Druggable Mitochondrial Targets for Treatment of Cerebral Ischemia

用于治疗脑缺血的可药物线粒体靶点

• 批准号: 10090670
• 负责人: Hülya Bayir
• 金额: $ 57.31万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10090670
• 关键词: Adolescence; Aerobic; Aftercare; Age; Antioxidants; Brain; Brain Injuries; Brain region; Cell Death; Cell Death Signaling Process; Cell Respiration; Cerebral Ischemia; Cerebral Ischemia-Hypoxia; Cerebrum; Child; Childhood; Clinical; Computer Models; Consumption; Critical Illness; DNA Damage; DNA Repair; Data; Development; Dose; Event; Failure; Female; Generations; Glucose; Gramicidin S; Heart Arrest; Histologic; Image; In Vitro; Infant; Injury; Intracranial Hemorrhages; Ischemia; Link; Mediating; Metabolism; Microscopy; Mitochondria; Mitochondrial DNA; Modeling; Motor; NADH; Necrosis; Nerve Degeneration; Neurological outcome; Neurons; Nuclear; Organism; Outcome; Oxygen; Pathogenesis; Pharmaceutical Preparations; Placebos; Poly Adenosine Diphosphate Ribose; Poly(ADP-ribose) Polymerases; Polymers; Quality of life; Randomized; Rattus; Reactive Oxygen Species; Regimen; Reporting; Research; Resolution; Role; Septic Shock; Shock; Source; Status Epilepticus; Stroke; Structure-Activity Relationship; Therapeutic; Time; Traumatic Brain Injury; Western Blotting; age related; apoptosis inducing factor; base; cognitive testing; deprivation; druggable target; improved; in vivo; in vivo imaging; infancy; inhibitor/antagonist; lipidomics; liquid chromatography mass spectrometry; male; metabolic rate; nanomolar; neonatal hypoxic-ischemic brain injury; neuroinflammation; neuron loss; neuroprotection; novel; preservation; prevent; release factor; severe injury; sex; survivorship; targeted treatment; tool

Quality survival after brain injury is currently the greatest challenge for critically ill or injured infants and children. A universal contributor limiting quality survivorship is the devastating impact of hypoxic-ischemic encephalopathy (HIE), either as a primary consequence in cases of cardiac arrest, stroke, or intracranial hemorrhage or as secondary sequelae in cases of status epilepticus, circulatory or septic shock, neuroinflammation, or traumatic brain injury (TBI); with the principal cause of HIE spanning from infancy through adolescence a consequence of cardiac arrest. As to-date a cure for HIE has not been discovered, a paradigm-shifting strategy is likely necessary to improve neurological outcome for victims of HIE. Accordingly, we have developed a new class of therapeutics to treat HIE via preservation of critical cellular energy stores by selectively targeting poly(ADP-ribose) polymerase (PARP) in mitochondria (mtPARP), linking the mitochondria-targeting moieties hemi-gramicidin S (XJB) or triphenylphosphonium (TPP) to PARP inhibitors used clinically. Ischemia-induced PARP overactivation triggered by DNA damage consumes NAD+, generating branch chain poly(ADP-ribose) polymers (PARylation) resulting in ATP depletion, energy failure, and cell death by necrosis and/or apoptosis-inducing factor (AIF)-mediated parthanatos. As mitochondria are the major source of ATP and NAD+ in aerobic organisms, preservation of mitochondrial energy stores represents a logical “druggable” target for mitigation of HIE. We recently reported that the mitochondria- targeting PARP1 inhibitor XJB-veliparib preserves NAD+ stores and prevents neuronal death after oxygen- glucose deprivation (OGD) in vitro at nanomolar concentrations. Importantly, XJB-veliparib selectively targets mitochondria and thereby does not impede nuclear DNA repair in vitro. We present provocative pilot data suggesting that XJB-veliparib and the readily translatable mitochondria-targeting compound TPP-veliparib may be efficacious after cardiac arrest in post-natal day (PND) 17 rats, a developmental age equivalent to a young child and a time associated with peak cerebral metabolism. This new class of therapeutics has the advantage of preventing PARP-mediated energy failure and cell death by selectively targeting mtPARP while sparing PARP1-facilitated nuclear DNA repair and provide a tool to definitively establish (or refute) a role for mtPARP in the pathogenesis of HIE. If proven effective, mtPARP1 inhibitors would represent novel, safe (in terms of nuclear DNA repair), and translatable therapies to mitigate HIE, with special potential in the highly vulnerable, developing brain where metabolic rate is at its peak.

脑损伤后的高质量生存是危重或受伤婴儿目前面临的最大挑战 孩子们。限制质量生存的一个普遍因素是缺氧缺血的破坏性影响 脑病(HIE)，作为心脏骤停、中风或颅内疾病的主要后果 在癫痫持续状态、循环或感染性休克的情况下，出血或继发性后遗症， 神经炎，或创伤性脑损伤(TBI)；HIE的主要原因从婴儿时期就开始 青春期是心脏骤停的后果。到目前为止，还没有发现治愈HIE的方法。 范式转换策略可能是改善HIE患者神经预后所必需的。 因此，我们开发了一种新的治疗方法，通过保存关键的 细胞通过选择性地靶向线粒体中的聚(ADP-核糖)聚合酶(PARP)(MtPARP)来储存能量， 线粒体靶向半谷氨酸S或三苯基膦与PARP的连接 临床上使用的抑制剂。DNA损伤引发的缺血诱导的PARP过度激活消耗NAD+， 产生支链聚(ADP-核糖)聚合物(PAR化)，导致ATP耗尽，能量衰竭， 以及由坏死和/或凋亡诱导因子(AIF)介导的副酒精性细胞死亡。就像线粒体一样 好氧生物中ATP和NAD+的主要来源，线粒体能量储存的保存 代表了减轻HIE的合乎逻辑的“可用药”靶点。我们最近报道了线粒体- 靶向PARP1抑制剂XJB-veliparib保存NAD+储存并防止缺氧后神经元死亡 在体外纳摩尔浓度的葡萄糖剥夺(OGD)。重要的是，xjb-veliparib选择性靶向 因此，它不会阻碍体外的核DNA修复。我们提出了具有挑衅性的试点数据 提示XJB-veliparib和易翻译的线粒体靶向化合物TPP-veliparib可能 出生后17天(PND)大鼠心脏骤停后有效，发育年龄相当于年轻的 儿童和与大脑新陈代谢高峰相关的时间。这种新的治疗方法具有优势 选择性靶向mtPARP预防PARP介导的能量衰竭和细胞死亡 PARP1促进的核DNA修复，并提供一个工具来明确确立(或驳斥)mtPARP的作用 在HIE的发病机制中起重要作用。 如果证明有效，mtPARP1抑制剂将代表新的、安全的(就核DNA修复而言)， 和可翻译的疗法来缓解HIE，在高度脆弱的发育中的大脑具有特殊的潜力 代谢率最高的地方。