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

Abstract

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.

• Authors: D Salvemini, E Mazzon, L Dugo, D P Riley, I Serraino, A P Caputi, S Cuzzocrea
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 132 Issue 4 Pg. 815-27 (Feb 2001) ISSN: 0007-1188 [Print] England
• PMID: 11181422 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

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