AGMATINASE INHIBITORS FOR HYPOXIC-ISCHEMIC NEW BORN BRAIN DAMAGE

描述(申请人提供)：低血流量和低氧脑(脑缺氧-缺血)是早产儿和足月儿脑损伤的可能病因。这一重要的临床问题是脑性瘫痪的主要原因，目前还没有可用的治疗方法。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周围的谷氨酸水平上升所致。通过几种机制中的任何一种进行谷氨酸拮抗都可以改善损伤的半影区。然而，现有的合成谷氨酸受体拮抗剂耐受性很差。L-精氨酸的脱羧基产物胍丁胺中可能存在一种天然的温和的试剂。直到最近才发现胍丁胺是在大脑中合成的。已有研究表明，缺氧缺血时脑苷丁胺浓度升高，这可能是大脑的一种自然防御机制，因为该物质既是兴奋性N-甲基-D-天冬氨酸(NMDA)受体的内源性拮抗剂，也是一氧化氮合酶(NOS)的抑制剂或诱导型一氧化氮合酶(NOS)，具有促炎作用。事实上，实验治疗已经揭示了胍丁胺注射对大鼠幼鼠的神经保护作用，在体内，胍丁胺将直接保护培养中的神经元。然而，在大脑中注射足够的胍丁胺会导致全身高水平的胍丁胺，这会导致不想要的副作用。为了克服这一点，我们建议选择性地阻断胍丁素酶的药物将只在最需要的地方增加内源性胍丁胺池。这是因为大脑中的胍丁胺水平是由其降解酶--胍丁素酶来调节的。我们制备了一系列合成化合物，并对它们进行了定量构效关系(QSAR)分析。使用每个原子的几何和电子描述符来预测一类对琼脂糖苷酶具有选择性的化合物，得到了线性关联。具体目标1将测试我们已经合成的第一种化合物，名为APG，对暴露在缺氧缺血中的大鼠幼鼠的神经保护效果。特定的AIM-2将使用短干扰RNA技术来减少细胞中的脱氧核糖核酸酶，从而起到神经保护作用。特定的目标-3将确定其他合成化合物是否直接作用于培养的神经元。SPICAL-AIM-4将测试哪种化合物对暴露在缺氧缺血中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围产期婴儿脑损伤的方法。

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.