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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：
7928776
负责人：
Leonardo Jose de Moura Carvalho
金额：
$ 41.22万
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/7928776
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 Hand 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 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 neutrophil 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的5岁以下儿童，即使给予抗疟疾治疗，死亡率也很高。目前迫切需要能够提高患者生存率和降低患者后遗症的辅助治疗方法。在伯氏疟原虫ANKA （PbA）小鼠CM模型中，CM与低一氧化氮（NO）生物利用度有关，外源性NO处理可阻止CM的发展。另一方面，血浆游离血红素被认为与CM的发生有关。我们认为恢复NO和/或对抗血红素毒性是CM辅助治疗的潜在有效途径。本提案的总体目标是确定一种或多种基于一氧化氮修复和/或游离血红素解毒的治疗策略，这些治疗策略作为脑型疟疾的辅助治疗具有很高的疗效，使用arthemeter作为抗疟疾药物。与单独使用心律失常相比，这种治疗方法将显著提高患者的生存率，理想情况下，其副作用和毒性可以忽略不计，并且具有良好的临床应用潜力。将使用CM的PbA模型。首先，感染小鼠将接受三种不同剂量的一氧化氮供体化合物的治疗：DPTA-NO、含NO纳米颗粒、s -亚硝基聚乙二醇白蛋白、GSNO、亚硝酸盐和硝化甘油，以及5-磷酸二酯酶抑制剂西地那非。还将测试旨在阻断血红素（重组血红蛋白，血红素，原卟啉IX和中卟啉IX）的有害作用，诱导血红素氧化酶-1 （HO-1：高压氧，姜黄素，呋喃-2-基-3-吡啶-2-基-丙烯酮，-脱氧- 12,14-前列腺素J2）或提供抗氧化保护以抵抗血红素诱导的氧化应激（n-乙酰半胱氨酸，去铁胺）的化合物。能够阻止小鼠CM发展的化合物将在联合治疗方案中进行测试，目的是挽救早期或晚期已建立CM的小鼠。对于每次治疗，将评估肝脏、肾脏和呼吸生理，以确定化合物的毒性，在NO供者的情况下，还将监测血压。此外，通过活体显微镜观察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的体外共培养系统中进行测试。我们希望能够确定一种或多种化合物，可以转发给临床试验。脑型疟疾是恶性疟原虫感染的一种主要并发症，每年造成数十万人死亡，特别是5岁以下儿童。即使接受抗疟疾治疗，CM仍显示出10-20%的死亡率，幸存者可能会留下后遗症。因此，迫切需要与抗疟疾治疗相协调的辅助治疗，以提高患者的康复率和质量。在本提案中，我们打算使用动物模型开发基于一氧化氮修复和/或血红素解毒的辅助疗法，这些疗法可能会转化为临床应用。