Testing brain penetrant iron chelators and investigating putative clearance pathway in ICH

测试脑渗透铁螯合剂并研究 ICH 中假定的清除途径

基本信息

批准号：
10201369
负责人：
Sylvain DORE
金额：
$ 38.13万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10201369
关键词：
Acids Address Adult Affinity Aftercare Albumins Anatomy Animals Attenuated Autologous Bilirubin Binding Blood Blood gas Brain Brain Edema Brain hemorrhage C57BL/6 Mouse CD3 Antigens CD36 gene Carboxylic Acids Cell Death Cells Cerebral hemisphere hemorrhage Chelating Agents Chemistry Clinical Trials Cremophor Cytolysis Data Deferoxamine Dose Enzyme-Linked Immunosorbent Assay Enzymes Erythrocytes Ethylenediamines Female Future Glial Fibrillary Acidic Protein Gliosis Glucose Goals H ferritin Half-Life Hematocrit procedure Hematoma Hemoglobin Hemoglobin concentration result Hemorrhage Homeostasis Human Hydroxyl Radical In Situ Nick-End Labeling Individual Inflammation Inflammatory Injections Injury International Iron Iron Chelating Agents Knock-out Knowledge Lead Literature Liver Measures Medical Mitochondria Modeling Monitor Motor Mus Neuroanatomy Neurons Operative Surgical Procedures Organ Outcome Oxidative Stress Pathogenesis Pathology Pathway interactions Phagocytes Pharmaceutical Preparations Phase Physiological Plasma Pre-Clinical Model Process Prodrugs Reaction Time Regimen Role Safety Secondary to Serum Serum iron level result Stress Stroke Testing Therapeutic Thiazoles Time Toxic effect Traumatic Brain Injury White Blood Cell Count procedure analog base brain cell clinical investigation compare effectiveness design effective therapy efficacy testing experimental study fluoro jade forced swim test heme oxygenase-1 improved innovation lipophilicity male mortality nephrotoxicity neurobehavioral novel outcome forecast phase III trial prevent primary outcome prolyl-proline receptor response secondary outcome stroma free hemoglobin symposium therapeutic target tool

项目摘要

Intracerebral hemorrhage (ICH) is a serious medical condition caused by bleeding in the brain. It should be noted that at the last AHA/ASA International Stroke Conference in Feb. 2019, findings were presented from a Phase III trial showing that deferoxamine (DFO) was futile against ICH. One potential explanation is that DFO does not cross the BBB, and it has significant toxicity issues. Thus, the main focus now is to determine the efficacy and therapeutic window of a novel, safe, and effective therapy against ICH by testing unique brain penetrant iron chelators. To achieve this goal, and based on the literature and our preliminary data, we will test potent and selective iron chelators such as HBED, and their efficacy will be compared to other iron chelators such as the DADMDFT analog and DFO. After intracranial bleeding, red blood cells lyse and release large amounts of hemoglobin (Hb). These have to be actively phagocytosed, after which the heme (which cannot be recycled) gets degraded to generate iron intracellularly. Under normal physiological conditions, iron homeostasis should be maintained; however, when there are too many (heme) substrates, there is also too much iron, a process called iron dyshomeostasis. Our overall hypothesis is that a lipophilic brain penetrant iron chelator would be effective against ICH. Notably, HBED also has a much better safety profile compared to DFO, which was noted after a thorough Phase I safety trial. We observed that HBED was most potent after a traumatic brain injury model. Also, we found that DADMDFT provides benefits by improving functional and anatomical outcomes in the stroma-free Hb injection model. Besides binding iron, HBED binds ferrous (toxic) iron and converts it into ferric (nontoxic) iron in cells and mitochondria, preventing prooxidant and proinflammatory cascades. Aim 1 is to investigate the efficacy of HBED over DADMDFT and DFO in improving neurobehavioral and anatomical outcomes after ICH. We will determine and compare the optimal dose-response and therapeutic window of HBED, DADMDFT, and DFO in adult male mice and in parallel in females. Aims 2, 3, and 4 are to investigate the importance of the known phagocytic receptors CD36 and CD163 for RBCs and Hb, respectively, using the autologous blood ICH preclinical model. We will use the single and double knockouts (versus matched C57BL/6 littermates) that we have already generated. The goal is to understand mechanistically the respective role of these phagocytic receptors because they should participate in the clearance of RBCs and hemoglobin and test the added benefits of the optimal iron chelator, helping to limit the oxidative/inflammatory stress cascades. Toxicity will be monitored, along with brain and serum iron levels over time, after treatment with the iron chelator. This project is timely, and we believe we have assembled a unique team with the tools, animals, models, and expertise necessary to rigorously perform these experiments. We are confident that we can accomplish the proposed aims to inform our stroke partners, allowing them to design a rigorous clinical trial.

脑出血（ICH）是由大脑出血引起的严重医疗状况。应该注意在2019年2月的最后一次AHA/ASA国际中风会议上，从一个阶段提出了调查结果 III审判表明，脱铁胺（DFO）对ICH是徒劳的。一个潜在的解释是DFO没有越过BBB，并且存在重大毒性问题。因此，现在的主要重点是确定功效和通过测试独特的脑渗透铁，针对ICH的新颖，安全且有效治疗的治疗窗口螯合剂。为了实现这一目标，并基于文献和我们的初步数据，我们将测试有效的选择性铁螯合剂（例如HBED）及其功效将与其他铁螯合剂（例如 dadmdft模拟和DFO。颅内出血后，红细胞裂解并释放大量血红蛋白（HB）。这些必须积极吞噬吞噬，之后血红素（无法回收）降解以产生铁细胞内。在正常的生理条件下，应保持铁稳态；但是，什么时候有太多（血红素）底物，也有太多的铁，一个称为铁dyshomeostasis的过程。我们的总体上假设是亲脂性脑渗透铁螯合剂对ICH有效。值得注意的是，挂钩与DFO相比，与DFO相比，安全性得多要好得多，DFO在一项全面的I期安全试验后被指出。我们观察到，在创伤性脑损伤模型之后，HBED是最有效的。另外，我们发现dadmdft 通过改善无基质HB注射模型中的功能和解剖结局来提供益处。除了结合铁外，HBED还结合亚铁（有毒）铁，并将其转化为细胞中的铁（无毒）铁线粒体，防止促炎和促炎级联反应。 AIM 1是研究HAPD在DADMDFT和DFO上的功效，以改善神经行为和 ICH之后的解剖结局。我们将确定并比较最佳剂量反应和治疗性成年雄性小鼠和女性平行的HBED，DADMDFT和DFO的窗户。目标2、3和4是研究已知的吞噬受体CD36和CD163的重要性分别对RBC和HB的重要性使用自体血液临床前模型。我们将使用单个和双重淘汰赛（与匹配我们已经生成的C57BL/6同窝。目标是机械理解各自的这些吞噬受体的作用，因为它们应该参与RBC和血红蛋白的清除率并测试最佳铁螯合剂的额外好处，有助于限制氧化/炎症应激级联。随着时间的流逝，将监测毒性，并在铁螯合物。这个项目是及时的，我们相信我们已经通过工具，动物，模型和严格执行这些实验所需的专业知识。我们相信我们可以完成拟议的目的是通知我们的中风合作伙伴，使他们能够设计严格的临床试验。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Critical Role of Hemopexin Mediated Cytoprotection in the Pathophysiology of Sickle Cell Disease.

DOI：
10.3390/ijms22126408
发表时间：
2021-06-15
期刊：
International journal of molecular sciences
影响因子：
5.6
作者：
Ashouri R;Fangman M;Burris A;Ezenwa MO;Wilkie DJ;Doré S
通讯作者：
Doré S

Nutritional Supplementation of Naturally Occurring Vitamin D to Improve Hemorrhagic Stroke Outcomes.

DOI：
10.3389/fneur.2021.670245
发表时间：
2021
期刊：
Frontiers in neurology
影响因子：
3.4
作者：
Ashouri R;Fangman M;Brielmaier J;Fields ZA;Campo N;Doré S
通讯作者：
Doré S

Genome-Wide Association Study of Clinical Outcome After Aneurysmal Subarachnoid Haemorrhage: Protocol.

DOI：
10.1007/s12975-021-00978-2
发表时间：
2022-08
期刊：
TRANSLATIONAL STROKE RESEARCH
影响因子：
6.9
作者：
Gaastra, Ben;Alexander, Sheila;Bakker, Mark K.;Bhagat, Hemant;Bijlenga, Philippe;Blackburn, Spiros;Collins, Malie K.;Dore, Sylvain;Griessenauer, Christoph;Hendrix, Philipp;Hong, Eun Pyo;Hostettler, Isabel C.;Houlden, Henry;IIhara, Koji;Jeon, Jin Pyeong;Kim, Bong Jun;Kumar, Munish;Morel, Sandrine;Nyquist, Paul;Ren, Dianxu;Ruigrok, Ynte M.;Werring, David;Galea, Ian;Bulters, Diederik;Tapper, Will
通讯作者：
Tapper, Will

Effects of Sound Interventions on the Permeability of the Blood-Brain Barrier and Meningeal Lymphatic Clearance.