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

Daniela Salvemini, Emanuela Mazzon, Laura Dugo, Dennis P. Riley, Ivana Serraino, Achille P. Caputi, Salvatore Cuzzocrea

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Abstract

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 lung tissues and subsequent lipid peroxidation, and increased production of nitrite/nitrate (NOx), prostaglandin E 2 (PGE 2), tumour necrosis factor α, (TNFα), interleukin-1β (IL-1β), 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.

Original languageEnglish
Pages (from-to)815-827
Number of pages13
JournalBritish Journal of Pharmacology
Volume132
Issue number4
Publication statusPublished - 2001

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Keywords

  • Adhesion molecules
  • Cytokines
  • Inflammation
  • Superoxide anions
  • Superoxide dismutase mimetic

ASJC Scopus subject areas

  • Pharmacology

Cite this

Salvemini, D., Mazzon, E., Dugo, L., Riley, D. P., Serraino, I., Caputi, A. P., & Cuzzocrea, S. (2001). Pharmacological manipulation of the inflammatory cascade by the superoxide dismutase mimetic, M40403. British Journal of Pharmacology, 132(4), 815-827.