Protective effects of a new stable, highly active SOD mimetic, M40401 in splanchnic artery occlusion and reperfusion.
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)=1.2x10(+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 microg 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 ( approximately microg 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.
Cuzzocrea
S
S
Institute of Pharmacology, School of Medicine, University of Messina, Italy School of Medicine, University of Messina, Italy. salvator@www.unime.it
Mazzon
E
E
Dugo
L
L
Caputi
A P
AP
Aston
K
K
Riley
D P
DP
Salvemini
D
D
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D001157:Arterial Occlusive Diseases / Q000473:pathology / Q000517:prevention & control*; D002384:Catalysis; D016207:Cytokines / Q000096:biosynthesis; D005455:Fluorescent Antibody Technique; D007082:Ileum / Q000098:blood supply; D007958:Leukocyte Count; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D008345:Manganese; D009566:Nitrates / Q000097:blood / Q000378:metabolism; D009573:Nitrites / Q000097:blood; D009942:Organometallic Compounds / Q000627:therapeutic use*; D019007:P-Selectin / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*; D013152:Splanchnic Circulation / Q000187:drug effects*; D013482:Superoxide Dismutase / Q000737:chemistry*; D013481:Superoxides / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; C426066:M40401; D009566:Nitrates; D009573:Nitrites; D009942:Organometallic Compounds; D019007:P-Selectin; D013481:Superoxides; C039642:peroxynitric acid; C121876:imisopasem manganese; C002744:3-nitrotyrosine; D014443:Tyrosine; D008345:Manganese; D008315:Malondialdehyde; D009195:Peroxidase; D013482:Superoxide Dismutase