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 50 mu g/kg single or multiple doses. Yet, in a rat Icing radioprotection study, at higher 0.6-1 mg/kg closes, clue to its high accumulation and micellar character, it became toxic. To avoid the toxicity, herein the pulmonary radioprotection of MaTnHex-2-PyP5+ was assessed at 50 [mu g/kg. Fischer rats were irradiated to their right hemithorax (28 Gy) and treated with 0.05 mg/kg/day of MnTnHex-2-PyP5+ for 2 weeks by subcutaneously implanted osmotic pumps, starting at 211 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-beta 1, VEGF(A) and HIF-1 alpha. 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-beta 1, VEGF (A) and HIF-1 alpha 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+. (C) 2014 The Authors. Published by Elsevier B.V.