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.