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Late administration of Mn porphyrin-based SOD mimic enhances diabetic complications.

Ali DK, Oriowo M, Tovmasyan A, Batinic-Haberle I, Benov L - Redox Biol (2013)

Bottom Line: The effect of the treatment on activities of glutathione peroxidase, superoxide dismutase, catalase, glutathione reductase, glucose-6-phosphate dehydrogenase, glyceraldehyde-3-phosphate dehydrogenase, and glyoxalases I and II as well as malondialdehyde and GSH/GSSG ratio were determined in kidneys.Our data showed that delayed administration of MnTM-2-PyP(5+) did not protect against oxidative damage and did not prevent diabetic complications.The data support the concept that the overall biological effect of a redox-active MnP is determined by (i) the relative concentrations of oxidants and reductants, i.e. the cellular redox environment and (ii) MnP biodistribution.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, Faculty of Medicine, Kuwait University, P.O. Box 24923, Safat 13110, Kuwait.

ABSTRACT
Mn(III) N-alkylpyridylporphyrins (MnPs) have demonstrated protection in various conditions where increased production of reactive oxygen/reactive nitrogen species (ROS/RNS), is a key pathological factors. MnPs can produce both pro-oxidative and antioxidative effects depending upon the cellular redox environment that they encounter. Previously we reported (Free Radic. Res. 39: 81-8, 2005) that when the treatment started at the onset of diabetes, Mn(III) meso-tetrakis(N-methylpyridinium-2-yl)porphyrin, MnTM-2-PyP(5+) suppressed diabetes-induced oxidative stress. Diabetes, however, is rarely diagnosed at its onset. The aim of this study was to investigate if MnTM-2-PyP(5+) can suppress oxidative damage and prevent diabetic complications when administered more than a week after the onset of diabetes. Diabetes was induced by streptozotocin. The MnP-based treatment started 8 days after the onset of diabetes and continued for 2 months. The effect of the treatment on activities of glutathione peroxidase, superoxide dismutase, catalase, glutathione reductase, glucose-6-phosphate dehydrogenase, glyceraldehyde-3-phosphate dehydrogenase, and glyoxalases I and II as well as malondialdehyde and GSH/GSSG ratio were determined in kidneys. Kidney function was assessed by measuring lysozyme and total protein in urine and blood urea nitrogen. Vascular damage was evaluated by assessing vascular reactivity. Our data showed that delayed administration of MnTM-2-PyP(5+) did not protect against oxidative damage and did not prevent diabetic complications. Moreover, MnTM-2-PyP(5+) contributed to the kidney damage, which seems to be a consequence of its pro-oxidative action. Such outcome can be explained by advanced oxidative damage which already existed at the moment the therapy with MnP started. The data support the concept that the overall biological effect of a redox-active MnP is determined by (i) the relative concentrations of oxidants and reductants, i.e. the cellular redox environment and (ii) MnP biodistribution.

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Vascular responsiveness to vasoconstrictor and vasodilator. (A) Carbachol-induced relaxation of aorta ring segments from control and diabetic rats. Artery segments were pre-contracted with noradrenaline (10−7 M). ■ represents responses to carbachol in aorta segments from control rats while ▼ and ▲ represent responses in aorta segments from streptozotocin-treated rats with and without treatment with MnTM-2-PyP. Each point on the graph is the mean±S.E. of five experiments. (B) Reactivity of thoracic aorta segments to noradrenaline in control and diabeticrats. ■ Represents responses to noradrenaline in aorta segments from control rats while ▼ and ▲ represent responses in aorta segments from streptozotocin-treated rats with and without treatment with MnTM-2-PyP. Each point on the graph is the mean±S.E. of five experiments.
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f0020: Vascular responsiveness to vasoconstrictor and vasodilator. (A) Carbachol-induced relaxation of aorta ring segments from control and diabetic rats. Artery segments were pre-contracted with noradrenaline (10−7 M). ■ represents responses to carbachol in aorta segments from control rats while ▼ and ▲ represent responses in aorta segments from streptozotocin-treated rats with and without treatment with MnTM-2-PyP. Each point on the graph is the mean±S.E. of five experiments. (B) Reactivity of thoracic aorta segments to noradrenaline in control and diabeticrats. ■ Represents responses to noradrenaline in aorta segments from control rats while ▼ and ▲ represent responses in aorta segments from streptozotocin-treated rats with and without treatment with MnTM-2-PyP. Each point on the graph is the mean±S.E. of five experiments.

Mentions: Stimulation with noradrenaline (10−9–10−4 M) induced reproducible and concentration-dependent contractions of aorta segments from the control and diabetic rats (Fig. 4A). The concentration–response curve of the aorta segments from diabetic rats was displaced to the left but there was no change in the response maximum. Treatment of control rats with MnTM-2PyP did not affect the response to NA (not shown) and failed to reverse the leftward displacement of NA concentration–response curve in diabetic rats (Fig. 4A).


Late administration of Mn porphyrin-based SOD mimic enhances diabetic complications.

Ali DK, Oriowo M, Tovmasyan A, Batinic-Haberle I, Benov L - Redox Biol (2013)

Vascular responsiveness to vasoconstrictor and vasodilator. (A) Carbachol-induced relaxation of aorta ring segments from control and diabetic rats. Artery segments were pre-contracted with noradrenaline (10−7 M). ■ represents responses to carbachol in aorta segments from control rats while ▼ and ▲ represent responses in aorta segments from streptozotocin-treated rats with and without treatment with MnTM-2-PyP. Each point on the graph is the mean±S.E. of five experiments. (B) Reactivity of thoracic aorta segments to noradrenaline in control and diabeticrats. ■ Represents responses to noradrenaline in aorta segments from control rats while ▼ and ▲ represent responses in aorta segments from streptozotocin-treated rats with and without treatment with MnTM-2-PyP. Each point on the graph is the mean±S.E. of five experiments.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3815015&req=5

f0020: Vascular responsiveness to vasoconstrictor and vasodilator. (A) Carbachol-induced relaxation of aorta ring segments from control and diabetic rats. Artery segments were pre-contracted with noradrenaline (10−7 M). ■ represents responses to carbachol in aorta segments from control rats while ▼ and ▲ represent responses in aorta segments from streptozotocin-treated rats with and without treatment with MnTM-2-PyP. Each point on the graph is the mean±S.E. of five experiments. (B) Reactivity of thoracic aorta segments to noradrenaline in control and diabeticrats. ■ Represents responses to noradrenaline in aorta segments from control rats while ▼ and ▲ represent responses in aorta segments from streptozotocin-treated rats with and without treatment with MnTM-2-PyP. Each point on the graph is the mean±S.E. of five experiments.
Mentions: Stimulation with noradrenaline (10−9–10−4 M) induced reproducible and concentration-dependent contractions of aorta segments from the control and diabetic rats (Fig. 4A). The concentration–response curve of the aorta segments from diabetic rats was displaced to the left but there was no change in the response maximum. Treatment of control rats with MnTM-2PyP did not affect the response to NA (not shown) and failed to reverse the leftward displacement of NA concentration–response curve in diabetic rats (Fig. 4A).

Bottom Line: The effect of the treatment on activities of glutathione peroxidase, superoxide dismutase, catalase, glutathione reductase, glucose-6-phosphate dehydrogenase, glyceraldehyde-3-phosphate dehydrogenase, and glyoxalases I and II as well as malondialdehyde and GSH/GSSG ratio were determined in kidneys.Our data showed that delayed administration of MnTM-2-PyP(5+) did not protect against oxidative damage and did not prevent diabetic complications.The data support the concept that the overall biological effect of a redox-active MnP is determined by (i) the relative concentrations of oxidants and reductants, i.e. the cellular redox environment and (ii) MnP biodistribution.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, Faculty of Medicine, Kuwait University, P.O. Box 24923, Safat 13110, Kuwait.

ABSTRACT
Mn(III) N-alkylpyridylporphyrins (MnPs) have demonstrated protection in various conditions where increased production of reactive oxygen/reactive nitrogen species (ROS/RNS), is a key pathological factors. MnPs can produce both pro-oxidative and antioxidative effects depending upon the cellular redox environment that they encounter. Previously we reported (Free Radic. Res. 39: 81-8, 2005) that when the treatment started at the onset of diabetes, Mn(III) meso-tetrakis(N-methylpyridinium-2-yl)porphyrin, MnTM-2-PyP(5+) suppressed diabetes-induced oxidative stress. Diabetes, however, is rarely diagnosed at its onset. The aim of this study was to investigate if MnTM-2-PyP(5+) can suppress oxidative damage and prevent diabetic complications when administered more than a week after the onset of diabetes. Diabetes was induced by streptozotocin. The MnP-based treatment started 8 days after the onset of diabetes and continued for 2 months. The effect of the treatment on activities of glutathione peroxidase, superoxide dismutase, catalase, glutathione reductase, glucose-6-phosphate dehydrogenase, glyceraldehyde-3-phosphate dehydrogenase, and glyoxalases I and II as well as malondialdehyde and GSH/GSSG ratio were determined in kidneys. Kidney function was assessed by measuring lysozyme and total protein in urine and blood urea nitrogen. Vascular damage was evaluated by assessing vascular reactivity. Our data showed that delayed administration of MnTM-2-PyP(5+) did not protect against oxidative damage and did not prevent diabetic complications. Moreover, MnTM-2-PyP(5+) contributed to the kidney damage, which seems to be a consequence of its pro-oxidative action. Such outcome can be explained by advanced oxidative damage which already existed at the moment the therapy with MnP started. The data support the concept that the overall biological effect of a redox-active MnP is determined by (i) the relative concentrations of oxidants and reductants, i.e. the cellular redox environment and (ii) MnP biodistribution.

Show MeSH
Related in: MedlinePlus