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

基本信息

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
项目类别：
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

项目摘要

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)，该药物可阻断导致创伤性脑损伤 (TBI) 的两个主要病理生理途径。 R-503 既是 1) 核 DNA 修复酶聚（ADP-核糖）聚合酶（“PARP”）的有效抑制剂（IC50=20 nM），又是 2) 基于二氢硫辛酸（“DHL”）的氧化还原催化剂，是一种超氧化物歧化酶模拟物、一种过氧化氢酶模拟物和一种过氧亚硝酸盐分解催化剂。上述两个功能部分的共价连接形成单一治疗剂预计会同时和共定位地中断 TBI 损伤的氧化剂和 PARP 途径。这两种途径与 TBI 发病机制的相关性已在 TBI 实验模型和临床环境中得到充分证实。目前已在 TBI 患者中证实 PARP 过度激活，会消耗其底物 (NAD+)，从而耗尽 ATP 储备并引发能量衰竭、细胞稳态丧失、神经元坏死和脑梗塞。 PARP 激活与 TBI 的相关性不仅在于脑损伤的发生，而且在恢复阶段也很重要：最近的数据表明，PARP 激活通过刺激小胶质细胞及其上调来阻断对 TBI（神经发生）的恢复反应NF-:B 介导的转录，在炎症细胞因子、趋化因子、粘附分子和炎症介质（包括基质金属蛋白酶）的表达中发挥核心作用。尽管 PARP 激活对于 TBI 的起始和恢复阶段具有明显的中心作用，但显然存在其他不依赖于 PARP 的氧化还原介导损伤的下游效应器。因此，单独的 PARP 抑制所提供的临床益处水平可能不够强大。因此，我们假设从 TBI 中更全面的恢复需要：1）消除上游氧化和亚硝化氧化还原应激，2）抑制下游 PARP 活性。我们将在 TBI 实验模型中寻求证实这一假设，在该模型中，大鼠遭受明确的皮质挫伤创伤，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）的治疗）、DHL 和 INO-1001 的组合以及假损伤组。将采用复苏模式，即在皮质挫伤后 2 小时引入治疗剂并持续 2 周。神经行为监测将包括第 14 天的运动任务评估（平衡木平衡、平衡木行走、莫里斯水迷宫），以及死后脑组织分析，以获取氧化还原和炎症损伤的形态和生化证据，如组织学评分、脂质过氧化、蛋白质亚硝化、PARP 激活、细胞凋亡以及 TNF-1、MIP-11、核 NF- 的浓度：。确认 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，将为继续开发 R-503 作为 TBI 紧急复苏和恢复的一流药物提供理由。公共卫生相关性：细胞损伤反应的诱导对于严重头部创伤后的最终神经学结果有重要贡献。目前，还没有批准的治疗措施可以阻止皮质挫伤后引发的炎症和细胞死亡程序。我们正在开发一种针对这种情况的基本机制的新药，并将在临床相关的动物模型中测试该药物。