Potential stroke therapeutic efficacy of FumET-CORM through the Nrf2 pathway

FumET-CORM 通过 Nrf2 通路的潜在中风治疗功效

基本信息

批准号：
9751526
负责人：
Sylvain DORE
金额：
$ 41.94万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9751526
关键词：
3-Dimensional Acute Address Adult Adverse effects Aftercare Animal Model Animals Anti-inflammatory Astrocytes Biological Blood Brain Brain Edema Brain Injuries Brain Ischemia C57BL/6 Mouse CD31 Antigens Cells Cerebral Ischemia Clinic Clinical Cognitive Cognitive deficits Data Dissociation Distal Documentation Dose Drug effect disorder Endothelial Cells Enzymes Exhibits Exploratory/Developmental Grant Exposure to FTH1 gene Female Fumarates Future Gases Glial Fibrillary Acidic Protein Haptoglobins Heme Iron Histologic Histology Histopathology Immunoglobulin G Infarction Inflammation Injury Ischemic Brain Injury Ischemic Stroke Liver Mediating Methodology Microglia Middle Cerebral Artery Occlusion Monitor Motor Activity Mus NQO1 gene Neurologic Neurologic Deficit Neurons Nuclear Outcome Outcome Measure Oxidative Stress Pathway interactions Pharmaceutical Preparations Pharmacologic Substance Phase Play Positioning Attribute Property Proteins Protocols documentation Recovery Regimen Reperfusion Therapy Reporting Research Research Project Grants Resistance Role SOD2 gene Stains Stroke Stroke prevention Testing Therapeutic Therapeutic Uses Time Toxic effect Treatment Efficacy Treatment Protocols Work aged base brain cell cell type cognitive change heme oxygenase-1 in vivo insight iron metabolism male mouse model nervous system disorder neuroprotection neutrophil novel object recognition preclinical development primary outcome protective effect response small molecule stroke outcome stroke patient stroke therapy tool trait transcription factor treatment response

项目摘要

We and others have been pioneers in targeting the transcriptional factor Nrf2, a master regulator of oxidative stress and inflammation, as a promising strategy for stroke therapy. We and others have also documented the possibility that CO and “CO donor” can provide neuroprotection. Accumulated evidence from the PI's lab show that small molecules such as the dimethyl fumarate (DMF), a typical Nrf2 inducer being used in the clinic, and CO at low doses, contrary to the traditional view as a toxic agent, have displayed sustained neuroprotective efficacy against ischemic brain damage and functional deficits notably via the Nrf2 pathway. Consequently, we would predict that a molecule containing both a methyl fumarate and CO-releasing molecule unit (i.e. FumET-CORM) could have an intriguing and promising therapeutic potential. Our preliminary results showed that CO or DMF exposure is protective in both transient and permanent focal cerebral ischemia mouse models. FumET-CORM has already been shown to exhibit anti-inflammatory property. This prompts us to work on the hypothesis that the new FumET-CORM would be protective against neurological deficits and infarct after permanent distal middle cerebral artery occlusion (pdMCAO); and that this beneficial effect would be, at least partially, regulated by the Nrf2 cytoprotective pathway. In AIM 1, we will determine whether FumET-CORM (vs its inactive iFumET-CORM) is protective against neurological deficits and brain damage following pdMCAO. We will test a dose response and a therapeutic window protocols to determine the optimal beneficial dose regimen in male and female adult mice. Primary outcomes will be based on neurological/cognitive changes, and various IHC staining will be performed to start exploring the implications of various putative pathways. Toxicity will also be monitored. The optimal dose/treatment regimen will be extended in the aged littermates. In AIM 2, we will examine whether the Nrf2 pathway plays a significant role in the FumET-CORM “dual- action drug” beneficial mechanism and start addressing which brain cell type(s) is responsible for such neuroprotection by first using a co-immunostaining approach. Using the optimal conditions from Aim 1, we will evaluate the contribution of Nrf2 pathway using global Nrf2-/- C57BL/6 mice, and also address which brain cell type(s) reveal the most profound Nrf2-related changes. This would then dictate the future test of the most appropriate inducible Nrf2 flox-cre mice – using the latest and most selective cre mice. Together, we will test the hypothesis that some of the imputed beneficial effects of the FumET-CORM “dual-action drug” on brain damage are attributed at least in part to Nrf2 and which cells can be most responsible for the putative neuroprotection. This could be administered to ischemic stroke patients and potentially other acute brain insults. This R21 mechanism is now necessary us to obtain the data now required to test this working hypothesis, and we have the team and expertise to accomplish this 2yr-proposal.

我们和其他人一直是针对转录因子NRF2的先驱，NRF2是氧化的主要调节剂压力和炎症是中风治疗的承诺策略。我们和其他人也记录了 CO和“ CO供体”可以提供神经保护作用的可能性。 PI实验室表演中积累了证据小分子，例如富马酸二甲基二甲基（DMF），诊所中使用的典型NRF2诱导剂，以及低剂量的CO与传统视图作为有毒药物形成鲜明对比，已显示出持续的神经保护作用对缺血性脑损伤和功能性缺陷的功效特别是通过NRF2途径。因此，我们将预测含有富马酸甲酯和共释的分子分子单位（即烟雾）可能具有有趣且有希望的治疗潜力。我们的初步结果表明，CO或DMF暴露在瞬态和永久性焦点中受到保护脑缺血小鼠模型。烟雾体已显示出表现出抗炎作用财产。这促使我们提出了这样的假设，即新的烟雾会受到保护神经系统定义和梗塞脑远端中部动脉闭塞（PDMCAO）；那这种有益的效果至少部分地受到NRF2细胞保护途径的调节。在AIM 1中，我们将确定是否保护Fumet-corm（Vs and Intivive Ifumet-corm）免受 PDMCAO后神经缺陷和脑损伤。我们将测试剂量反应和治疗窗户方案确定雄性和雌性小鼠最佳有益剂量方案。基本的结果将基于神经/认知的变化，并且将进行各种IHC染色以开始探索各种推定途径的含义。毒性也将受到监测。最佳剂量/治疗方案将在老年同窝室中扩展。在AIM 2中，我们将检查NRF2途径是否在Fumet-Corm“双重”中起重要作用动作药物的有益机制，并开始解决哪种脑细胞类型的原因首先使用共免疫染色方法通过神经保护作用。使用AIM 1的最佳条件，我们将使用全局NRF2 - / - C57BL/6小鼠评估NRF2途径的贡献，还解决了哪种脑细胞类型揭示了最深刻的NRF2相关变化。然后，这将决定最多的测试适当的诱导NRF2 Flox-Cre小鼠 - 使用最新和最选择性的Cre小鼠。我们将共同测试以下假设，即烟雾群的某些估算有益作用关于脑损伤的“双重药物”至少部分归因于NRF2，哪些细胞可以是最多的负责推定的神经保护作用。这可以用于缺血性中风患者，并且潜在的其他急性大脑侮辱。现在，我们有必要将此R21机制获取现在所需的数据为了检验这一工作假设，我们拥有团队和专业知识来完成这2年。