PARP inhibitor and Redox Catalyst Conjugate for Traumatic Brain Injury

PARP 抑制剂和氧化还原催化剂缀合物治疗创伤性脑损伤

• 批准号: 8249310
• 负责人: Kanneganti Murthy
• 金额: $ 25.66万
• 依托单位: RADIKAL THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-01-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8249310
• 关键词: Acute; Address; Animal Model; Apoptosis; Binding; Biochemical; Biological; Biological Models; Blinded; Blood; Brain; Brain Infarction; Brain Injuries; Breathing; Caring; Cell Adhesion Molecules; Cell Nucleus; Cerebrum; Chemicals; Clinic; Clinical; Cortical Contusions; Craniocerebral Trauma; DNA Damage; DNA Repair Enzymes; Data; Development; Dose; Drug Delivery Systems; Electron Transport; Equilibrium; Excision; Exhibits; Experimental Models; Failure; Functional disorder; Gene Activation; Generations; Genetic; Genetic Transcription; Histologic; Histology; Homeostasis; Hydrogen Peroxide; In Vitro; Induction of Apoptosis; Infiltration; Inflammation; Inflammation Mediators; Inflammatory; Inhibitory Concentration 50; Injury; Interruption; Investigation; Lipid Peroxidation; Macrophage Inflammatory Protein-1; Measures; Mediating; Medical; Medicine; Metalloproteases; Microglia; Mitochondria; Modeling; Monitor; Motor; Multiple Organ Failure; Mus; Necrosis; Nervous System Physiology; Neurologic; Neurologic Dysfunctions; Neurological outcome; Neurons; Nitrosation; Nuclear; Nuclear Envelope; Oxidants; Oxidation-Reduction; PARP inhibition; Pathogenesis; Pathway interactions; Peroxonitrite; Pharmaceutical Preparations; Pharmacodynamics; Phase; Placebo Control; Plasma; Play; Poly Adenosine Diphosphate Ribose; Poly(ADP-ribose) Polymerases; Property; Protein Isoforms; Proteins; Randomized; Rattus; Recovery; Relative (related person); Reporting; Resuscitation; Rodent; Rodent Model; Role; Schedule; Serum; Severities; Stress; Sulfhydryl Compounds; Superoxide Dismutase; TBI Patients; TNF gene; Testing; Therapeutic; Therapeutic Agents; Tissues; Trauma; Traumatic Brain Injury; Up-Regulation; Walking; Zymosan; apoptosis inducing factor; base; brain tissue; catalase; catalyst; cell injury; chemokine; clinically relevant; college; cytokine; dihydrolipoate; in vivo Model; inhibitor/antagonist; innovation; instrument; lung injury; mimetics; morris water maze; neurobehavioral; neurogenesis; neurological recovery; neuroprotection; neutrophil; novel; novel therapeutics; professor; prospective; receptor; response; response to injury; transcription factor

DESCRIPTION (provided by applicant): Radikal Therapeutics (RTX) is developing a novel bifunctional agent (R-503) that blocks two principal pathophysiolgoical pathways that contribute to traumatic brain injury (TBI). R-503 is both 1) a potent inhibitor of the nuclear DNA repair enzyme poly(ADP-ribose) polymeras ("PARP") (IC50=20 nM), and 2) a dihydrolipoate ("DHL")-based redox catalyst that is a superoxide dismutase mimetic, a catalase mimetic, and a peroxynitrite decomposition catalyst. The covalent linkage of both of the above functional moieties to form a single therapeutic agent is expected to create simultaneous and co-localized interruption of both the oxidant and PARP pathways of injury in TBI. The relevance of both pathways to the pathogenesis of TBI has been well established in experimental models of TBI and in the clinical setting. Overactivation of PARP, now confirmed in patients with TBI, consumes its substrate (NAD+), thereby depleting ATP stores and provoking energetic failure, loss of cellular homeostasis, neuronal necrosis, and brain infarction. The relevance of PARP activation to TBI is not merely in the initiation of brain injury, but also figures prominently in the recovery phase: Recent data indicate that PARP activation blocks the restorative response to TBI (neurogenesis) via its stimulation of microglial cells and its upregulation of NF-:B mediated transcription, which plays a central role in the expression of inflammatory cytokines, chemokines, adhesion molecules and inflammatory mediators, including matrix metalloproteases. Despite the apparent centrality of PARP activation to the initiation and recovery phases of TBI, there are clearly additional PARP-independent downstream effectors of redox-mediated injury. Accordingly, the level of clinical benefit afforded by stand-alone PARP inhibition is not likely to be sufficiently robust. Accordingly, we hypothesize that more comprehensive recovery from TBI wil require both: 1) the elimination of upstream oxidative and nitrosative redox stress, and 2) inhibition of downstream PARP activity. We will seek to confirm this hypothesis in an experimental model of TBI in which rats are subjected to a well- defined cortical contusion trauma, by comparing treatment with R-503, DHL (a redox catalyst), INO-1001 (a monofunctional PARP inhibitor), a combination of DHL and INO-1001, and a sham injury group. A resuscitation paradigm will be employed, whereby therapeutic agents will be introduced 2 h after cortical contusion and continued for 2 weeks. Neurobehavioral monitoring will include assessment of motor tasks (beam balance, beam walking, Morris water maze) on day 14, and post-mortem analysis of brain tissue for morphologic and biochemical evidence of redox and inflammatory injury, as manifested by histology score, levels of lipid peroxidation, protein nitrosation, PARP activation, apoptosis, and concentrations of TNF-1, MIP- 11, nuclear NF-: . Confirmation that RTX's bifunctional approach confers unique therapeutic superiority over a monofunctional PARP inhibitor and redox catalyst, and their combination, would provide justification for the continued development of R-503 as a first-in-class agent for emergent resuscitation and recovery of TBI. PUBLIC HEALTH RELEVANCE: The induction of cellular injury responses contributes importantly to the ultimate neurological outcome after severe head trauma. At present, there are no approved therapeutic measures that arrest inflammation and cell death programs that are triggered after cortical contusion. We are developing a novel drug that targets the basic mechanisms of this condition and will test this agent in a clinically-relevant animal model.

描述（由申请人提供）：Radikal Therapeutics（RTX）正在开发一种新型双功能药物（R-503），可阻断导致创伤性脑损伤（TBI）的两种主要病理生理通路。R-503是1）核DNA修复酶聚（ADP-核糖）聚合酶（“PARP”）的有效抑制剂（IC 50 =20 nM），和2）基于二氢硫辛酸（“DHL”）的氧化还原催化剂，其是超氧化物歧化酶模拟物、过氧化氢酶模拟物和过氧亚硝酸盐分解催化剂。上述两个功能部分形成单一治疗剂的共价连接预期产生TBI中损伤的氧化剂和PARP途径的同时和共定位中断。这两种途径与TBI发病机制的相关性已经在TBI的实验模型和临床环境中得到了很好的建立。PARP的过度激活，现在在TBI患者中得到证实，消耗其底物（NAD+），从而耗尽ATP储存并引起能量衰竭、细胞稳态丧失、神经元坏死和脑梗死。PARP激活与TBI的相关性不仅在于脑损伤的起始，而且在恢复阶段也是显著的：最近的数据表明，PARP激活通过刺激小胶质细胞和上调NF-：B介导的转录阻断对TBI的恢复性应答（神经发生），NF-：B介导的转录在炎性细胞因子、趋化因子、粘附分子和炎性介质（包括基质金属蛋白酶）的表达中起核心作用。尽管PARP激活对TBI的起始和恢复阶段具有明显的中心性，但显然存在氧化还原介导的损伤的额外PARP独立下游效应物。因此，单独PARP抑制提供的临床获益水平不太可能足够稳健。因此，我们假设从TBI更全面的恢复将需要：1）消除上游氧化和亚硝化氧化还原应激，和2）抑制下游PARP活性。我们将通过比较R-503、DHL（一种氧化还原催化剂）、INO-1001（一种单功能PARP抑制剂）、DHL和INO-1001的组合以及假损伤组，在大鼠遭受明确的皮质挫伤创伤的TBI实验模型中寻求证实这一假设.将采用复苏范例，其中治疗剂将在皮质挫伤后2小时引入并持续2周。神经行为监测将包括第14天的运动任务（平衡木、平衡木行走、Morris水迷宫）评估，以及脑组织的尸检分析，以获得氧化还原和炎症损伤的形态学和生化证据，如组织学评分、脂质过氧化水平、蛋白质亚硝化、PARP活化、细胞凋亡和TNF-1、MIP- 11、核NF-κ B的浓度所示。RTX的双功能方法相对于单功能PARP抑制剂和氧化还原催化剂及其组合具有独特的治疗优势，这一确认将为R-503作为TBI紧急复苏和恢复的一流药物的持续开发提供理由。 公共卫生相关性：细胞损伤反应的诱导对严重头部创伤后的最终神经结局有重要贡献。目前，还没有批准的治疗措施来阻止皮质挫伤后触发的炎症和细胞死亡程序。我们正在开发一种针对这种疾病基本机制的新药，并将在临床相关的动物模型中测试这种药物。