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 (*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.
Salvemini
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D
MetaPhore Pharmaceuticals, 1910 Innerbelt Business Center Drive, St. Louis, Missouri, MO 63114, USA. dsalvemini@metaphore.com
Mazzon
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E
Dugo
L
L
Riley
D P
DP
Serraino
I
I
Caputi
A P
AP
Cuzzocrea
S
S
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D016207:Cytokines / Q000096:biosynthesis; D004249:DNA Damage; D015232:Dinoprostone / Q000096:biosynthesis; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008345:Manganese; D009566:Nitrates / Q000378:metabolism; D009942:Organometallic Compounds / Q000494:pharmacology*; D019007:P-Selectin / Q000032:analysis; D010998:Pleurisy / Q000188:drug therapy; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013481:Superoxides / Q000378:metabolism*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D009566:Nitrates; D009942:Organometallic Compounds; D019007:P-Selectin; D013481:Superoxides; D018799:Intercellular Adhesion Molecule-1; C039642:peroxynitric acid; C121876:imisopasem manganese; D008345:Manganese; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone