Abstract
1. Splanchnic artery occlusion shock (SAO) causes an enhanced formation of reactive oxygen species (ROS), which contribute to the pathophysiology of shock. Here we have investigated the effects of M40401, a new S,S-dimethyl substituted biscyclohexylpyridine Mn-based superoxide dismutase mimetic (SODm, k cat= 1.2 × 10 +9 M -1 S -1 at pH=7.4), in rats subjected to SAO shock. 2. Treatment of rats with M40401 (applied at 0.25, 2.5 or 25 μg kg -1, 15 min prior to reperfusion), attenuated the mean arterial blood and the migration of polymorphonuclear cells (PMNs) caused by SAO-shock. M40401 also attenuated the ileum injury (histology) as well as the increase in the tissue levels of myeloperoxidase (MPO) and malondialdehyde (MDA) caused by SAO shock in the ileum. 3. Immunohistochemical analysis for nitrotyrosine revealed a positive staining in ileum from SAO-shocked rats. The degree of staining for nitrotyrosine was markedly reduced in tissue sections obtained from SAO-shocked rats which had received M40401. Reperfused ileum tissue sections from SAO-shocked rats showed positive staining for P-selectin and for anti-intercellular adhesion molecule (ICAM-1) in the vascular endothelial cells. M40401 treatment markedly reduced the intensity and degree of P-selectin and ICAM-1 in tissue sections from SAO-shocked rats. M40401 treatment significantly improved survival. 4. Additionally, the very high catalytic activity of this new mimetic (comparable to the native human Cu/Zn SOD enzyme and exceeding the activity of the human Mn SOD enzyme) translates into a very low dose (∼μg kg -1) required to afford protection in this SAO model of ischemia reperfusion injury. 5. Taken together, our results clearly demonstrate that M40401 treatment exerts a protective effect, and part of this effect may be due to inhibition of the expression of adhesion molecules and peroxynitrite-related pathways with subsequent reduction of neutrophil-mediated cellular injury.
| Original language | English |
|---|---|
| Pages (from-to) | 19-29 |
| Number of pages | 11 |
| Journal | British Journal of Pharmacology |
| Volume | 132 |
| Issue number | 1 |
| Publication status | Published - 2001 |
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Keywords
- M40401
- Nitric oxide
- Peroxynitrite
- Poly (ADP ribose) synthetase
- Reperfusion
- Shock
- Superoxide dismutase mimetic
ASJC Scopus subject areas
- Pharmacology
Cite this
Protective effects of a new stable, highly active SOD mimetic, M40401 in splanchnic artery occlusion and reperfusion. / Cuzzocrea, Salvatore; Mazzon, Emanuela; Dugo, Laura; Caputi, Achille P.; Aston, Karl; Riley, Dennis P.; Salvemini, Daniela.
In: British Journal of Pharmacology, Vol. 132, No. 1, 2001, p. 19-29.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Protective effects of a new stable, highly active SOD mimetic, M40401 in splanchnic artery occlusion and reperfusion
AU - Cuzzocrea, Salvatore
AU - Mazzon, Emanuela
AU - Dugo, Laura
AU - Caputi, Achille P.
AU - Aston, Karl
AU - Riley, Dennis P.
AU - Salvemini, Daniela
PY - 2001
Y1 - 2001
N2 - 1. Splanchnic artery occlusion shock (SAO) causes an enhanced formation of reactive oxygen species (ROS), which contribute to the pathophysiology of shock. Here we have investigated the effects of M40401, a new S,S-dimethyl substituted biscyclohexylpyridine Mn-based superoxide dismutase mimetic (SODm, k cat= 1.2 × 10 +9 M -1 S -1 at pH=7.4), in rats subjected to SAO shock. 2. Treatment of rats with M40401 (applied at 0.25, 2.5 or 25 μg kg -1, 15 min prior to reperfusion), attenuated the mean arterial blood and the migration of polymorphonuclear cells (PMNs) caused by SAO-shock. M40401 also attenuated the ileum injury (histology) as well as the increase in the tissue levels of myeloperoxidase (MPO) and malondialdehyde (MDA) caused by SAO shock in the ileum. 3. Immunohistochemical analysis for nitrotyrosine revealed a positive staining in ileum from SAO-shocked rats. The degree of staining for nitrotyrosine was markedly reduced in tissue sections obtained from SAO-shocked rats which had received M40401. Reperfused ileum tissue sections from SAO-shocked rats showed positive staining for P-selectin and for anti-intercellular adhesion molecule (ICAM-1) in the vascular endothelial cells. M40401 treatment markedly reduced the intensity and degree of P-selectin and ICAM-1 in tissue sections from SAO-shocked rats. M40401 treatment significantly improved survival. 4. Additionally, the very high catalytic activity of this new mimetic (comparable to the native human Cu/Zn SOD enzyme and exceeding the activity of the human Mn SOD enzyme) translates into a very low dose (∼μg kg -1) required to afford protection in this SAO model of ischemia reperfusion injury. 5. Taken together, our results clearly demonstrate that M40401 treatment exerts a protective effect, and part of this effect may be due to inhibition of the expression of adhesion molecules and peroxynitrite-related pathways with subsequent reduction of neutrophil-mediated cellular injury.
AB - 1. Splanchnic artery occlusion shock (SAO) causes an enhanced formation of reactive oxygen species (ROS), which contribute to the pathophysiology of shock. Here we have investigated the effects of M40401, a new S,S-dimethyl substituted biscyclohexylpyridine Mn-based superoxide dismutase mimetic (SODm, k cat= 1.2 × 10 +9 M -1 S -1 at pH=7.4), in rats subjected to SAO shock. 2. Treatment of rats with M40401 (applied at 0.25, 2.5 or 25 μg kg -1, 15 min prior to reperfusion), attenuated the mean arterial blood and the migration of polymorphonuclear cells (PMNs) caused by SAO-shock. M40401 also attenuated the ileum injury (histology) as well as the increase in the tissue levels of myeloperoxidase (MPO) and malondialdehyde (MDA) caused by SAO shock in the ileum. 3. Immunohistochemical analysis for nitrotyrosine revealed a positive staining in ileum from SAO-shocked rats. The degree of staining for nitrotyrosine was markedly reduced in tissue sections obtained from SAO-shocked rats which had received M40401. Reperfused ileum tissue sections from SAO-shocked rats showed positive staining for P-selectin and for anti-intercellular adhesion molecule (ICAM-1) in the vascular endothelial cells. M40401 treatment markedly reduced the intensity and degree of P-selectin and ICAM-1 in tissue sections from SAO-shocked rats. M40401 treatment significantly improved survival. 4. Additionally, the very high catalytic activity of this new mimetic (comparable to the native human Cu/Zn SOD enzyme and exceeding the activity of the human Mn SOD enzyme) translates into a very low dose (∼μg kg -1) required to afford protection in this SAO model of ischemia reperfusion injury. 5. Taken together, our results clearly demonstrate that M40401 treatment exerts a protective effect, and part of this effect may be due to inhibition of the expression of adhesion molecules and peroxynitrite-related pathways with subsequent reduction of neutrophil-mediated cellular injury.
KW - M40401
KW - Nitric oxide
KW - Peroxynitrite
KW - Poly (ADP ribose) synthetase
KW - Reperfusion
KW - Shock
KW - Superoxide dismutase mimetic
UR - http://www.scopus.com/inward/record.url?scp=0035146709&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0035146709&partnerID=8YFLogxK
M3 - Article
C2 - 11156557
AN - SCOPUS:0035146709
VL - 132
SP - 19
EP - 29
JO - British Journal of Pharmacology
JF - British Journal of Pharmacology
SN - 0007-1188
IS - 1
ER -