title: Robust rat pulmonary radioprotection by a lipophilic Mn N-alkylpyridylporphyrin, MnTnHex-2-PyP(5+).
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+).
authors.affiliation: 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.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Gauter-Fleckenstein
authors.affiliation: Department of Radiation Oncology, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Julio S
authors.initials: JS
authors.lastname: Reboucas
authors.affiliation: 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.
authors.forename: Katharina
authors.initials: K
authors.lastname: Fleckenstein
authors.affiliation: Department of Radiation Oncology, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Artak
authors.initials: A
authors.lastname: Tovmasyan
authors.affiliation: Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, USA ; Biostatistics and Computational Biology Core, RadCCORE, Duke University Medical Center, Durham, USA.
authors.forename: Kouros
authors.initials: K
authors.lastname: Owzar
authors.affiliation: Biostatistics and Computational Biology Core, RadCCORE, Duke University Medical Center, Durham, USA.
authors.forename: Chen
authors.initials: C
authors.lastname: Jiang
authors.affiliation: Department of Radiation Oncology, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Ines
authors.initials: I
authors.lastname: Batinic-Haberle
authors.affiliation: 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.
authors.forename: Zeljko
authors.initials: Z
authors.lastname: Vujaskovic
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects / Q000528:radiation effects; D004307:Dose-Response Relationship, Radiation; D004334:Drug Administration Schedule; D005260:Female; D055104:Infusions, Subcutaneous; D008168:Lung / Q000187:drug effects* / Q000473:pathology / Q000528:radiation effects*; D008665:Metalloporphyrins / Q000008:administration & dosage* / Q000494:pharmacology; D010084:Oxidation-Reduction / Q000187:drug effects / Q000528:radiation effects; D011837:Radiation-Protective Agents / Q000008:administration & dosage* / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects
chemical_list: D008665:Metalloporphyrins; C583825:Mn(III) ortho-tetrakis(N-hexylpyridinium-2-yl)porphyrin; D011837:Radiation-Protective Agents
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