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: 7076306
• 负责人: JOHN E PILETZ
• 金额: $ 20.05万
• 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 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7076306
• 关键词: brain; hypoxia; ischemia

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）：大脑低血流量和低氧（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，目前尚无治疗方法。大量证据表明，这种情况下的大部分脑损伤是由于低血流灌注区域谷氨酸水平升高所致。几种机制中任何一种的谷氨酸拮抗作用都可以改善损伤的半影。然而，现有的合成谷氨酸受体拮抗剂的耐受性较差。胍丁胺（L-精氨酸的脱羧产物）中可能存在一种天然且温和的试剂。最近才发现胍丁胺是在大脑中合成的。研究表明，缺氧缺血期间脑内胍丁胺浓度会增加，这可能是大脑的自然防御机制，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，也是促炎性一氧化氮合酶 (NOS) 的抑制剂或诱导形式。事实上，实验治疗表明，注射胍丁胺对体内幼鼠具有神经保护作用，并且胍丁胺将直接保护培养物中的神经元。然而，向大脑注射足够的胍丁胺会导致全身高水平的胍丁胺，从而导致不必要的副作用。为了克服这个问题，我们建议选择性阻断胍丁胺酶的药物仅在最需要的地方增加内源性胍丁胺库。这是因为大脑中的胍丁胺水平受到其降解酶胍丁胺酶的调节。我们制备了一系列合成化合物，并对它们进行定量结构活性关系（QSAR）分析。使用每个原子的几何和电子描述符获得线性相关性，以预测对胍丁胺酶具有选择性的一类化合物。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）对暴露于缺氧缺血的幼鼠的神经保护功效。 Specific Aim-2 将使用短干扰 RNA 技术来减少细胞中的胍丁胺酶并具有神经保护作用。具体的 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。具体的 Aim-4 将测试哪种化合物对暴露于缺氧缺血的幼鼠最具神经保护作用。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。