001的疗效，我们将使用液体冲击损伤模型（FPI）治疗中度损伤下产生闭合性头部损伤，其特征是明显的生理变化和相对较少的组织学损伤。该项目的目标是探索CNB-001对TBI的治疗潜力，并确定这些作用的潜在机制。具体来说，我们将评估在饮食中添加CNB-001恢复脑外伤后突触可塑性和能量代谢紊乱的能力，并结合CNB-001对认知、情绪障碍和运动功能障碍的影响。值得注意的是，我们对CNB-001疗效的综合研究考虑了对大脑之外的运动行为的分析。我们的初步数据非常令人兴奋，证明了CNB-001抵消了脑外伤后脊髓中BDNF水平的降低。这些数据非常令人兴奋，有助于了解TBI患者常见的步态功能障碍，并为开发治疗方法提供可能性。此外，鉴于初步证据显示CNB-001可能影响BDNF活性，以及BDNF调节突触可塑性和能量代谢的能力，我们将评估BDNF介导CNB-001的部分作用。我们将研究分子机制及其与行为的关系，期望为应用CNB-001作为治疗TBI患者的药物提供证据。基于以上考虑，我们的具体挑战是：1)开发一种临床有效的治疗TBI的药物，能够保护神经元免受多种应激的损伤，并支持突触功能和细胞的能量供应；2)以微创的方式将药物输送到大脑，以达到最佳的适用性，甚至在侮辱/挑战之前。

DESCRIPTION (provided by applicant): This application addresses the broad Challenge Area (15) Translational Science, and Specific Challenging Topic 15-NS-103 as our proposal is a "Demonstration of "proof-of-concept" for a new therapeutic approach in a neurological disease. The application may also apply to the Broad Challenge Area (03) Biomarkers discovery and validation, and Specific Challenging Topics: 03-NS-102 Standardization and validation of neurological biomarkers, as we are examining levels of BDNF and synaptic plasticity markers that can be implemented as biomarkers for traumatic brain injury 03-DK-105 Nutrient biomarkers, as our proposal is related to the identification and validation of sensitive and predictive biomarkers to evaluate status of a specific nutrient (curcumin derivative). Traumatic brain injury (TBI) affects more than 1,500,000 Americans every year, making TBI one of the most common causes of disability for the general population. The treatment of TBI is exceptionally complex as TBI can result from a large variety of insults and mechanisms to broad brain areas that compromise neural function with long-term cognitive implications. Therefore, proper treatment of TBI should require therapies that can properly address the multiple weaknesses, particularly those related to long-term neuronal function and plasticity underlying the cognitive and behavioral impairment. To address the need for broadly neuroprotective drugs, we have identified a potent synthetic derivative of curcumin, namely CNB-001, that may comprehensively normalize several of the neuronal processes that are disrupted after TBI. The natural product curcumin, which is the precursor of CNB-001, has shown excellent efficacy in counteracting dysfunction in several models of neurodegenerative diseases such as Alzheimer's, cerebral ischemia, promoting neurogenesis in the adult hippocampus, and in our hands, counteracting learning impairment resulting after TBI. CNB-001 has the advantage to be several times more potent than curcumin, orally active with rapid absorption into the blood and to the brain. CNB-001 has both neuroprotective and neuronal function enhancing properties, suggesting CNB-001 as a unique candidate drug for treating TBI and other neurodegenerative disorders. To assay the efficacy of our compound CNB-001, we will use the fluid percussion injury model (FPI) for TBI that produces a closed head wound characterized by marked physiological changes with a relative paucity of histological damage under moderate injury. The goal of this project is to explore the therapeutic potential of CNB-001 for TBI and to determine potential mechanisms for these actions. Specifically, we will evaluate the ability of CNB-001 supplemented in the diet to restore synaptic plasticity and energy metabolism disrupted after TBI, in conjunction with CNB-001 effects on counteracting cognitive, mood disorders, and motor dysfunction. It is noteworthy that our comprehensive study of CNB-001 efficacy considers the analysis of motor behavior beyond the brain. Our preliminary data are very exciting to demonstrate that CNB-001 counteracts a reduction in BDNF levels in the spinal cord after TBI. These data are very exciting and relevant to help understanding gait dysfunction common in TBI patients, and offering the possibility for developing a therapy. In addition, given preliminary evidence showing the potential of CNB-001 to affect BDNF activity, and the capacity of BDNF to modulate synaptic plasticity and energy metabolism, we will evaluate the role of BDNF mediating some of the actions of CNB-001. We will study molecular mechanisms in conjunction with their relationship to behavior, expecting to provide evidence for applying CNB-001 as a therapeutic for treating TBI patients. Based on all above consideration, our specific challenges are: 1) to develop a clinically effective drug for treating TBI with the capacity to protect neurons to damage in response to multiple stresses, and to support synaptic function and energy supply to cells; 2) to deliver the drug to the brain in a minimally invasive fashion for optimal applicability even before the insult/challenge. PUBLIC HEALTH RELEVANCE: The goal of this project is to explore the therapeutic potential of a broad-spectrum drug for TBI and to determine its potential mechanisms using fluid percussion injury model in rats. We have a comprehensive approach to evaluate the ability of CNB-001 to restore synaptic plasticity and energy metabolism in conjunction with counteracting dysfunction in cognition, mood, and locomotion, in the brain and spinal cord. We expect to generate valuable pre-clinical information that will entitle us to initiate the steps for seeking IND approval.