Fe Porphyrin-Based SOD Mimic and Redox-Active Compound, (OH)FeTnHex-2-PyP<sup>4+</sup>, in a Rodent Ischemic Stroke (MCAO) Model: Efficacy and Pharmacokinetics as Compared to Its Mn Analogue, (H<sub>2</sub>O)MnTnHex-2-PyP<sup>5+</sup>
Mn(III) meso-tetrakis(N-n-hexylpyridinium-2-yl)porphyrin, (H<sub>2</sub>O)MnTnHex-2-PyP<sup>5+</sup> (MnHex) carrying long hexyl chains, is a lipophilic mimic of superoxide dismutase (SOD) and a redox-active drug candidate. MnHex crosses the blood–brain barrier, and improved...
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MDPI AG
2020-06-01
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language |
English |
format |
Article |
sources |
DOAJ |
author |
Litao Li Artak Tovmasyan Huaxin Sheng Bin Xu Romulo S. Sampaio Julio S. Reboucas David S. Warner Ines Batinic-Haberle Ivan Spasojevic |
spellingShingle |
Litao Li Artak Tovmasyan Huaxin Sheng Bin Xu Romulo S. Sampaio Julio S. Reboucas David S. Warner Ines Batinic-Haberle Ivan Spasojevic Fe Porphyrin-Based SOD Mimic and Redox-Active Compound, (OH)FeTnHex-2-PyP<sup>4+</sup>, in a Rodent Ischemic Stroke (MCAO) Model: Efficacy and Pharmacokinetics as Compared to Its Mn Analogue, (H<sub>2</sub>O)MnTnHex-2-PyP<sup>5+</sup> Antioxidants MnTnHex-2-PyP5+ FeTnHex-2-PyP5+ SOD mimics pharmacokinetics rodent middle cerebral artery occlusion MCAO |
author_facet |
Litao Li Artak Tovmasyan Huaxin Sheng Bin Xu Romulo S. Sampaio Julio S. Reboucas David S. Warner Ines Batinic-Haberle Ivan Spasojevic |
author_sort |
Litao Li |
title |
Fe Porphyrin-Based SOD Mimic and Redox-Active Compound, (OH)FeTnHex-2-PyP<sup>4+</sup>, in a Rodent Ischemic Stroke (MCAO) Model: Efficacy and Pharmacokinetics as Compared to Its Mn Analogue, (H<sub>2</sub>O)MnTnHex-2-PyP<sup>5+</sup> |
title_short |
Fe Porphyrin-Based SOD Mimic and Redox-Active Compound, (OH)FeTnHex-2-PyP<sup>4+</sup>, in a Rodent Ischemic Stroke (MCAO) Model: Efficacy and Pharmacokinetics as Compared to Its Mn Analogue, (H<sub>2</sub>O)MnTnHex-2-PyP<sup>5+</sup> |
title_full |
Fe Porphyrin-Based SOD Mimic and Redox-Active Compound, (OH)FeTnHex-2-PyP<sup>4+</sup>, in a Rodent Ischemic Stroke (MCAO) Model: Efficacy and Pharmacokinetics as Compared to Its Mn Analogue, (H<sub>2</sub>O)MnTnHex-2-PyP<sup>5+</sup> |
title_fullStr |
Fe Porphyrin-Based SOD Mimic and Redox-Active Compound, (OH)FeTnHex-2-PyP<sup>4+</sup>, in a Rodent Ischemic Stroke (MCAO) Model: Efficacy and Pharmacokinetics as Compared to Its Mn Analogue, (H<sub>2</sub>O)MnTnHex-2-PyP<sup>5+</sup> |
title_full_unstemmed |
Fe Porphyrin-Based SOD Mimic and Redox-Active Compound, (OH)FeTnHex-2-PyP<sup>4+</sup>, in a Rodent Ischemic Stroke (MCAO) Model: Efficacy and Pharmacokinetics as Compared to Its Mn Analogue, (H<sub>2</sub>O)MnTnHex-2-PyP<sup>5+</sup> |
title_sort |
fe porphyrin-based sod mimic and redox-active compound, (oh)fetnhex-2-pyp<sup>4+</sup>, in a rodent ischemic stroke (mcao) model: efficacy and pharmacokinetics as compared to its mn analogue, (h<sub>2</sub>o)mntnhex-2-pyp<sup>5+</sup> |
publisher |
MDPI AG |
series |
Antioxidants |
issn |
2076-3921 |
publishDate |
2020-06-01 |
description |
Mn(III) meso-tetrakis(N-n-hexylpyridinium-2-yl)porphyrin, (H<sub>2</sub>O)MnTnHex-2-PyP<sup>5+</sup> (MnHex) carrying long hexyl chains, is a lipophilic mimic of superoxide dismutase (SOD) and a redox-active drug candidate. MnHex crosses the blood–brain barrier, and improved neurologic outcome and decreased infarct size and inflammation in a rat middle cerebral artery occlusion (MCAO) ischemic stroke model. Yet, the dose and the therapeutic efficacy of Mn porphyrin were limited by an adverse effect of arterial hypotension. An equally lipophilic Fe analog, (OH)FeTnHex-2-PyP<sup>4+</sup> (FeHex), is as redox-active and potent SOD mimic in vitro. With different coordination geometry of the metal site, FeHex has one hydroxo (OH) ligand (instead of water) bound to the Fe center in the axial position. It has ~2 orders of magnitude higher efficacy than MnHex in an SOD-deficient <i>E. coli</i> model of oxidative stress. In vivo, it does not cause arterial hypotension and is less toxic to mice. We thus evaluated FeHex <i>versus</i> MnHex in a rodent MCAO model. We first performed short- and long-term pharmacokinetics (PK) of both porphyrins in the plasma, brain, and liver of rats and mice. Given that damage to the brain during stroke occurs very rapidly, fast delivery of a sufficient dose of drug is important. Therefore, we aimed to demonstrate if, and how fast after reperfusion, Fe porphyrin reaches the brain relative to the Mn analog. A markedly different plasma half-life was found with FeHex (~23 h) than with MnHex (~1.4 h), which resulted in a more than 2-fold higher plasma exposure (AUC) in a 7-day twice-daily treatment of rats. The increased plasma half-life is explained by the much lower liver retention of FeHex than typically found in Mn analogs. In the brain, a 3-day mouse PK study showed similar levels of MnHex and FeHex. The same result was obtained in a 7-day rat PK study, despite the higher plasma exposure of FeHex. Importantly, in a short-term PK study with treatment starting 2 h post MCAO, both Fe- and Mn- analogs distributed at a higher level to the injured brain hemisphere, with a more pronounced effect observed with FeHex. While a 3-day mouse MCAO study suggested the efficacy of Fe porphyrin, in a 7-day rat MCAO study, Mn-, but not Fe porphyrin, was efficacious. The observed lack of FeHex efficacy was discussed in terms of significant differences in the chemistry of Fe<i> </i><i>vs</i> the Mn center of metalloporphyrin; relative to MnHex, FeHex has the propensity for axial coordination, which in vivo would preclude the reactivity of the Fe center towards small reactive species. |
topic |
MnTnHex-2-PyP5+ FeTnHex-2-PyP5+ SOD mimics pharmacokinetics rodent middle cerebral artery occlusion MCAO |
url |
https://www.mdpi.com/2076-3921/9/6/467 |
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doaj-d83788040c914f609e0dafa1e226aa0f2020-11-25T03:07:58ZengMDPI AGAntioxidants2076-39212020-06-01946746710.3390/antiox9060467Fe Porphyrin-Based SOD Mimic and Redox-Active Compound, (OH)FeTnHex-2-PyP<sup>4+</sup>, in a Rodent Ischemic Stroke (MCAO) Model: Efficacy and Pharmacokinetics as Compared to Its Mn Analogue, (H<sub>2</sub>O)MnTnHex-2-PyP<sup>5+</sup>Litao Li0Artak Tovmasyan1Huaxin Sheng2Bin Xu3Romulo S. Sampaio4Julio S. Reboucas5David S. Warner6Ines Batinic-Haberle7Ivan Spasojevic8Multidisciplinary Neuroprotection Laboratories, Departments of Anesthesiology, Biomedical Engineering, Neurobiology, and Neurosurgery, Duke University School of Medicine, Durham, NC 27710, USADepartment of Radiation Oncology, Duke University School of Medicine, Durham, NC 27710, USAMultidisciplinary Neuroprotection Laboratories, Departments of Anesthesiology, Biomedical Engineering, Neurobiology, and Neurosurgery, Duke University School of Medicine, Durham, NC 27710, USAMultidisciplinary Neuroprotection Laboratories, Departments of Anesthesiology, Biomedical Engineering, Neurobiology, and Neurosurgery, Duke University School of Medicine, Durham, NC 27710, USADepartamento de Química, CCEN, Universidade Federal da Paraíba, João Pessoa, PB 58051-900, BrazilDepartamento de Química, CCEN, Universidade Federal da Paraíba, João Pessoa, PB 58051-900, BrazilMultidisciplinary Neuroprotection Laboratories, Departments of Anesthesiology, Biomedical Engineering, Neurobiology, and Neurosurgery, Duke University School of Medicine, Durham, NC 27710, USADepartment of Radiation Oncology, Duke University School of Medicine, Durham, NC 27710, USADepartment of Medicine, Duke University School of Medicine, Durham, NC 27710, USAMn(III) meso-tetrakis(N-n-hexylpyridinium-2-yl)porphyrin, (H<sub>2</sub>O)MnTnHex-2-PyP<sup>5+</sup> (MnHex) carrying long hexyl chains, is a lipophilic mimic of superoxide dismutase (SOD) and a redox-active drug candidate. MnHex crosses the blood–brain barrier, and improved neurologic outcome and decreased infarct size and inflammation in a rat middle cerebral artery occlusion (MCAO) ischemic stroke model. Yet, the dose and the therapeutic efficacy of Mn porphyrin were limited by an adverse effect of arterial hypotension. An equally lipophilic Fe analog, (OH)FeTnHex-2-PyP<sup>4+</sup> (FeHex), is as redox-active and potent SOD mimic in vitro. With different coordination geometry of the metal site, FeHex has one hydroxo (OH) ligand (instead of water) bound to the Fe center in the axial position. It has ~2 orders of magnitude higher efficacy than MnHex in an SOD-deficient <i>E. coli</i> model of oxidative stress. In vivo, it does not cause arterial hypotension and is less toxic to mice. We thus evaluated FeHex <i>versus</i> MnHex in a rodent MCAO model. We first performed short- and long-term pharmacokinetics (PK) of both porphyrins in the plasma, brain, and liver of rats and mice. Given that damage to the brain during stroke occurs very rapidly, fast delivery of a sufficient dose of drug is important. Therefore, we aimed to demonstrate if, and how fast after reperfusion, Fe porphyrin reaches the brain relative to the Mn analog. A markedly different plasma half-life was found with FeHex (~23 h) than with MnHex (~1.4 h), which resulted in a more than 2-fold higher plasma exposure (AUC) in a 7-day twice-daily treatment of rats. The increased plasma half-life is explained by the much lower liver retention of FeHex than typically found in Mn analogs. In the brain, a 3-day mouse PK study showed similar levels of MnHex and FeHex. The same result was obtained in a 7-day rat PK study, despite the higher plasma exposure of FeHex. Importantly, in a short-term PK study with treatment starting 2 h post MCAO, both Fe- and Mn- analogs distributed at a higher level to the injured brain hemisphere, with a more pronounced effect observed with FeHex. While a 3-day mouse MCAO study suggested the efficacy of Fe porphyrin, in a 7-day rat MCAO study, Mn-, but not Fe porphyrin, was efficacious. The observed lack of FeHex efficacy was discussed in terms of significant differences in the chemistry of Fe<i> </i><i>vs</i> the Mn center of metalloporphyrin; relative to MnHex, FeHex has the propensity for axial coordination, which in vivo would preclude the reactivity of the Fe center towards small reactive species.https://www.mdpi.com/2076-3921/9/6/467MnTnHex-2-PyP5+FeTnHex-2-PyP5+SOD mimicspharmacokineticsrodent middle cerebral artery occlusionMCAO |