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: 10592289
• 负责人: Hülya Bayir
• 金额: $ 56.93万
• 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/10592289
• 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; Mitochondria; Mitochondrial DNA; Modeling; Motor; NADH; Necrosis; Nerve Degeneration; Neurological outcome; Nuclear; Organism; Outcome; Oxygen; Pathogenesis; Pharmaceutical Preparations; Placebos; Poly Adenosine Diphosphate Ribose; Poly(ADP-ribose) Polymerase Inhibitor; Poly(ADP-ribose) Polymerases; Polymers; Quality of life; Randomized; Rattus; Reactive Oxygen Species; Regimen; Reporting; Research; Role; Septic Shock; Shock; Source; Status Epilepticus; Stroke; Structure-Activity Relationship; Therapeutic; Time; Traumatic Brain Injury; Western Blotting; age related; apoptosis inducing factor; cognitive testing; deprivation; druggable target; improved; in vivo; in vivo imaging; infancy; inhibitor; lipidomics; liquid chromatography mass spectrometry; male; metabolic rate; nanomolar; neonatal hypoxic-ischemic brain injury; neuroinflammation; neuron loss; neuronal survival; neuroprotection; novel; postnatal; preservation; prevent; release factor; severe injury; sex; superresolution microscopy; survivorship; targeted treatment; tool; translational potential

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目前危重或受伤婴儿面临的最大挑战， 孩子一个普遍的贡献者限制生存质量是缺氧缺血性的破坏性影响， 脑病（HIE），无论是作为心脏骤停、中风或颅内出血病例的主要后果， 出血或癫痫持续状态、循环或败血性休克病例中的继发后遗症， 神经炎症或创伤性脑损伤（TBI）; HIE的主要原因从婴儿期开始 心脏骤停的后果。由于迄今为止尚未发现治疗HIE的方法， 范式转换策略可能是必要的，以改善神经功能的结果为受害者的HIE。 因此，我们已经开发了一种新的治疗方法，通过保留关键的 通过选择性靶向线粒体中的聚（ADP-核糖）聚合酶（PARP）（mtPARP）来储存细胞能量， 将PARP靶向部分半短杆菌肽S（XJB）或三苯基磷（TPP）连接至PARP 临床上使用的抑制剂。由DNA损伤引发的缺血诱导的PARP过度激活消耗NAD+， 产生分支链聚（ADP-核糖）聚合物（PAR化），导致ATP消耗，能量衰竭， 以及由坏死和/或凋亡诱导因子（AIF）介导的死亡引起的细胞死亡。就像线粒体 需氧生物中ATP和NAD+的主要来源，保存线粒体能量储存 代表减轻HIE的逻辑“可用药”靶标。我们最近报道了线粒体- 靶向PARP 1抑制剂XJB-维利帕尼保护NAD+储存并防止氧- 葡萄糖剥夺（OGD）在体外以纳摩尔浓度。重要的是，XJB-维利帕尼选择性靶向 线粒体，从而不妨碍体外核DNA修复。我们提出挑衅性的试点数据 这表明XJB-维利帕尼和易于翻译的靶向大肠杆菌的化合物TPP-维利帕尼可以 在出生后第17天（PND）的大鼠心脏骤停后有效，发育年龄相当于年轻的 儿童和与大脑代谢高峰相关的时间。这种新型疗法的优势在于 通过选择性地靶向mtPARP而不使用 PARP 1-促进核DNA修复，并提供一种工具，以明确建立（或反驳）mtPARP的作用 在新生儿缺氧缺血性脑病发病机制中的作用 如果证明有效，mtPARP 1抑制剂将代表新颖、安全（就核DNA修复而言）， 和可翻译的疗法，以减轻缺氧缺血性脑病，具有特殊的潜力，在高度脆弱的，发展中的大脑 代谢率达到最高点