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

Publication ,  Journal Article
Gauter-Fleckenstein, B; Reboucas, JS; Fleckenstein, K; Tovmasyan, A; Owzar, K; Jiang, C; Batinic-Haberle, I; Vujaskovic, Z
Published in: Redox Biol
2014

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+).

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Published In

Redox Biol

DOI

ISSN

2213-2317

Publication Date

2014

Volume

2

Start / End Page

400 / 410

Location

Netherlands

Related Subject Headings

  • Signal Transduction
  • Rats, Inbred F344
  • Rats
  • Radiation-Protective Agents
  • Oxidation-Reduction
  • Metalloporphyrins
  • Lung
  • Infusions, Subcutaneous
  • Female
  • Drug Administration Schedule
 

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Gauter-Fleckenstein, B., Reboucas, J. S., Fleckenstein, K., Tovmasyan, A., Owzar, K., Jiang, C., … Vujaskovic, Z. (2014). Robust rat pulmonary radioprotection by a lipophilic Mn N-alkylpyridylporphyrin, MnTnHex-2-PyP(5+). Redox Biol, 2, 400–410. https://doi.org/10.1016/j.redox.2013.12.017
Gauter-Fleckenstein, Benjamin, Julio S. Reboucas, Katharina Fleckenstein, Artak Tovmasyan, Kouros Owzar, Chen Jiang, Ines Batinic-Haberle, and Zeljko Vujaskovic. “Robust rat pulmonary radioprotection by a lipophilic Mn N-alkylpyridylporphyrin, MnTnHex-2-PyP(5+).Redox Biol 2 (2014): 400–410. https://doi.org/10.1016/j.redox.2013.12.017.
Gauter-Fleckenstein B, Reboucas JS, Fleckenstein K, Tovmasyan A, Owzar K, Jiang C, et al. Robust rat pulmonary radioprotection by a lipophilic Mn N-alkylpyridylporphyrin, MnTnHex-2-PyP(5+). Redox Biol. 2014;2:400–10.
Gauter-Fleckenstein, Benjamin, et al. “Robust rat pulmonary radioprotection by a lipophilic Mn N-alkylpyridylporphyrin, MnTnHex-2-PyP(5+).Redox Biol, vol. 2, 2014, pp. 400–10. Pubmed, doi:10.1016/j.redox.2013.12.017.
Gauter-Fleckenstein B, Reboucas JS, Fleckenstein K, Tovmasyan A, Owzar K, Jiang C, Batinic-Haberle I, Vujaskovic Z. Robust rat pulmonary radioprotection by a lipophilic Mn N-alkylpyridylporphyrin, MnTnHex-2-PyP(5+). Redox Biol. 2014;2:400–410.
Journal cover image

Published In

Redox Biol

DOI

ISSN

2213-2317

Publication Date

2014

Volume

2

Start / End Page

400 / 410

Location

Netherlands

Related Subject Headings

  • Signal Transduction
  • Rats, Inbred F344
  • Rats
  • Radiation-Protective Agents
  • Oxidation-Reduction
  • Metalloporphyrins
  • Lung
  • Infusions, Subcutaneous
  • Female
  • Drug Administration Schedule