Pharmacological manipulation of the inflammatory cascade by the superoxidedismutase mimetic, M40403

Citation
D. Salvemini et al., Pharmacological manipulation of the inflammatory cascade by the superoxidedismutase mimetic, M40403, BR J PHARM, 132(4), 2001, pp. 815-827
Citations number
76
Categorie Soggetti
Pharmacology & Toxicology
Journal title
BRITISH JOURNAL OF PHARMACOLOGY
ISSN journal
00071188 → ACNP
Volume
132
Issue
4
Year of publication
2001
Pages
815 - 827
Database
ISI
SICI code
0007-1188(200102)132:4<815:PMOTIC>2.0.ZU;2-N
Abstract
1 M40403 is a low molecular weight: synthetic manganese containing superoxi de dismutase mimetic (SODm) that removes superoxide anions (O-2(-)) without interfering with other reactive species known to be involved in inflammato ry responses (e.g. nitric oxide, NO and peroxynitrite, ONOO-). 2 As such. M40403 represents an important pharmacological tool to dissect t he roles of O-2(-) in acute and chronic inflammation. For this purpose, the pharmacological profile of M40403 was evaluated in carrageenan-induced ple urisy. 3 Injection of carrageenan into the pleural cavity of rats elicited an acut e 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 a s nitrotyrosine and poly (ADP-ribose) synthetase (PARS) as determined by im munohistochemical 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 d evelopment of the inflammatory response by altering key components of the i nflammatory cascade. Therefore, synthetic enzymes of SOD such as M40403, of fers a novel therapeutic approach for the management of various inflammator y diseases where these radicals have been postulated to play a role.