Periventricular White Matter Injury Prevention

脑室周围白质损伤的预防

• 批准号: 8413645
• 负责人: SCOTT A. RIVKEES
• 金额: $ 4.68万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2012-01-03
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8413645
• 关键词: Acute; Adverse event; Affect; Animal Model; Animals; Brain; Brain Injuries; Calcium; Caring; Cell Culture Techniques; Cell Proliferation; Cells; Cerebral Palsy; Child; Clinical; Development; Diazoxide; Diffuse; Diffusion; Dose; Etiology; Generic Drugs; Goals; Health Benefit; Hyperinsulinism; Impairment; Individual; Infant; Lead; Lethal Dose 50; Libraries; Long-Term Effects; Low Birth Weight Infant; Membrane Potentials; Modeling; Morbidity - disease rate; Mus; Necrosis; Neonatal; Neuraxis; Newborn Infant; Oligodendroglia; Periventricular white matter injury; Pharmaceutical Chemistry; Play; Premature Infant; Prevention; Property; Public Health; Reporting; Research; Risk; Rodent; Role; Staging; Testing; Therapeutic Agents; Therapeutic Index; Time; Toxic effect; Toxicology; United States; United States Food and Drug Administration; White Matter Disease; Work; behavior test; clinical application; cost; drug development; high throughput screening; hypertension treatment; injury prevention; myelination; neuropathology; novel; novel strategies; novel therapeutics; pre-clinical; prevent; public health relevance; response; white matter; white matter injury

DESCRIPTION (provided by applicant): Five to twenty percent of low birth weight preterm infants manifest some form of periventricular white matter injury (PWMI), making it the most common form of brain injury affecting premature infants 1-2. PWMI includes a spectrum of brain injury ranging from diffuse white matter disease to focal necrosis 2-4. PWMI is associated with significant morbidity, as affected individuals may have profound intellectual impairment and cerebral palsy 5-7. Highlighting the magnitude of PWMI, each year in the United States more than 400,000 infants are born prematurely 8. Of these infants, 150,000 are born at risk for PWMI, and about 25,000 children per year will develop PWMI. World-wide, 1,000,000 infants will be born each year at risk for PWMI, and about 250,000 children per year will develop PWMI. It is estimated the lifetime care costs for infants who develop cerebral palsy due to PWMI exceeds $1.5 million per infant9. Thus, finding a prevention and treatment for PWMI is of major public health importance. Oligodendrocytes (OLs) are the myelinating cells of the central nervous system and play a critical role in white matter formation 10-13. It is believed that due to loss of Pre-oligodendrocytes (PreOLs), which are proliferative cells that develop into myelinating OLs, plays a major role in PWMI causation 3. Presently, we are unaware of pharmacological approaches that specifically target PreOLs, resulting in increased proliferation of these cells and increased brain myelination. Recently, we used high-throughput screening to identify compounds ("hits") that would stimulate PreOL proliferation. These studies proved to be highly successful. We identified diazoxide as a stimulator of PreOL proliferation and showed that this compound promotes myelination in a murine model of PWMI. Diazoxide acts by activating KATP channels 14-15. We also found that other KATP activators stimulate PreOL proliferation. We also identified KATP channel component in OLs. We thus hypothesize that diazoxide will be a potential novel therapeutic for PWMI, and that we have discovered a novel therapy for PWMI. We propose to extend our study of diazoxide in preclinical, proof-of-concept studies involving cell culture and animal studies. These studies have been developed with direction form the US Food and Drug Administration and experts in central nervous system (CNS) medicinal chemistry. More specifically we will: 1. Assess diazoxide neonatal toxicity. 2. Define OL-stage specific responses to diazoxide. 3. Evaluate protection against PWMI in animal models. 4. Assess long-term effects of neonatal diazoxide therapy. 5. Identify alternative diazoxide-derivative compounds These studies will focus on the lead compound diazoxide for several reasons. First, diazoxide is a generic drug that is approved by the US Food and Drug Administration (FDA) for the acute treatment of hypertension and the treatment of hyperinsulinism in infants15-16. Second, diazoxide is currently the treatment of choice for infants with hyperinsulinism, and major adverse events related to diazoxide use in infants have not been reported 17. Third, there is favorable clinical and commercial precedent for developing new use indications for generic drugs18-20. Fourth, toxicology studies show that diazoxide has a very broad therapeutic index, with an LD50 value greater than 500 mg/kg in neonatal rodents. This value compares very favorably with the effective 10 mg/kg dose used in our studies. As such, we will avoid the high costs and the lengthy time frame associated with new drug development in applying FDA-approved, generic drugs for novel clinical applications. The long-term goal of this work is to develop novel therapeutic agent for the treatment of PWMI in premature infants. Ultimately, research such as this will lead to important discoveries with significant public health benefit for treating and preventing white matter injury in the tens of thousands of premature infants born and hospitalized each year. PUBLIC HEALTH RELEVANCE: The goal of this work is to assess the utility of diazoxide as a therapeutic agent for the treatment of white matter injuries in premature infants. We anticipate that these studies will lead to the development of novel approaches for treating and preventing white matter injury in the tens of thousands of premature infants born and hospitalized each year.

描述（由申请人提供）：5%至20%的低出生体重早产儿表现出某种形式的脑室周围白色物质损伤（PWMI），使其成为影响早产儿的最常见脑损伤形式1-2。PWMI包括一系列脑损伤，范围从弥漫性白色病变到局灶性坏死2-4。PWMI与显著的发病率相关，因为受影响的个体可能具有严重的智力障碍和脑瘫5-7。 突显PWMI的严重性，在美国每年有超过40万婴儿早产8。在这些婴儿中，有15万人出生时有患PWMI的风险，每年约有25，000名儿童会患上PWMI。在全世界范围内，每年将有1，000，000名婴儿出生时有患PWMI的风险，每年约有250，000名儿童将患上PWMI。据估计，因PWMI而患脑瘫的婴儿的终身护理费用超过每名婴儿150万美元9。因此，寻找预防和治疗PWMI的方法具有重大的公共卫生意义。 少突胶质细胞（OL）是中枢神经系统的髓鞘形成细胞，并且在白色物质形成中起关键作用10-13。据信，由于前少突胶质细胞（PreOL）（其是发育成髓鞘形成OL的增殖细胞）的损失，在PWMI病因3中起主要作用。目前，我们不知道特异性靶向PreOL的药理学方法，导致这些细胞增殖增加和脑髓鞘形成增加。 最近，我们使用高通量筛选来鉴定将刺激PreOL增殖的化合物（“命中”）。这些研究证明是非常成功的。我们鉴定了二氮嗪作为PreOL增殖的刺激剂，并表明该化合物在PWMI小鼠模型中促进髓鞘形成。 二氮嗪通过激活KATP通道14-15起作用。我们还发现其他KATP激活剂刺激PreOL增殖。我们还鉴定了OLs中的KATP通道组分。因此，我们假设，二氮嗪将是一个潜在的新型治疗PWMI，我们已经发现了一种新的治疗PWMI。 我们建议扩展我们的研究二氮嗪在临床前，概念验证研究，涉及细胞培养和动物研究。这些研究是在美国食品药品监督管理局和中枢神经系统（CNS）药物化学专家的指导下进行的。更具体地说，我们将：1。评估二氮嗪新生儿毒性。2.定义OL阶段对二氮嗪的特异性反应。3.在动物模型中评价对PWMI的保护作用。4.评估新生儿二氮嗪治疗的长期效果。5.确定替代的二氮嗪衍生物化合物这些研究将集中在铅化合物二氮嗪有几个原因。首先，二氮嗪是一种仿制药，经美国食品药品监督管理局（FDA）批准，用于治疗高血压和婴儿高胰岛素血症的急性治疗15 -16。其次，二氮嗪是目前治疗高胰岛素血症婴儿的首选药物，尚未报告与婴儿使用二氮嗪相关的主要不良事件17。第三，为仿制药开发新的使用适应症有良好的临床和商业先例18 -20。第四，毒理学研究表明，二氮嗪具有非常广泛的治疗指数，在新生啮齿动物中的LD 50值大于500 mg/kg。该值与我们研究中使用的有效剂量10 mg/kg相比非常有利。因此，我们将避免与新药开发相关的高成本和漫长的时间框架，将FDA批准的仿制药用于新的临床应用。 这项工作的长期目标是开发治疗早产儿PWMI的新型治疗药物。最终，像这样的研究将导致重要的发现，对治疗和预防每年出生和住院的数万名早产儿的白色损伤具有重大的公共卫生效益。 公共卫生关系：这项工作的目标是评估二氮嗪作为治疗早产儿白色物质损伤的治疗剂的效用。我们预计这些研究将导致开发新的方法来治疗和预防每年出生和住院的数万名早产儿的白色损伤。