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

Br J Pharmacol. 2001 Feb;132(4):815-27. doi: 10.1038/sj.bjp.0703841.


1. M40403 is a low molecular weight, synthetic manganese containing superoxide dismutase mimetic (SODm) that removes superoxide anions (*O2-) 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 *O2- 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 lung tissues and subsequent lipid peroxidation, and increased production of nitrite/nitrate (NOx), prostaglandin E2 (PGE2), tumour necrosis factor alpha, (TNFalpha), interleukin-1beta (IL-1beta), interleukin-6 (IL-6) and interleukin-10 (IL-10). 4. All parameters of inflammation were attenuated by M40403 except for NOx, PGE2 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 *O2- 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Cytokines / biosynthesis
  • DNA Damage
  • Dinoprostone / biosynthesis
  • Intercellular Adhesion Molecule-1 / analysis
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Male
  • Manganese
  • Nitrates / metabolism
  • Organometallic Compounds / pharmacology*
  • P-Selectin / analysis
  • Pleurisy / drug therapy
  • Prostaglandin-Endoperoxide Synthases / physiology
  • Rats
  • Rats, Sprague-Dawley
  • Superoxides / metabolism*


  • Anti-Inflammatory Agents, Non-Steroidal
  • Cytokines
  • Nitrates
  • Organometallic Compounds
  • P-Selectin
  • Superoxides
  • Intercellular Adhesion Molecule-1
  • peroxynitric acid
  • imisopasem manganese
  • Manganese
  • Prostaglandin-Endoperoxide Synthases
  • Dinoprostone