Robust rat pulmonary radioprotection by a lipophilic Mn N-alkylpyridylporphyrin, MnTnHex-2-PyP(5+)

Authors

Benjamin Gauter-Fleckenstein, Department of Radiation Oncology, Duke University School of Medicine, Durham, NC 27710, USA ; Department of Radiation Oncology, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Julio S. Reboucas, Department of Radiation Oncology, Duke University School of Medicine, Durham, NC 27710, USA.
Katharina Fleckenstein, Department of Radiation Oncology, Duke University School of Medicine, Durham, NC 27710, USA ; Department of Radiation Oncology, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Artak Tovmasyan, Department of Radiation Oncology, Duke University School of Medicine, Durham, NC 27710, USA.
Kouros Owzar, Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, USA ; Biostatistics and Computational Biology Core, RadCCORE, Duke University Medical Center, Durham, USA.
Chen Jiang, Biostatistics and Computational Biology Core, RadCCORE, Duke University Medical Center, Durham, USA.
Ines Batinic-Haberle, Department of Radiation Oncology, Duke University School of Medicine, Durham, NC 27710, USA.
Zeljko Vujaskovic, Department of Radiation Oncology, Duke University School of Medicine, Durham, NC 27710, USA ; Division of Translational Radiation Sciences, Department of Radiation Oncology, University of Maryland, 655W Baltimore Street, Bressler Research Building, 8-025, Baltimore, MD 21201, USA.

Document Type

Article

Abstract

With the goal to enhance the distribution of cationic Mn porphyrins within mitochondria, the lipophilic Mn(III)meso-tetrakis(N-n-hexylpyridinium-2-yl)porphyrin, MnTnHex-2-PyP(5+) has been synthesized and tested in several different model of diseases, where it shows remarkable efficacy at as low as 50 µg/kg single or multiple doses. Yet, in a rat lung radioprotection study, at higher 0.6-1 mg/kg doses, due to its high accumulation and micellar character, it became toxic. To avoid the toxicity, herein the pulmonary radioprotection of MnTnHex-2-PyP(5+) was assessed at 50 µg/kg. Fischer rats were irradiated to their right hemithorax (28 Gy) and treated with 0.05 mg/kg/day of MnTnHex-2-PyP(5+) for 2 weeks by subcutaneously-implanted osmotic pumps, starting at 2 h post-radiation. The body weights and breathing frequencies were followed for 10 weeks post-radiation, when the histopathology and immunohistochemistry were assessed. Impact of MnTnHex-2-PyP(5+) on macrophage recruitment (ED-1), DNA oxidative damage (8-OHdG), TGF-β1, VEGF(A) and HIF-1α were measured. MnTnHex-2-PyP(5+) significantly decreased radiation-induced lung histopathological (H&E staining) and functional damage (breathing frequencies), suppressed oxidative stress directly (8-OHdG), or indirectly, affecting TGF-β1, VEGF (A) and HIF-1α pathways. The magnitude of the therapeutic effects is similar to the effects demonstrated under same experimental conditions with 120-fold higher dose of ~5000-fold less lipophilic Mn(III)meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin, MnTE-2-PyP(5+).

Keywords

8-OHdG, 8-hydroxy-2'-deoxyguanosine, AKT, protein kinase B (PKB), a serine/threonine-specific protein kinase, ALS, amyotrophic laterial sclerosis, AP-1, activator protein-1, AT, ataxia telangiectasia, BBB, blood brain barrier, Breathing frequencies, CNS, central nervous system, CO3−, carbonate radical, ClO−, hypochlorite, ETC, mitochondrial electron transport chain, Fischer rats, GMP, good manufacturing practice, GS−, monodeprotonated glutathione, HIF-1α, hypoxia inducible factor-1, HO2−, monodeprotonated hydrogen peroxide, Histopathology, I/R, ischemia reperfusion, Immunohistochemistry, Lung injury, MCAO, middle cerebral artery occlusion, Manganese porphyrins, MnP, Mn porphyrin, MnTDE-2-ImP5+, Mn(III) tetrakis[N, N'-diethylimidazolium-2-yl)porphyrin, AEOL10150, MnTE-2-PyP5+, MnTE-2-PyP5+, Mn(III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin (AEOL10113), MnTnBuOE-2-PyP5+, Mn(III) meso-tetrakis(N-(n-butoxyethyl)pyridinium-2-yl)porphyrin, MnTnHex-2-PyP5+, MnTnHex-2-PyP5+, Mn(III) meso-tetrakis(N-(n-hexyl)pyridinium-2-yl)porphyrin (AEOL10113), NF-κB, nuclear factor κB, NHE, normal hydrogen electrode, NO, nitric oxide, NOX4, NADPH oxidase, isoform 4 E1/2, Half-wave metal-centered reduction potential, Nrf-2, nuclear factor-erythroid-derived 2-like 2, O2−, superoxide, ONOO−, peroxynitrite, PI3K, phosphatidylinositide 3-kinase, PTEN, phosphoinositide 3-phosphatase, Radioprotection, Redox-modulators, SAH, subarachnoid hemorrhage, SOD, superoxide dismutase, SP-1, specificity protein-1, TF, transcription factor, TGF-β1, one of the 3 members of the TGF-β transforming growth factor-β family, VEGF, vascular endothelial growth factor, mTOR, mammalian target of rapamycin (mTOR), a serine/threonine protein kinase

Medical Subject Headings

Animals; Body Weight (drug effects, radiation effects); Dose-Response Relationship, Radiation; Drug Administration Schedule; Female; Infusions, Subcutaneous; Lung (drug effects, pathology, radiation effects); Metalloporphyrins (administration & dosage, pharmacology); Oxidation-Reduction (drug effects, radiation effects); Radiation-Protective Agents (administration & dosage, pharmacology); Rats; Rats, Inbred F344; Signal Transduction (drug effects, radiation effects)

Publication Date

1-1-2014

Publication Title

Redox biology

ISSN

2213-2317

Volume

2

First Page

400

Last Page

10

PubMed ID

24624330

Digital Object Identifier (DOI)

10.1016/j.redox.2013.12.017

Recommended Citation

Gauter-Fleckenstein, Benjamin; Reboucas, Julio S.; Fleckenstein, Katharina; Tovmasyan, Artak; Owzar, Kouros; Jiang, Chen; Batinic-Haberle, Ines; and Vujaskovic, Zeljko, "Robust rat pulmonary radioprotection by a lipophilic Mn N-alkylpyridylporphyrin, MnTnHex-2-PyP(5+)" (2014). Translational Neuroscience. 1292.
https://scholar.barrowneuro.org/neurobiology/1292