AGMATINASE INHIBITORS FOR HYPOXIC-ISCHEMIC NEW BORN BRAIN DAMAGE

描述（由申请人提供）：低血流量和低脑氧（脑缺氧-缺血）是早产儿和足月婴儿脑损伤的公认病因。这一重要的临床问题是脑瘫的主要病因，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周围谷氨酸水平升高。谷氨酸拮抗剂通过几种机制中的任何一种都可以改善损伤的半暗区。然而，现有的合成谷氨酸受体拮抗剂耐受性差。在精氨酸的脱羧产物——精氨酸中可能存在一种天然的温和剂。胍丁氨酸是最近才被发现在大脑中合成的。研究表明，在缺氧缺血时，脑agmatine浓度升高，这可能是脑的自然防御机制，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，也是促炎的一氧化氮合酶（NOS）的抑制剂或诱导形式。事实上，实验治疗表明，注射agmatine对大鼠幼崽具有神经保护作用，在体内，agmatine将直接保护培养的神经元。然而，向大脑注射足够的胍丁氨酸会导致全身性的高水平胍丁氨酸，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氨酸酶的药物只在最需要的地方增加内源性胍丁氨酸池。这是因为大脑中的agmatinine水平是由其降解酶agmatinase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分析。利用每个原子的几何描述符和电子描述符得到线性相关性，预测一类化合物对agmatinase的选择性。特异性目标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大鼠幼崽的神经保护作用。特异性Aim-2将利用短干扰RNA技术减少细胞中的agmatinase，起到神经保护作用。特异性Aim-3将决定其他合成化合物是否直接作用于培养的神经元。特异性Aim-4将测试哪种化合物对暴露于缺氧缺血的大鼠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。

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.