Title

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

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

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