Open Access
Antioxidants, volume 9, issue 6, pages 467
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+
Li Litao
1
,
Tovmasyan Artak
2
,
Sheng Huaxin
1
,
Xu Bin
1
,
Sampaio Romulo S
3
,
Reboucas Julio S.
3
,
Warner David S.
1
,
Batinic-Haberle Ines
2
,
Spasojevic Ivan
4, 5
1
Multidisciplinary Neuroprotection Laboratories, Departments of Anesthesiology, Biomedical Engineering, Neurobiology, and Neurosurgery, Duke University School of Medicine, Durham, NC 27710, USA
|
2
Department of Radiation Oncology, Duke University School of Medicine, Durham, NC 27710, USA
|
3
Departamento de Química, CCEN, Universidade Federal da Paraíba, João Pessoa, PB 58051-900, Brazil
|
4
Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA
|
5
PK/PD Core Laboratory, Duke Cancer Institute, Duke University School of Medicine, Durham, NC 27710, USA
|
Publication type: Journal Article
Publication date: 2020-06-01
PubMed ID:
32492872
Biochemistry
Molecular Biology
Cell Biology
Clinical Biochemistry
Physiology
Abstract
Mn(III) meso-tetrakis(N-n-hexylpyridinium-2-yl)porphyrin, (H2O)MnTnHex-2-PyP5+ (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-PyP4+ (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 E. coli model of oxidative stress. In vivo, it does not cause arterial hypotension and is less toxic to mice. We thus evaluated FeHex versus 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 vs. 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.
Citations by journals
|
1
|
|
|
International Journal of Molecular Sciences
|
International Journal of Molecular Sciences
1 publication, 16.67%
|
|
Pain
|
Pain
1 publication, 16.67%
|
|
Antioxidants
|
Antioxidants
1 publication, 16.67%
|
|
Journal of Intensive Medicine
|
Journal of Intensive Medicine
1 publication, 16.67%
|
|
Redox Report
|
Redox Report
1 publication, 16.67%
|
|
Clinical Interventions in Aging
|
Clinical Interventions in Aging
1 publication, 16.67%
|
|
1
|
Citations by publishers
|
1
2
|
|
|
Multidisciplinary Digital Publishing Institute (MDPI)
|
Multidisciplinary Digital Publishing Institute (MDPI)
2 publications, 33.33%
|
|
Wolters Kluwer Health
|
Wolters Kluwer Health
1 publication, 16.67%
|
|
Elsevier
|
Elsevier
1 publication, 16.67%
|
|
Taylor & Francis
|
Taylor & Francis
1 publication, 16.67%
|
|
Dove Medical Press
|
Dove Medical Press
1 publication, 16.67%
|
|
1
2
|
- We do not take into account publications that without a DOI.
- Statistics recalculated only for publications connected to researchers, organizations and labs registered on the platform.
- Statistics recalculated weekly.
{"yearsCitations":{"type":"bar","data":{"show":true,"labels":[2020,2021,2022,2023],"ids":[0,0,0,0],"codes":[0,0,0,0],"imageUrls":["","","",""],"datasets":[{"label":"Citations number","data":[1,3,1,1],"backgroundColor":["#3B82F6","#3B82F6","#3B82F6","#3B82F6"],"percentage":["16.67","50","16.67","16.67"],"barThickness":null}]},"options":{"indexAxis":"x","maintainAspectRatio":true,"scales":{"y":{"ticks":{"precision":0,"autoSkip":false,"font":{"family":"Montserrat"},"color":"#000000"}},"x":{"ticks":{"stepSize":1,"precision":0,"font":{"family":"Montserrat"},"color":"#000000"}}},"plugins":{"legend":{"position":"top","labels":{"font":{"family":"Montserrat"},"color":"#000000"}},"title":{"display":true,"text":"Citations per year","font":{"size":24,"family":"Montserrat","weight":600},"color":"#000000"}}}},"journals":{"type":"bar","data":{"show":true,"labels":["International Journal of Molecular Sciences","Pain","Antioxidants","Journal of Intensive Medicine","Redox Report","Clinical Interventions in Aging"],"ids":[14627,649,16381,28504,9714,15516],"codes":[0,0,0,0,0,0],"imageUrls":["\/storage\/images\/resized\/MjH1ITP7lMYGxeqUZfkt2BnVLgjkk413jwBV97XX_medium.webp","\/storage\/images\/resized\/6QE8LXWrLpkoy5A2te6hw7who46GeCoTYIstuoAz_medium.webp","\/storage\/images\/resized\/MjH1ITP7lMYGxeqUZfkt2BnVLgjkk413jwBV97XX_medium.webp","\/storage\/images\/resized\/GDnYOu1UpMMfMMRV6Aqle4H0YLLsraeD9IP9qScG_medium.webp","\/storage\/images\/resized\/5YZtvLvkPZuc2JHOaZsjCvGSHFCuC3drUwN3YAc5_medium.webp","\/storage\/images\/resized\/wVWp6zaxUsMdR03dYMdOZoesUrVGtNMWkHKByIvT_medium.webp"],"datasets":[{"label":"","data":[1,1,1,1,1,1],"backgroundColor":["#3B82F6","#3B82F6","#3B82F6","#3B82F6","#3B82F6","#3B82F6"],"percentage":[16.67,16.67,16.67,16.67,16.67,16.67],"barThickness":13}]},"options":{"indexAxis":"y","maintainAspectRatio":false,"scales":{"y":{"ticks":{"precision":0,"autoSkip":false,"font":{"family":"Montserrat"},"color":"#000000"}},"x":{"ticks":{"stepSize":null,"precision":0,"font":{"family":"Montserrat"},"color":"#000000"}}},"plugins":{"legend":{"position":"top","labels":{"font":{"family":"Montserrat"},"color":"#000000"}},"title":{"display":true,"text":"Journals","font":{"size":24,"family":"Montserrat","weight":600},"color":"#000000"}}}},"publishers":{"type":"bar","data":{"show":true,"labels":["Multidisciplinary Digital Publishing Institute (MDPI)","Wolters Kluwer Health","Elsevier","Taylor & Francis","Dove Medical Press"],"ids":[202,32,17,18,417],"codes":[0,0,0,0,0],"imageUrls":["\/storage\/images\/resized\/MjH1ITP7lMYGxeqUZfkt2BnVLgjkk413jwBV97XX_medium.webp","\/storage\/images\/resized\/6QE8LXWrLpkoy5A2te6hw7who46GeCoTYIstuoAz_medium.webp","\/storage\/images\/resized\/GDnYOu1UpMMfMMRV6Aqle4H0YLLsraeD9IP9qScG_medium.webp","\/storage\/images\/resized\/5YZtvLvkPZuc2JHOaZsjCvGSHFCuC3drUwN3YAc5_medium.webp","\/storage\/images\/resized\/wVWp6zaxUsMdR03dYMdOZoesUrVGtNMWkHKByIvT_medium.webp"],"datasets":[{"label":"","data":[2,1,1,1,1],"backgroundColor":["#3B82F6","#3B82F6","#3B82F6","#3B82F6","#3B82F6"],"percentage":[33.33,16.67,16.67,16.67,16.67],"barThickness":13}]},"options":{"indexAxis":"y","maintainAspectRatio":false,"scales":{"y":{"ticks":{"precision":0,"autoSkip":false,"font":{"family":"Montserrat"},"color":"#000000"}},"x":{"ticks":{"stepSize":null,"precision":0,"font":{"family":"Montserrat"},"color":"#000000"}}},"plugins":{"legend":{"position":"top","labels":{"font":{"family":"Montserrat"},"color":"#000000"}},"title":{"display":true,"text":"Publishers","font":{"size":24,"family":"Montserrat","weight":600},"color":"#000000"}}}}}
Metrics
Cite this
GOST |
RIS |
BibTex |
MLA
Cite this
GOST
Copy
Li L. et al. 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+ // Antioxidants. 2020. Vol. 9. No. 6. p. 467.
GOST all authors (up to 50)
Copy
Li L., Tovmasyan A., Sheng H., Xu B., Sampaio R. S., Reboucas J. S., Warner D., Batinic-Haberle I., Spasojevic I. 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+ // Antioxidants. 2020. Vol. 9. No. 6. p. 467.
Cite this
RIS
Copy
TY - JOUR
DO - 10.3390/antiox9060467
UR - https://doi.org/10.3390%2Fantiox9060467
TI - 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+
T2 - Antioxidants
AU - Li, Litao
AU - Tovmasyan, Artak
AU - Sheng, Huaxin
AU - Sampaio, Romulo S
AU - Warner, David S.
AU - Batinic-Haberle, Ines
AU - Spasojevic, Ivan
AU - Xu, Bin
AU - Reboucas, Julio S.
PY - 2020
DA - 2020/06/01 00:00:00
PB - Multidisciplinary Digital Publishing Institute (MDPI)
SP - 467
IS - 6
VL - 9
PMID - 32492872
SN - 2076-3921
ER -
Cite this
BibTex
Copy
@article{2020_Li,
author = {Litao Li and Artak Tovmasyan and Huaxin Sheng and Romulo S Sampaio and David S. Warner and Ines Batinic-Haberle and Ivan Spasojevic and Bin Xu and Julio S. Reboucas},
title = {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+},
journal = {Antioxidants},
year = {2020},
volume = {9},
publisher = {Multidisciplinary Digital Publishing Institute (MDPI)},
month = {jun},
url = {https://doi.org/10.3390%2Fantiox9060467},
number = {6},
pages = {467},
doi = {10.3390/antiox9060467}
}
Cite this
MLA
Copy
Li, Litao, et al. “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+.” Antioxidants, vol. 9, no. 6, Jun. 2020, p. 467. https://doi.org/10.3390%2Fantiox9060467.