Robust rat pulmonary radioprotection by a lipophilic Mn N-alkylpyridylporphyrin, MnTnHex-2-PyP5+
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-PyP5+ has been synthesized and tested in several different model of diseases, where it shows remarkable efficacy at as low as 50μg/kg single or multiple doses. Yet, in a rat lung radioprotection study, at higher 0.6-1mg/kg doses, due to its high accumulation and micellar character, it became toxic. To avoid the toxicity, herein the pulmonary radioprotection of MnTnHex-2-PyP5+ was assessed at 50μg/kg. Fischer rats were irradiated to their right hemithorax (28Gy) and treated with 0.05mg/kg/day of MnTnHex-2-PyP5+ for 2 weeks by subcutaneously-implanted osmotic pumps, starting at 2h 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-PyP5+ on macrophage recruitment (ED-1), DNA oxidative damage (8-OHdG), TGF-β1, VEGF(A) and HIF-1α were measured. MnTnHex-2-PyP5+ 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-PyP5+. © 2014 The Authors.
Gauter-Fleckenstein, B; Reboucas, JS; Fleckenstein, K; Tovmasyan, A; Owzar, K; Jiang, C; Batinic-Haberle, I; Vujaskovic, Z
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