Novel Prophylactic Pharmacotherapy in an Animal Model of Closed Head Injury

闭合性头部损伤动物模型中的新型预防性药物治疗

• 批准号: 8392095
• 负责人: Shawn Acheson
• 金额: --
• 依托单位: DURHAM VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-10-01 至 2016-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8392095
• 关键词: Adhesions; Afghanistan; Allopregnanolone; Animal Model; Animals; Apoptosis; Apoptotic; Applications Grants; Attention; BCL-2 Protein; Behavioral; Bilateral; Biological Assay; Cell Count; Clinical Trials; Closed head injuries; Collaborations; Combined Modality Therapy; Complex; Development; Enzyme-Linked Immunosorbent Assay; Exposure to; Functional disorder; Future; General Anesthesia; Goals; Hippocampus (Brain); Impairment; Individual; Inflammatory; Injury; Interleukin-6; Intubation; Iraq; Ischemia; Ischemic Stroke; Learning; Measures; Mechanical ventilation; Medicine; Memory; Methodology; Military Personnel; Modeling; Morbidity - disease rate; Nature; Nerve Degeneration; Niacinamide; Operative Surgical Procedures; Outcome; Pathology; Patients; Pharmacotherapy; Physiological; Population; Process; Progesterone; Prophylactic treatment; Proteomics; Recovery; Recovery of Function; Relative (related person); Research Design; Rodent Model; Safety; Scientist; Staining method; Stains; Surgical incisions; Tactile; Techniques; Testing; Therapeutic Studies; Trauma; Traumatic Brain Injury; Tumor Necrosis Factor-alpha; Work; base; brain tissue; caspase-3; cytochrome c; cytokine; design; dietary supplements; disability; economic cost; experience; fluoro jade; follow-up; functional disability; high risk; human TNF protein; improved; knowledge base; morris water maze; mortality; neuroinflammation; neuron loss; neurosteroids; neurotoxic; novel; pre-clinical; pre-clinical research; prevent; prophylactic; research study; response; skills; somatosensory; tissue preparation

DESCRIPTION (provided by applicant): Although much progress has been made in the development of body armor and military trauma medicine, there have been only two successful clinical trials in the last 40 years to find safe and effective pharmacotherapies to treat or prevent the complex pathophysiology associated with TBI. Prophylactic therapies represent a powerful pharmacological approach to deal with TBI pathology that has not yet received widespread attention. This approach could be uniquely valuable in high-risk populations such as our current military personnel. To be effective in a military field setting, prophylactic compounds must have excellent safety profiles; they must be well tolerated; and easily administered. Given these constraints, dietary supplements such as nicotinamide (NAM) and neuroactive steroids like allopregnanolone (ALLOP) would be ideal candidates. We have chosen to investigate these compounds based on their multifunctional nature, demonstrated efficacy in pre-clinical research, as well as their relative safety and availability. NAM and ALLOP have both been shown to ameliorate numerous TBI-related pathophysiological processes and improve recovery of behavioral function when administered post-injury. Although they have not been expressly tested as prophylactic agents in TBI, there is evidence that pre-injury administration of NAM or neurosteroids (e.g., progesterone) has beneficial effects on recovery of function following experimentally induced ischemia. Given the significant overlap in pathophysiology of ischemic stroke and TBI, there is reason to hypothesize that pretreatment with NAM, ALLOP or NAM+ALLOP will ameliorate the effects of TBI in a rodent model of closed head injury. The primary objective of this project is to investigate the prophylactic effects of allopregnanolone (ALLOP) and nicotinamide (NAM) in a combination therapy study using a pre-clinical animal model of TBI. These studies are designed to evaluate the prophylactic effects of NAM, ALLOP, and NAM+ALLOP on functional recovery (Aim1), physiological impairment such as neurodegeneration (Aim 2) and pathophysiological mechanisms of secondary injury including neuroinflammatory cytokines, and markers of apoptosis (Aim 2).

描述（由申请人提供）： 尽管防弹衣和军事创伤医学的发展取得了很大进展，但在过去 40 年中，只有两次成功的临床试验找到了安全有效的药物疗法来治疗或预防与 TBI 相关的复杂病理生理学。预防性治疗代表了一种治疗 TBI 病理学的强大药理学方法，但尚未受到广泛关注。这种方法对于高危人群（例如我们目前的军事人员）可能具有独特的价值。为了在军事领域发挥作用，预防性化合物必须具有出色的安全性。它们必须具有良好的耐受性；并且易于管理。考虑到这些限制，烟酰胺 (NAM) 等膳食补充剂和四氢孕酮 (ALLOP) 等神经活性类固醇将是理想的选择。我们选择研究这些化合物是基于它们的多功能性质、临床前研究中证明的功效以及它们的相对安全性和可用性。 NAM 和 ALLOP 均已被证明可以改善许多与 TBI 相关的病理生理过程，并在受伤后使用时改善行为功能的恢复。尽管尚未明确将它们作为 TBI 的预防药物进行测试，但有证据表明，受伤前给予 NAM 或神经类固醇（例如黄体酮）对实验诱发的缺血后功能恢复具有有益作用。鉴于缺血性中风和 TBI 的病理生理学显着重叠，有理由假设 NAM、ALLOP 或 NAM+ALLOP 预处理将改善 TBI 对闭合性头部损伤啮齿动物模型的影响。该项目的主要目标是使用 TBI 临床前动物模型进行联合治疗研究，研究别孕酮 (ALLOP) 和烟酰胺 (NAM) 的预防作用。这些研究旨在评估 NAM、ALLOP 和 NAM+ALLOP 对功能恢复 (Aim1)、神经变性等生理损伤 (Aim 2) 以及继发性损伤的病理生理机制（包括神经炎症细胞因子和细胞凋亡标记物）的预防作用（Aim 2）。