D. Salvemini et al., Pharmacological manipulation of the inflammatory cascade by the superoxidedismutase mimetic, M40403, BR J PHARM, 132(4), 2001, pp. 815-827
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.