Models for evaluating the anti-inflammatory effects of inhibitors of arachidonic acid metabolism

Abstract

Inhibitors of arachidonic acid metabolism were characterized by their ability to modulate slow reacting substance (SRS) and prostaglandin E2 (PGE2) release from stimulated mouse peritoneal macrophages in-vitro. Differential effects of cyclo-oxygenase (CO) and lipoxygenase (LO) enzyme inhibitors and compounds which inhibit both enzymes were demonstrated using several animal models of inflammation. Carrageenan-impregnated sponges implanted subcutaneously in rats and immune-complexes injected intraperitoneally in mice produced inflammatory responses characterized respectively by polymorphonuclear (PMN) cell infiltration and by increased vascular permeability. Dual CO/LO inhibitors (eg. BW 755c and timegadine) were capable of suppressing both parameters and reduced SRS and PGE2 formation in-vivo. In contrast, selective CO inhibitors (e.g. indomethacin, naproxen and R-830) were less active against permeability, and potentiated SRS release. Although selective CO inhibitors reduced PMN migration, this occurred at doses which exceeded those required for inhibition of PGE2. Compounds possessing LO inhibitory activity suppressed the cellular component of an Arthus type reaction in the rat pleural cavity, but were less active than selective CO inhibitors against carrageenan-induced paw oedema in rats.

Neutralization of Macrophage Inflammatory Protein 2 (MIP-2) and MIP-1α Attenuates Neutrophil Recruitment in the Central Nervous System during Experimental Bacterial Meningitis

“…The contribution of complement factors to the development of CSF pleocytosis has been shown (9). The importance of arachidonic acid pathway metabolites such as leukotrienes and bacterial cell wall products as chemoattractants in bacterial meningitis was shown in rabbits with pneumococcal meningitis (3,20).…”

Comparative anti-inflammatory effects of roxithromycin, azithromycin and clarithromycin

“…Individual NSAIDs act on separate parts of the inflammatory cascade; for example, indomethacin and nimesulide reduce the production of prostaglandins by inhibiting cyclooxygenase, while others inhibit 5-lipooxygenase, an enzyme that is important in leukotriene biosynthesis. 25,27 These different modes of action lead to different responses in various models of inflammation, and the results of such studies require careful analysis.…”

Pharmacological modification of 12-O-tetradecanoylphorbol-13-acetate induced inflammation and epidermal cell proliferation in mouse skin

“…The selective eyclooxygenase inhibitor indomethacin (0.1 -1.0 mg/ear) inhibited both oedema and PMN influx although at doses greater than required to inhibit PGE z production (section e). BW755C, phenidone and AA 861 (0.1 -1.0 mg/ear) which are less potent inhibitors of cyclooxygenase than indomethacin but also inhibit lipoxygenase [7,8] had a similar profile of activity to the selective cyclooxygenase inhibitor. The inhibitory effect of all four drugs against oedema decreased between 3 and 6h.…”