Efficacy and safety of a new hexadentate iron chelator therapy for TBI-induced chronic disabilities in a rodent model

新型六齿铁螯合剂治疗啮齿动物模型中 TBI 引起的慢性残疾的功效和安全性

• 批准号: 10268189
• 负责人: PRODIP K. BOSE
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-10-01 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10268189
• 关键词: 3-nitrotyrosine; Acceleration; Address; Affect; Afghanistan; Aftercare; Amygdaloid structure; Animals; Anti-Inflammatory Agents; Anxiety; Anxiety Disorders; Apoptosis; Area; Behavior; Biological Assay; Blood - brain barrier anatomy; Blood Vessels; Brain; Brain Stem; Brain-Derived Neurotrophic Factor; Caring; Cell Death; Cell Nucleus; Characteristics; Chelating Agents; Chronic; Chronic Disease; Clinical Treatment; Cognition Disorders; Cognitive; Data; Deceleration; Deferoxamine; Degenerative Disorder; Deposition; Diffuse; Diffuse Axonal Injury; Disease; Dose; Endothelium; Equilibrium; Excision; Florida; Foundations; Functional disorder; Future; Gait; Gait abnormality; Head; Health system; Healthcare; Healthcare Systems; Hemorrhage; Hippocampus (Brain); Histologic; Histology; Human; Immunohistochemistry; Inflammation; Inflammatory; Injury; Interleukin-1; Interleukin-5; Intervention; Iraq; Iron; Legal patent; Magnetic Resonance Imaging; Measures; Mediating; Molecular; Morbidity - disease rate; Motor; NF-kappa B; Nerve Degeneration; Neurobiology; Neurodegenerative Disorders; New Agents; Oxidative Stress; Pathway interactions; Pharmaceutical Preparations; Phenotype; Population; Positioning Attribute; Preclinical Testing; Predisposition; Prevention strategy; Progressive Disease; Protocols documentation; Quality of life; Reactive Oxygen Species; Rehabilitation therapy; Reporting; Research; Risk; Risk Factors; Rodent Model; Safety; Spastic Gait; Structure of thyroid parafollicular cell; TBI treatment; TNF gene; Testing; Therapeutic; Tight Junctions; Time; Tissues; Toxic effect; Translations; Traumatic Brain Injury; Treatment Efficacy; Universities; Up-Regulation; Vascular Endothelial Growth Factors; Vestibular nucleus structure; Veterans; Work; behavior test; behavioral study; biomarker evaluation; brain tissue; catalyst; chelation; clinically relevant; cognitive disability; cognitive function; disability; disability risk; effective intervention; effective therapy; equilibration disorder; experimental study; healing; in vivo; inflammatory marker; innovation; insight; locus ceruleus structure; motor disorder; nerve injury; nerve supply; neuroinflammation; noradrenergic; preclinical evaluation; preclinical study; protective factors; quantitative imaging; rehabilitation strategy; relating to nervous system; safety testing; sensory cortex; spasticity; therapy development; treatment strategy; vascular inflammation; white matter

Traumatic brain injury (TBI) care and rehabilitation presents significant current and future challenges to the Veterans Health System (VHS). In addition to specific disabilities, there is a growing concern that TBI may significantly elevate risk factors for long-term chronic inflammation-induced progressive disease. Currently, effective therapies to address both of these issues are hampered by the lack of a sufficient neurobiological foundation to guide refinement of therapy for disability, and prevention strategies for chronic disease. Acceleration/deceleration TBI causes micro-vessel shear injury, blood brain barrier (BBB) dysfunction, and micro-bleeding. Iron deposited by diffuse micro-bleeds fuels inflammation through reactive oxygen species (ROS), and other inflammatory pathways may further induce progressive disabilities. There is an urgent need to address both specific disabilities and risk factors for long term progressive disease, and to develop effective therapies that have excellent potential for translation. The proposed pre-clinical studies will increase our understanding of microbleed (iron)-induced inflammation and the potential therapeutic benefits provided by a new iron chelating drug to address three long-term hallmark TBI disabilities that significantly impact the quality of life. The proposal will test the preclinical evaluation of the safety and efficacy of a new hexadentate iron chelator, NaHBED, to remove microbleed-induced iron, a powerful catalyst of inflammation, and to upregulate neural and vascular trophic agents to protect and heal injured neural and vascular tissues. Accordingly, three specific aims are proposed: Specific Aim 1: To correlate TBI-induced chronic disorders with cellular/molecular changes in LC and specific neural substrates of test behaviors in three functional domains. Tests for motor, anxiety, cognitive functions, and a comprehensive safety protocol will be conducted immediately before and monthly for 3 months post-treatment to evaluate the safety and efficacy of treatment. Clinically relevant state of the art Susceptibility weighted imaging (SWI)/Quantitative Susceptibility Mapping (QSM) MRI, and histological and immunohistological experiments will be performed to chart the time course for iron removal and/or further iron deposition. Specific Aim 2: (Therapeutic efficacy). To determine the efficacy of NaHBED therapy in mitigating long-term motor, cognitive and anxiety disabilities. Chronic treatment will be initiated at 6 months post- TBI using a dose shown in preliminary work to be effective. In addition, to temporal characteristics and progress of iron elimination and/or further iron deposition following NaHBED therapy (SWI/QSM MRI), the therapeutic impact on chronic motor, anxiety, and cognitive disabilities will be assessed immediately before and monthly for 3 months following the initiation of treatment. Specific Aim 3: To determine the safety and efficacy of NaHBED in reducing iron toxicity and up-regulating of trophic factors at the cellular level in the neural regions for motor, cognitive, and anxiety behaviors, using comprehensive histological, immunohistochemical, and molecular assays. We propose that treatment will significantly decrease the magnitude of long-term motor, cognitive and anxiety disabilities and these improvements will be correlated with significant decreases in a) cell death, b) iron deposition and neurodegenerative markers for inflammation and ROS, c) normalization of BBB markers, and d) significant increases in neural and vascular protective factors in the specific neural centers that provide key neural substrates for the studied behaviors. These chronic TBI studies address specifically highlighted RR&D concerns regarding TBI-induced long-term disabilities, and long-term degenerative disease (RX-18-014). In particular, these studies will provide new insights regarding TBI-induced factors that potentially contribute to significant chronic inflammation-induced TBI disabilities. Since these risk factors are prevalent in both impact acceleration (vehicular) TBI as well as blast TBI, they affect the predominant VHS TBI population. If our proposed treatment is determined to be safe and effective in the chronic TBI setting, it is well positioned for immediate translation to clinical treatment and rehabilitation since it obtained an IND approval for other disorder.

创伤性脑损伤（TBI）护理和康复提出了重大的当前和未来挑战 退伍军人卫生系统（VHS）。除了特定的残疾外，越来越担心TBI可能 长期慢性炎症引起的进行性疾病的危险因素显着提升。现在， 缺乏足够的神经生物学，可以阻碍解决这两个问题的有效疗法 基金会指导治疗治疗的残疾和预防慢性疾病的策略。 加速/减速TBI会导致微Vessel剪切损伤，血脑屏障（BBB）功能障碍，并且 微量流血。通过反应性氧气沉积的铁燃烧炎症 （ROS）和其他炎症途径可能会进一步引起进行性残疾。迫切需要 解决长期进行性疾病的特定残疾和危险因素，并发展有效 具有巨大翻译潜力的疗法。拟议的临床前研究将增加我们的 了解微粒（铁）引起的炎症以及A提供的潜在治疗益处 新的铁螯合药物可解决三种长期标志性TBI残疾，从而对质量产生重大影响 生活。该提案将测试对新六核铁的安全性和功效的临床前评估 螯合剂，无效，以去除微粒引起的铁，强大的炎症催化剂，并上调 神经和血管营养剂，以保护和治愈受伤的神经和血管组织。因此，三个 提出了具体目的：具体目的1：将TBI诱导的慢性疾病与细胞/分子相关联 在三个功能域中测试行为的LC和特定神经底物的变化。电机测试， 焦虑，认知功能和全面的安全协议将在和 治疗后3个月每月一次，以评估治疗的安全性和功效。临床相关状态 ART易感性加权成像（SWI）/定量敏感性映射（QSM）MRI和组织学 并将进行免疫组织学实验，以绘制去除铁和/或进一步的时间过程 铁沉积。特定目标2 ：（治疗功效）。确定纳维疗法在 缓解长期运动，认知和焦虑障碍。慢性治疗将在6个月后开始 TBI使用初步工作中显示的剂量有效。此外，时间特征和进步 Nahbed治疗后的消除铁消除和/或进一步的铁沉积（SWI/QSM MRI），治疗性 对慢性运动，焦虑和认知障碍的影响将立即评估 开始治疗后3个月。特定目的3：确定不纳布的安全性和功效 在降低铁毒性和在神经区域的细胞水平上的营养因子上调时， 认知和焦虑行为，使用全面的组织学，免疫组织化学和分子 测定。我们建议治疗将显着降低长期运动，认知和 焦虑障碍和这些改善将与a）细胞死亡的显着降低相关，b）铁 炎症和ROS的沉积和神经退行性标记，c）BBB标记的归一化，D） 特定神经中心中神经和血管保护因子的显着增加，这些因素提供了关键 研究行为的神经底物。这些慢性TBI研究特别突出了RR＆D 对TBI引起的长期残疾和长期退行性疾病的担忧（RX-18-014）。在 特别是，这些研究将提供有关TBI引起的因素的新见解，这些因素可能有助于 大量慢性炎症引起的TBI残疾。由于这些危险因素在两种影响方面都普遍存在 加速度（车辆）TBI以及BLAST TBI，它们会影响VHS TBI的主要人群。如果我们提议 确定治疗在慢性TBI环境中是安全有效的，它可以很好地立即 转化为临床治疗和康复，因为它获得了其他疾病的IND批准。