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Nitric Oxide Restoration & Heme Detoxification as Adjunctive Therapies for Cerebr

一氧化氮恢复

基本信息

批准号：
8126272
负责人：
Leonardo Jose de Moura Carvalho
金额：
$ 40.37万
依托单位：
LA JOLLA BIOENGINEERING INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-10 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8126272
关键词：
5 year old 9-deoxy-delta-9-prostaglandin D2 Adverse effects Affect Affinity Africa South of the Sahara Albumins Anemia Animal Model Animals Antimalarials Antioxidants Area Artemisinins Binding Biological Availability Blood Blood Pressure Blood Vessels Blood flow Brain Carbon Monoxide Catabolism Cell Line Cell Survival Cerebral Malaria Cessation of life Child Clinical Clinical Trials Coculture Techniques Cognitive deficits Complication Curcumin Development Drug Formulations Drug Metabolic Detoxication Endothelial Cells Evaluation Functional disorder Furans Goals Haptoglobins Heme Hemoglobin Hemolysis Hemopexin Hemorrhage Human Hyperbaric Oxygen In Vitro Incidence Infection Intravenous Iron Kidney Leukocytes Liver Lung Macrophage Activation Malaria Mediating Mediator of activation protein Methemoglobin Microcirculation Modeling Monitor Mus Neurologic Neutrophil Activation Nitric Oxide Nitric Oxide Donors Nitrites Nitroglycerin Oxidative Stress Oxygen Parasites Pathway interactions Patients Pediatric Hospitals Pharmaceutical Preparations Phosphodiesterase Inhibitors Physiological Processes Plasma Plasmodium berghei Plasmodium falciparum Protein Isoforms Quinine Recombinants Recovery Respiratory physiology Safety Saline Scheme Staging Survivors System Testing Therapeutic procedure Toxic effect Translating Work analog artemisinine base clinical practice dosage heme oxygenase-1 improved in vivo inhibitor/antagonist intravital microscopy mesoporphyrin IX migration mortality nanoparticle oxidation phosphodiesterase V prevent protective effect protoporphyrin IX restoration sildenafil transmission process treatment strategy uptake

项目摘要

DESCRIPTION (provided by applicant): Cerebral malaria (CM) is a major complication of infection by Plasmodium falciparum. It affects mainly children under 5 years old in sub-Saharan Africa and shows a high mortality rate even when anti- malarial treatment is administered. Adjunctive therapies for CM capable of improving survival and decreasing incidence of sequelae are urgently needed. In the murine model of CM by Plasmodium berghei ANKA (PbA), CM has been associated to low nitric oxide (NO) bioavailability, and treatment with exogenous NO prevented CM development. On the other hand, plasma free heme has been incriminated in the genesis of CM. We propose that restoring NO and/or counteracting heme toxicity are potentially powerful approaches for adjunctive therapy of CM. The overall goal of this proposal is to define one or more treatment strategies based on NO restoration and/or free heme detoxification that show high efficacy as adjunctive therapy for cerebral malaria, using arthemeter as anti-malarial drug. Such a therapeutic procedure shall significantly improve survival in relation to arthemeter alone, ideally inducing negligible side effects and toxicity, and present good potential to be translated into clinical use. The PbA model of CM will be used. First, infected mice will be treated with three different dosages of each of the following NO donor compounds: DPTA-NO, NO-containing nanoparticles, S-nitroso- pegylated-albumin, GSNO, nitrite and nitroglycerin, as well as with the 5-phosphodiesterase inhibitor sildenafil. Compounds aimed at blocking the deleterious effect of heme (recombinant haptoglobin, hemopexin, protoporphyrin IX and mesoporphyrin IX), inducing hemeoxygenase-1 (HO-1: hyperbaric oxygen, curcumin, furan-2-yl-3-pyridin-2-yl-propenone, -deoxy-delta 12,14-prostaglandin J2) or providing anti-oxidant protection against heme-induced oxidative stress (N-Acethil cystein, desferoxamine) will be tested as well. The compounds able to prevent CM development in mice will be tested in a scheme of combined therapy with arthemeter with the purpose of rescuing mice with established CM at early or late stages. For each treatment, liver, kidney and respiratory physiology will be assessed to determine toxicity of the compounds, and in the case of NO donors blood pressure will also be monitored. In addition, the effect of the successful treatments on the brain microcirculation will be assessed by intravital microscopy and the expression of eNOS, nNOS, iNOS and HO-1will be determined. Finally, the compounds will also be tested in an in vitro system of co-culture of human brain endothelial cells and P. falciparum. We expect that to define one or more compounds that can be forwarded for clinical trials. Cerebral malaria (CM) is a major complication of infection by Plasmodium falciparum, causing hundreds of thousands of deaths every year particularly of children under 5 years old. Even receiving anti-malarial treatment, CM shows a 10-20% mortality rate, and survivors may present sequelae. Adjunctive therapies acting in concert with the anti- malarial treatment are then urgently needed to improve the rate and the quality of patient recovery. In this proposal, we intend to develop, using an animal model, adjunctive therapies based on nitric oxide restoration and/or heme detoxification that can be potentially translated into clinical use.

描述（由申请人提供）：脑型疟疾（CM）是恶性疟原虫感染的主要并发症。它主要影响撒哈拉以南非洲地区 5 岁以下的儿童，即使进行抗疟治疗，死亡率也很高。迫切需要能够提高生存率并降低后遗症发生率的 CM 辅助疗法。在伯氏疟原虫 ANKA (PbA) 的 CM 小鼠模型中，CM 与低一氧化氮 (NO) 生物利用度相关，并且外源性 NO 治疗可阻止 CM 的发展。另一方面，血浆游离血红素与 CM 的发生有关。我们认为恢复 NO 和/或抵消血红素毒性是 CM 辅助治疗的潜在有效方法。该提案的总体目标是定义一种或多种基于 NO 恢复和/或游离血红素解毒的治疗策略，使用 Arthemeter 作为抗疟疾药物，作为脑型疟疾的辅助治疗显示出高效。与单独的动脉计相比，这种治疗方法将显着提高生存率，理想情况下引起的副作用和毒性可以忽略不计，并且具有转化为临床应用的良好潜力。将使用 CM 的 PbA 模型。首先，用三种不同剂量的以下 NO 供体化合物治疗受感染的小鼠：DPTA-NO、含 NO 的纳米颗粒、S-亚硝基聚乙二醇化白蛋白、GSNO、亚硝酸盐和硝酸甘油，以及 5-磷酸二酯酶抑制剂西地那非。旨在阻断血红素（重组触珠蛋白、血红蛋白、原卟啉 IX 和中卟啉 IX）的有害作用、诱导血红素加氧酶-1（HO-1：高压氧、姜黄素、呋喃-2-基-3-吡啶-2-基-丙烯酮、-脱氧-δ 12,14-前列腺素）的化合物 J2) 或针对血红素诱导的氧化应激提供抗氧化保护（N-Acethil 半胱氨酸、去铁胺）也将进行测试。能够预防小鼠 CM 发展的化合物将在与 Arthemeter 联合治疗方案中进行测试，目的是拯救早期或晚期已形成 CM 的小鼠。对于每次治疗，将评估肝脏、肾脏和呼吸生理学以确定化合物的毒性，并且在NO供体的情况下还将监测血压。此外，将通过活体显微镜评估成功治疗对脑微循环的影响，并测定 eNOS、nNOS、iNOS 和 HO-1 的表达。最后，这些化合物还将在人脑内皮细胞和恶性疟原虫共培养的体外系统中进行测试。我们希望能够定义一种或多种可以进行临床试验的化合物。脑型疟疾 (CM) 是恶性疟原虫感染的主要并发症，每年导致数十万人死亡，尤其是 5 岁以下儿童。即使接受抗疟疾治疗，CM 的死亡率仍为 10-20%，幸存者可能会出现后遗症。因此迫切需要与抗疟疾治疗相配合的辅助治疗，以提高患者康复的速度和质量。在这项提案中，我们打算使用动物模型开发基于一氧化氮恢复和/或血红素解毒的辅助疗法，这些疗法有可能转化为临床应用。