AGMATINASE INHIBITORS FOR HYPOXIC-ISCHEMIC NEW BORN BRAIN DAMAGE

胍丁胺酶抑制剂治疗新生儿缺氧缺血性脑损伤

• 批准号: 7273890
• 负责人: JOHN E PILETZ
• 金额: $ 16.22万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-07 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7273890
• 关键词: Adverse effects; Agmatinase; Agmatine; Area; Arginine; Blood flow; Brain; Brain Hypoxia-Ischemia; Brain Injuries; Cells; Cerebral Ischemia-Hypoxia; Cerebral Palsy; Class; Clinical; Decarboxylation; Defense Mechanisms; Descriptor; Electronics; Enzymes; Etiology; Excitatory Amino Acid Antagonists; Glutamates; Goals; Human; Hypoxia; Infant; Inflammatory; Injection of therapeutic agent; N-Methyl-D-Aspartate Receptors; Neurons; Nitric Oxide Synthase; Oxygen; Perinatal Brain Injury; Quantitative Structure-Activity Relationship; RNA; Rattus; Series; Technology; Testing; blood perfusion; in vivo; inhibitor/antagonist; pup

DESCRIPTION (provided by applicant): Low blood flow and low oxygen to the brain (cerebral hypoxia-ischemia) is the putative etiology of brain injury in premature and term infants. This important clinical problem is a major cause of cerebral palsy, and no therapy is yet available. A wealth of evidence indicates that most of the brain damage in this situation is due to a rise in glutamate levels around the area of low blood perfusion. Glutamate antagonism by any of several mechanisms can ameliorate the penumbra of damage. However, the available synthetic glutamate receptor antagonists are poorly tolerated. A natural and milder agent may exist in agmatine, the decarboxylation product of L-arginine. Agmatine was only recently discovered to be synthesized in the brain. It has been shown that brain agmatine concentrations are increased during hypoxia-ischemia which maybe a natural defense mechanism of the brain since the substance is an endogenous antagonist of excitatory N-methyl-D-aspartate (NMDA) receptors as well as an inhibitor or the inducible form of nitric oxide synthase (NOS), which is pro-inflammatory. In fact, experimental treatments have revealed that agmatine injections are neuroprotective to rat pups, in vivo, and agmatine will directly protect neurons in culture. However, getting enough of an injection of agmatine into the brain leads to systemically high levels of agmatine which leads to unwanted side effects. To overcome this we are proposing that agents that selectively block agmatinase would raise endogenous pools of agmatine only where most needed. This is because agmatine levels in the brain are regulated by its degradative enzyme, agmatinase. We prepared a series of synthetic compounds and subjected them to analysis of quantitative structure activity relationships (QSAR). Linear correlations were obtained using geometric and electronic descriptors of each atom to predict a class of compounds with selectivity for agmatinase. Specific Aim 1 will test the first compound which we have already synthesized, designated APG, for neuroprotective efficacy in rat pups exposed to hypoxia-ischemia. Specific Aim-2 will use short-interfering RNA technology to diminish agmatinase in cells and be neuroprotective. Specific Aim-3 will determine if the other synthetic compounds act directly on cultured neurons. Specific Aim-4 will test which of the compounds is most neuroprotective in rat pups exposed to hypoxia-ischemia. The overall goal of these studies is to develop a treatment for perinatal brain damage in human infants.

描述（由申请人提供）：低血流量和脑低氧（脑缺氧-缺血）是早产儿和足月儿脑损伤的假定病因。这一重要的临床问题是脑瘫的主要原因，目前还没有治疗方法。大量证据表明，这种情况下的大部分脑损伤是由于低血液灌注区域周围谷氨酸水平的升高。通过几种机制中的任何一种的谷氨酸拮抗作用都可以改善损伤的半影区。然而，可用的合成谷氨酸受体拮抗剂耐受性差。胍丁胺是L-精氨酸的脱羧产物，可能是一种天然的温和剂。胍丁胺最近才被发现是在大脑中合成的。已经表明，在缺氧-缺血期间，脑胍丁胺浓度增加，这可能是脑的天然防御机制，因为该物质是兴奋性N-甲基-D-天冬氨酸（NMDA）受体的内源性拮抗剂以及一氧化氮合酶（NOS）的抑制剂或诱导形式，其是促炎性的。事实上，实验性治疗已经揭示，胍丁胺注射对大鼠幼崽具有神经保护作用，在体内，胍丁胺将直接保护培养中的神经元。然而，将足够的胍丁胺注射到大脑中会导致全身高水平的胍丁胺，从而导致不必要的副作用。为了克服这一点，我们建议选择性阻断胍丁胺酶的药物只在最需要的地方增加胍丁胺的内源性库。这是因为胍丁胺在大脑中的水平是由其降解酶胍丁胺酶调节的。我们制备了一系列的合成化合物，并对它们进行了定量构效关系（QSAR）分析。使用几何和电子描述符的每个原子，以预测一类化合物的胍丁胺酶的选择性，得到线性相关。具体目标1将测试我们已经合成的第一种化合物，命名为APG，在暴露于缺氧缺血的大鼠幼崽中的神经保护功效。Specific Aim-2将使用短干扰RNA技术来减少细胞中的胍基丁胺酶并具有神经保护作用。Specific Aim-3将确定其他合成化合物是否直接作用于培养的神经元。Specific Aim-4将测试哪种化合物在暴露于缺氧缺血的大鼠幼崽中最具神经保护作用。这些研究的总体目标是开发一种治疗人类婴儿围产期脑损伤的方法。

项目成果

Putative agmatinase inhibitor for hypoxic-ischemic new born brain damage.

• DOI: 10.1007/s12640-013-9376-5
• 发表时间: 2013-08
• 期刊: NEUROTOXICITY RESEARCH
• 影响因子: 3.7
• 作者: Piletz, John E.;Klenotich, Stephanie;Lee, Ken S.;Qian Long Zhu;Valente, Edward;Collins, Michael A.;Jones, Vyvyca;Lee, Soeb Nam;Feng Yangzheng
• 通讯作者: Feng Yangzheng