Pharmacological manipulation of the inflammatory cascade by the superoxide dismutase mimetic, M40403

1 M40403 is a low molecular weight: synthetic manganese containing superoxide dismutase mimetic (SODm) that removes superoxide anions (O-2(-)) without interfering with other reactive species known to be involved in inflammatory responses (e.g. nitric oxide, NO and peroxynitrite, ONOO-). 2 As such. M40403 represents an important pharmacological tool to dissect the roles of O-2(-) in acute and chronic inflammation. For this purpose, the pharmacological profile of M40403 was evaluated in carrageenan-induced pleurisy. 3 Injection of carrageenan into the pleural cavity of rats elicited an acute inflammatory response characterized by: fluid accumulation in the pleural cavity which contained a large number of neutrophils (PMNs) as well as an infiltration of PMNs in lune tissues and subsequent lipid peroxidation, and increased production of nitrite/nitrate (NOx), prostaglandin E-2 (PGE(2)), tumour necrosis factor alpha. (TNF alpha), interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6) and interleukin-10 (IL-10). 4 All parameters of inflammation were attenuated by M40403 except for NOx, PGE(2) and IL-10 which remained unaltered. Furthermore, carrageenan induced an upregulation of the adhesion molecules ICAM-1 and P-selectin, as well as nitrotyrosine and poly (ADP-ribose) synthetase (PARS) as determined by immunohistochemical analysis of lung tissues. 5 The degree of staining for the ICAM-1 P-selectin, nitrotyrosine and PARS was reduced by M40403. 6 These results clearly indicate that O-2(-) plays a critical role in the development of the inflammatory response by altering key components of the inflammatory cascade. Therefore, synthetic enzymes of SOD such as M40403, offers a novel therapeutic approach for the management of various inflammatory diseases where these radicals have been postulated to play a role.