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+.

dc.contributor.author

Li, Litao

dc.contributor.author

Tovmasyan, Artak

dc.contributor.author

Sheng, Huaxin

dc.contributor.author

Xu, Bin

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Sampaio, Romulo S

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Reboucas, Julio S

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Warner, David S

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Batinic-Haberle, Ines

dc.contributor.author

Spasojevic, Ivan

dc.date.accessioned

2021-06-01T13:42:36Z

dc.date.available

2021-06-01T13:42:36Z

dc.date.issued

2020-06

dc.date.updated

2021-06-01T13:42:34Z

dc.description.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.

dc.identifier

antiox9060467

dc.identifier.issn

2076-3921

dc.identifier.issn

2076-3921

dc.identifier.uri

https://hdl.handle.net/10161/23240

dc.language

eng

dc.publisher

MDPI AG

dc.relation.ispartof

Antioxidants (Basel, Switzerland)

dc.relation.isversionof

10.3390/antiox9060467

dc.subject

FeTnHex-2-PyP5+

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MCAO

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MnTnHex-2-PyP5+

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SOD mimics

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pharmacokinetics

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rodent middle cerebral artery occlusion

dc.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+.

dc.type

Journal article

duke.contributor.orcid

Sheng, Huaxin|0000-0002-4325-2940

duke.contributor.orcid

Spasojevic, Ivan|0000-0001-9890-6246

pubs.begin-page

467

pubs.end-page

467

pubs.issue

6

pubs.organisational-group

School of Medicine

pubs.organisational-group

Radiation Oncology

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Duke

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Clinical Science Departments

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Anesthesiology

pubs.organisational-group

Neurobiology

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Duke Institute for Brain Sciences

pubs.organisational-group

Surgery

pubs.organisational-group

Anesthesiology, Neuroanesthesia

pubs.organisational-group

Basic Science Departments

pubs.organisational-group

University Institutes and Centers

pubs.organisational-group

Institutes and Provost's Academic Units

pubs.publication-status

Published

pubs.volume

9

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