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: 8143078
• 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/8143078
• 关键词: Adhesions; Afghanistan; Allopregnanolone; Animal Model; Animals; Apoptosis; Apoptotic; Applications Grants; Attention; 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; Proteins; 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）： 尽管在身体装甲和军事创伤医学的发展方面取得了很多进展，但在过去40年中，只有两项成功的临床试验可以找到安全有效的药物治疗，以治疗或预防与TBI相关的复杂病理生理学。预防性疗法代表了一种强大的药理方法，用于处理尚未受到广泛关注的TBI病理学。这种方法在我们目前的军事人员等高风险人群中可能具有独特的价值。为了在军事领域有效，预防性化合物必须具有出色的安全性。他们必须容忍良好；并容易管理。鉴于这些限制，饮食补充剂，例如烟酰胺（NAM）和神经活性类固醇（如Alloprepregnanolone（Allop））将是理想的候选者。我们选择根据它们的多功能性质研究这些化合物，证明了临床前研究的功效，以及它们的相对安全性和可用性。 NAM和ALLOP都已证明可以改善许多与TBI相关的病理生理过程，并改善受伤后给药时行为功能的恢复。尽管尚未在TBI中明确测试过预防剂，但有证据表明，在实验诱导的缺血后，对NAM或神经类固醇的伤害前给药对功能的恢复具有有益的作用。鉴于缺血性中风和TBI的病理生理学显着重叠，有理由假设使用NAM，Allop或Nam+Allop进行预处理会改善TBI在封闭的头部损伤模型中的影响。该项目的主要目的是使用TBI的临床前动物模型研究Allopregnanolone（Allop）和烟酰胺（NAM）的预防作用。这些研究旨在评估NAM，ALLOP和NAM+ALLOP对功能恢复的预防作用（AIM1），生理障碍，例如神经退行性（AIM 2）（AIM 2）以及包括神经毒素性细胞因子的继发性损伤的病理生理机制，以及凋亡的标志（AIM 2）。