Fe porphyrin-based Redox Modulator in Experimental Stroke Outcome

基于铁卟啉的氧化还原调节剂在实验性中风结果中的应用

基本信息

批准号：
8642688
负责人：
Ines Batinic-Haberle
金额：
$ 7.77万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-01 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8642688
关键词：
8-hydroxy-2&apos -deoxyguanosine Aconitate Hydratase Adverse effects Aerobic Aftercare Alteplase Animals Antioxidants Binding Biological Biological Assay Biology Blood - brain barrier anatomy Blood flow Brain Cause of Death Cell Death Cell membrane Cells Central Nervous System Diseases Cerebrum Cessation of life Charge Chemistry Clinical Trials Complex Consumption Cytosol Dose Dose-Limiting Drug Metabolic Detoxication Enzymes Escherichia coli FDA approved Failure Free Radical Scavengers Free Radical Scavenging Generations Genetic Transcription Geometry Growth Heart Diseases Hour Hypotension Infarction Inflammation Inflammatory Interleukin-6 Ischemic Stroke Knowledge Ligands Malignant Neoplasms Measures Metalloporphyrins Metals Middle Cerebral Artery Occlusion Mitochondria Modeling Molecular Molecular Structure Mus NF-kappa B Nervous System Physiology Neurological outcome Neurons Nitrogen Outcome Oxidants Oxidation-Reduction Oxidative Stress Oxygen Pathway interactions Pharmaceutical Preparations Phase Physiological Plasma Play Porphyrins Process Production Property Protein Isoforms Rattus Reaction Relative (related person)Reperfusion Therapy Reporting Role Safety Series Signal Pathway Site Stroke Stroke prevention Sulfur Superoxide Dismutase System TNF gene Therapeutic Toxic effect Transcription Factor AP-1 Treatment Efficacy United States Ursidae Family analog attenuation base brain tissue cytokine improved interest lipophilicity metal complex mitochondrial membrane nervous system disorder nitrone oxidative damage post stroke public health relevance response screening transcription factor

项目摘要

DESCRIPTION (provided by applicant): Currently, there are no effective drugs for stroke other than thrombolytics. In the early phase of stroke mitochondria contribute to the production of reactive species. Thus therapeutics able to accumulate in mitochondria are preferable. Superoxide dismutase, both mitochondrial MnSOD and cytosolic Cu,ZnSOD isoform, plays a key role in ischemic stroke, maintaining the physiological redox status of the cell. These enzymes operate via redox-based reactions of their metal site (Fe, Cu, Ni and Mn) with O2-. Our focus has been study of redox-active metal complexes as therapeutics which can penetrate cell and mitochondrial membranes and the blood brain barrier (BBB). We have developed cationic complexes of Mn(III) with N- substituted pyridylporphyrins; a cyclic porphyrin ligand assures the extreme stability of the metal complex and thus integrity of the metal site where redox reactions of interest occur. The potency of these compounds approaches that of SOD enzymes. Like SOD enzymes, Mn porphyrins suppress oxidative stress and excessive inflammation via direct reactions with reactive species (e.g., O2-, .NO, and OONO-) and via redox modulation of NF-?B, HIF-1¿, AP-1, and SP-1 transcription. The early generation redox-active and lipophilic cationic compound (H2O)MnTnHex-2-PyP5+ crosses BBB and accumulates in mitochondria 3.6-fold more than in cytosol. It improved neurologic outcome and decreased infarct size and inflammation in a rat middle cerebral artery occlusion stroke model. Yet, the dose and the therapeutic efficacy of Mn porphyrin were limited due to an adverse effect of arterial hypotension. Its Fe analog, (OH)FeTnHex-2-PyP4+, was recently synthesized and fully characterized. Both Fe and Mn porphyrins are equally lipophilic, have similar ability to mimic SOD enzymes, but bear different coordination geometry of the metal site. Due to different molecular structure, Fe porphyrin does not cause arterial hypotension in experimental animals, it is less toxic, and exerts ~2-orders of magnitude higher efficacy in a SOD-deficient E. coli screening model of oxidative stress. When compared to Fe porphyrin, the failure of free radical scavenger, nitrone NXY-059 in stroke clinical trials may be attributed to its ~100-fold lower efficacy in scavenging free radicals, failure in E. coli screening model of oxidative stress, and inability to accumulate in mitochondria due to its anionic charge. We propose to define efficacy of Fe analog in a mouse stroke model, which will open access to a whole new class of drugs with higher potency and safety, not only for stroke but potentially other CNS disorders including CNS malignancies.

描述（由申请人提供）：目前，除了溶栓剂之外，尚无有效的中风药物。在中风早期，线粒体有助于产生活性物质，因此优选能够在线粒体中积累的治疗剂，即线粒体超氧化物歧化酶。 MnSOD 和胞质 Cu、ZnSOD 亚型在缺血性中风中发挥着关键作用，维持细胞的生理氧化还原状态，这些酶通过其金属位点的氧化还原反应发挥作用。（Fe、Cu、Ni 和 Mn）与 O2- 我们的重点是研究具有氧化还原活性的金属络合物作为治疗剂，该络合物可以穿透细胞和线粒体膜以及血脑屏障 (BBB)。 III) 具有 N-取代的吡啶基卟啉；环状卟啉配体确保了金属络合物的极端稳定性，从而确保了发生感兴趣的氧化还原反应的金属位点的完整性。与 SOD 酶一样，锰卟啉通过与活性物质（例如 O2-、NO 和 OONO-）直接反应以及通过 NF-κB、HIF-1¿ 的氧化还原调节来抑制氧化应激和过度炎症。、AP-1 和 SP-1 转录。早期产生的氧化还原活性和亲脂性阳离子化合物 (H2O)MnTnHex-2-PyP5+ 穿过 BBB，在线粒体中的积累量是细胞质中的 3.6 倍，它改善了神经系统结果并减少了梗塞。然而，由于锰卟啉的副作用，其剂量和治疗效果受到限制。其 Fe 类似物 (OH)FeTnHex-2-PyP4+ 最近被合成并得到充分表征，Fe 和 Mn 卟啉具有相同的亲脂性，具有相似的模拟 SOD 酶的能力，但具有不同的金属位点配位几何形状。由于分子结构不同，铁卟啉不会引起实验动物动脉低血压，毒性较小，并且在动物体内发挥约2个数量级的功效。缺乏 SOD 的大肠杆菌氧化应激筛选模型与铁卟啉相比，自由基清除剂硝酮 NXY-059 在中风临床试验中的失败可能归因于其清除自由基的功效低约 100 倍。在氧化应激的大肠杆菌筛选模型中，以及由于其阴离子电荷而无法在线粒体中积累，我们建议定义铁类似物在小鼠中风模型中的功效，这将有助于确定铁类似物在小鼠中风模型中的功效。开放获取具有更高效力和安全性的全新一类药物，不仅可以治疗中风，还可以治疗其他中枢神经系统疾病，包括中枢神经系统恶性肿瘤。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Complex chemistry and biology of redox-active compounds, commonly known as SOD mimics, affect their therapeutic effects.

氧化还原活性化合物（通常称为 SOD 模拟物）的复杂化学和生物学会影响其治疗效果。

DOI：
发表时间：
2014-05-20
期刊：
影响因子：
6.6
作者：
Batinic;Spasojevic, Ivan
通讯作者：
Spasojevic, Ivan

Fe Porphyrin-Based SOD Mimic and Redox-Active Compound, (OH)FeTnHex-2-PyP4+, in a Rodent Ischemic Stroke (MCAO) Model: Efficacy and Pharmacokinetics as Compared to Its Mn Analogue, (H2O)MnTnHex-2-PyP5+.

Fe 卟啉基 SOD 模拟物和氧化还原活性化合物 (OH)FeTnHex-2-PyP4 在啮齿动物缺血性中风 (MCAO) 模型中：与其 Mn 类似物 (H2O)MnTnHex-2-PyP5 相比的功效和药代动力学。

DOI：
发表时间：
2020
期刊：
影响因子：
0
作者：
Li, Litao;Tovmasyan, Artak;Sheng, Huaxin;Xu, Bin;Sampaio, Romulo S;Reboucas, Julio S;Warner, David S;Batinic;Spasojevic, Ivan
通讯作者：
Spasojevic, Ivan

Redox-Active Mn Porphyrin-based Potent SOD Mimic, MnTnBuOE-2-PyP(5+), Enhances Carbenoxolone-Mediated TRAIL-Induced Apoptosis in Glioblastoma Multiforme.

基于氧化还原活性的锰卟啉的强效 SOD 模拟物 MnTnBuOE-2-PyP(5)，可增强多形性胶质母细胞瘤中 Carbenoxolone 介导的 TRAIL 诱导的细胞凋亡。