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，转录因子 Nrf2 是氧化的主要调节因子压力和炎症，作为中风治疗的一种有前途的策略，我们和其他人也记录了这一点。 PI 实验室积累的证据表明，CO 和“CO 供体”可以提供神经保护作用。小分子，如富马酸二甲酯 (DMF)，一种临床上使用的典型 Nrf2 诱导剂，以及与作为有毒物质的传统观点相反，低剂量的 CO 具有持续的神经保护作用尤其是通过 Nrf2 途径对抗缺血性脑损伤和功能缺陷的功效。经过测试，我们预测含有富马酸甲酯和释放 CO 的分子分子单元（即 FumET-CORM）可能具有有趣且有前途的治疗潜力。初步结果表明，CO 或 DMF 暴露对短暂性和永久性局灶性损伤均具有保护作用。 FumET-CORM 已被证明具有抗炎作用。这促使我们假设新的 FumET-CORM 将具有保护作用。永久性远端大脑中动脉闭塞（pdMCAO）后的神经功能缺损和梗塞；这种有益作用至少部分是由 Nrf2 细胞保护途径调节的。在 AIM 1 中，我们将确定 FumET-CORM（与其非活动 iFumET-CORM）是否具有保护作用 pdMCAO 后的神经功能缺损和脑损伤我们将测试剂量反应和治疗方法。窗口方案以确定雄性和雌性成年小鼠的最佳有益剂量方案。结果将基于神经/认知变化，并且将进行各种 IHC 染色以开始还将监测各种假定的毒性途径的影响。老年同窝仔鼠的剂量/治疗方案将延长。在 AIM 2 中，我们将研究 Nrf2 通路是否在 FumET-CORM“双- 行动药物”的有益机制，并开始解决哪种脑细胞类型负责这种作用首先使用联合免疫染色方法进行神经保护，我们将使用目标 1 的最佳条件。使用全局 Nrf2-/- C57BL/6 小鼠评估 Nrf2 通路的贡献，并确定哪些脑细胞类型揭示了最深刻的 Nrf2 相关变化，这将决定未来最重要的测试。合适的诱导型 Nrf2 flox-cre 小鼠——使用最新且最具选择性的 cre 小鼠。我们将一起检验以下假设：FumET-CORM 的一些推定有益效果对脑损伤的“双重作用药物”至少部分归因于 Nrf2，哪些细胞最能发挥作用负责假定的神经保护，这可以用于缺血性中风患者和现在我们需要这种 R21 机制来获取现在所需的数据。为了测试这个工作假设，我们拥有团队和专业知识来完成这个为期两年的提案。