Assessment of a Human Recombinant Manganese Superoxide Dismutase in Models of Inflammation

Abstract

We evaluated a novel human recombinant preparation of manganese superoxide dismutase (MnSOD) for anti-inflammatory and anti-oxidant activity compared with a copper zinc (CuZn) SOD preparation. The results showed that administration of MnSOD (50, 100 and 200 micrograms kg-1) in the Freund's Complete Adjuvant (FCA) mediated paw oedema model suppressed the inflammation at 4 hours by 43, 25 and 43% (P < 0.001, P < 0.01 and P < 0.001 at respective doses). However, 24 hours post-challenge, MnSOD (50 and 100 micrograms kg-1), suppressed the inflammation by 19% (P < 0.001). In contrast, Mn SOD at higher doses (400-800 micrograms kg-1; 2 mgkg-1) exacerbated the inflammatory response at 4 hours. This pro-inflammatory response declined progressively by 24 hours. Furthermore, CuZn SOD produced no significant effects on the inflammatory response. In the carrageenan-induced synovitis model, Mn SOD (25 and 50 micrograms; intra-articular administration) exacerbated the inflammation at 48 hours. In contrast, Mn SOD at 5 micrograms produced a significant suppression (44%, P < 0.05) in knee joint swelling at 24 hours. The CuZn SOD preparation produced marked pro-inflammatory effects in the joints whilst it lacked activity in the FCA-mediated paw oedema model. These findings support a therapeutic potential of MnSOD in inflammatory disorders, however the compound has a complex pharmaco-dynamic profile.

Amelioration of antigen-induced arthritis in rats by transfer of extracellular superoxide dismutase and catalase genes

“…13,21 In rat adjuvant-induced foot pad oedema, administration of human recombinant MnSOD resulted in a reduction of paw swelling. 21 In a different model, antigen-induced arthritis in the mouse, amidated catalase suppressed the inflammatory response, whereas SOD had no effect. 13 It appears that superoxide radicals and hydrogen peroxide might exert different effects on the different animal models.…”

“…Rats that received cells overexpressing EC-SOD at a higher density of 1 Â 10 5 / joint did not show any effect compared with the control animals. It has been reported 21 that in the adjuvantinduced foot pad oedema model, pretreatment with different doses of MnSOD resulted in a bell-shaped curve, in which very high doses of MnSOD caused a loss of protection. Recently, Liochev and Fridovich 25 reported that CuZnSOD, besides its superoxide dismutase activity, has a superoxide reductase activity.…”

Effect of Lecithinized-Superoxide Dismutase on the Rat Colitis Model Induced by Dextran Sulfate Sodium.

“…It is also suggests that the inhibitory effect of PC-SOD on cellular infiltration may be partially due to the life extendency of NO. On the other hand, the dose-response curve for PC-SOD showed a bell-shape pattern, like free SOD (13,14). SOD produces H2O2 in the process of scavenging 02.…”

Superoxide Dismutase Mimetic Preserves the Glomerular Capillary Permeability Barrier to Protein

“…Further limiting the application of native SOD is its proinflammatory effect at high doses (Dowling et al, 1993), mediated via Fenton-type reactions (Mao et al, 1993), although low doses may have an anti-inflammatory action. These factors may contribute to the conflicting results of early studies with native SOD treatment to attenuate O 2 .…”