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 r eactive oxygen species (ROS), which contribute to the pathophysiology of sh ock. Here we have investigated the effects of M40401, a new S,S-dimethyl su bstituted biscyclohexylpyridine Mn-based superoxide dismutase mimetic (SODm , k(cat)=1.2 x 10(+9) M-1 s(-1) at pH = 7.4), in rats subjected to SAO shoc k. 2 Treatment of rats with M40401 (applied at 0.25, 2.5 or 25 mug kg(-1), 15 min prior to reperfusion), attenuated the mean arterial blood and the migra tion of polymorphonuclear cells (PMNs) caused by SAG-shock. M40401 also att enuated the ileum injury (histology) as well as the increase in the tissue levels of myeloperoxidase (MPO) and malondialdehyde (MDA) caused by SAG sho ck in the ileum. 3 Immunohistochemical analysis for nitrotyrosine revealed a positive staini ng in ileum from SAO-shocked rats. The degree of staining for nitrotyrosine was markedly reduced in tissue sections obtained from SAG-shocked rats whi ch had received M40401. Reperfused ileum tissue sections from SAG-shocked r ats showed positive staining for P-selectin and for anti-intercellular adhe sion molecule (ICAM-1) in the vascular endothelial cells. M40401 treatment markedly reduced the intensity and degree of P-selectin and ICAM-1 in tissu e sections from SAG-shocked rats. M40401 treatment significantly improved s urvival. 4 Additionally, the very high catalytic activity of this new mimetic (compa rable to the native human Cu/Zn SOD enzyme and exceeding the activity of th e human Mn SOD enzyme) translates into a very low dose (similar to mug kg(- 1)) required to afford protection in this SAO model of ischemia reperfusion injury. 5 Taken together, our results clearly demonstrate that M40401 treatment exe rts a protective effect, and part of this effect may be due to inhibition o f the expression of adhesion molecules and peroxynitrite-related pathways w ith subsequent reduction of neutrophil-mediated cellular injury.