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，即使服用抗疟疾治疗，也显示出高死亡率。急需提高后遗症生存率和降低后遗症的CM辅助疗法。在通过Berghei Anka疟原虫（PBA）的CM鼠模型中，CM与一氧化氮（NO）生物利用度低相关，并且使用外源性NO避免了CM的发育。另一方面，CM的起源已被定罪。我们建议恢复NO和/或抵消血红素毒性是CM辅助治疗的潜在强大方法。该提案的总体目标是基于没有恢复和/或游离血红素排毒来定义一种或多种治疗策略，这些治疗策略表现出高疗效作为脑疟疾的辅助疗法，使用Arthemeter作为抗癌症药物。这种治疗方法应仅与单独的肢体指数相关，从而显着提高生存率，理想地诱导可忽略不计的副作用和毒性，并具有良好的潜力，可以转化为临床使用。 CM的PBA模型将使用。首先，受感染的小鼠将接受以下每种供体化合物的三种不同剂量：dpta-no，无含有的纳米颗粒，s-硝基蛋白脂肪醛脂蛋白，gsno，硝酸盐，硝酸盐，硝酸盐和硝酸甘油，以及与5-磷酸二酯酶indibibytor sillibyitor sildennefil。旨在阻断血红素（重组haptoglobin，helepoglobin，protoporphyrin ix和中核氧IX），诱导血红素氧酶-1（HO-1：高压氧，高压氧，姜黄素，姜黄素，呋喃-2-基-3-五氧素2-二 - 基准 - 基准 - deoxy-deoxy-deeoxy-deeoxy-deeoxy-dexeoxy-d-deeoxy-d-deeoxy-d-deeoxy-d-d-deeoxy-d-deeoxy-deeoxy-de） J2）或提供针对血红素诱导的氧化应激（N- ACETHIL CYSTEIN，DESFEROXAMINE）的抗氧化剂保护。能够预防小鼠CM发育的化合物将在与Arthemeter联合疗法的方案中进行测试，目的是在早期或晚期挽救既定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，并且在没有供体的情况下，还将监测血压。此外，将通过内室显微镜以及eNOS，NNOS，INOS和HO-1 Will的表达来评估成功处理对脑微循环的影响。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。我们预计将定义一种或多种可以转发用于临床试验的化合物。脑疟疾（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，尤其是5岁以下的儿童。即使接受抗疟疾治疗，CM也显示出10-20％的死亡率，幸存者也可能出现后遗症。然后迫切需要与抗疟疾治疗一起起作用的辅助疗法以提高患者康复的速度和质量。在此提案中，我们打算使用动物模型，基于一氧化氮恢复和/或血红素排毒的辅助疗法来开发，这些疗法可能会被可能转化为临床用途。