Nitric Oxide Restoration & Heme Detoxification as Adjunctive Therapies for Cerebr

一氧化氮恢复

• 批准号: 8311681
• 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
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-10 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8311681
• 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

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5岁以下的儿童，即使在进行抗疟疾治疗的情况下，死亡率也很高。目前迫切需要能够提高生存率和降低后遗症发生率的CM辅助治疗。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，用外源性NO治疗可预防CM的发展。另一方面，血浆游离血红素已被牵连在CM的成因。我们建议，恢复NO和/或抵消血红素毒性的CM的持续治疗的潜在的强大的方法。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，其显示出作为脑型疟疾的连续治疗的高功效，使用arthemeter作为抗疟疾药物。这样的治疗程序相对于单独的关节炎计将显著提高存活率，理想地引起可忽略的副作用和毒性，并且呈现出转化为临床使用的良好潜力。将使用CM的PbA模型。首先，将用三种不同剂量的以下NO供体化合物中的每一种处理感染的小鼠：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，以及用5-磷酸二酯酶抑制剂西地那非。还将测试旨在阻断血红素的有害作用（重组触珠蛋白、血红素结合蛋白、原卟啉IX和中卟啉IX）、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、β-脱氧-δ 12，14-前列腺素J2）或提供抗氧化保护以对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。能够预防小鼠中CM发展的化合物将在联合治疗方案中用关节计进行测试，目的是挽救早期或晚期已建立CM的小鼠。对于每种治疗，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，还将在人脑内皮细胞和恶性疟原虫的体外共培养系统中测试化合物。我们希望能够确定一种或多种可以用于临床试验的化合物。脑型疟疾（CM）是恶性疟原虫感染的主要并发症，每年造成数十万人死亡，特别是5岁以下的儿童。即使接受抗疟疾治疗，CM显示10-20%的死亡率，幸存者可能会出现后遗症。因此，迫切需要与抗疟疾治疗协同作用的辅助疗法来提高患者恢复的速度和质量。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/或血红素解毒的预防性治疗，这些治疗可能会转化为临床应用。

项目成果

NO-Donor Dihydroartemisinin Derivatives as Multitarget Agents for the Treatment of Cerebral Malaria.

NO-供体二氢青蒿素衍生物作为治疗脑型疟疾的多靶点药物。

• DOI: 10.1021/acs.jmedchem.5b01036
• 发表时间: 2015
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Bertinaria,Massimo;Orjuela-Sanchez,Pamela;Marini,Elisabetta;Guglielmo,Stefano;Hofer,Anthony;Martins,YuriC;Zanini,GrazielaM;Frangos,JohnA;Gasco,Alberto;Fruttero,Roberta;Carvalho,LeonardoJM
• 通讯作者: Carvalho,LeonardoJM