Inhibition of Allergic and IMon Allergic Inflammation by Phospholipase A₂ Inhibitors

Note Phospholipase A2 Inhibition by Alkaloid Compounds from Phellodendron amurense Bark

“…Phospholipase A 2 (PLA 2 ) is a group of enzymes that hydrolyze the ester bonds of fatty acids from the sn-2-position of phospholipids. The release of arachidonic acid from cellular membranes and its conversion to leukotrienes and prostaglandins is a pivotal event in the mediator cascade involved in allergic and inflammatory processes, especially in the skin, were a type II PLA 2 is present (Gelb et al, 1994;Tibes et al, 1995). In the present paper, we describe the inhibition of PLA 2 and link this activity to the alkaloid fraction.…”

Phospholipase A2 inhibitors in inflammation

“…Inhibitors of PLA 2 can be assessed for their anti-inflammatory in vivo activity with the carrageenan-induced paw oedema model of the rat, the adjuvant-induced arthritis model of the rat and the phorbolester (TPA)-induced mouse ear oedema assay [49,[63][64][65][66][67]130,[134][135][136][137]. Besides these classical animal models of inflammation, the murine airpouch granuloma model of chronic inflammation [109], the PLA 2 -induced inflammation of the mouse paw [110], the IgE-mediated anaphylactic oedema after passive sensitisation [63] and the croton oilinduced oedema of the mouse ear were used [66].…”

“…Besides these classical animal models of inflammation, the murine airpouch granuloma model of chronic inflammation [109], the PLA 2 -induced inflammation of the mouse paw [110], the IgE-mediated anaphylactic oedema after passive sensitisation [63] and the croton oilinduced oedema of the mouse ear were used [66]. The antiasthmatic properties of cPLA 2 inhibitors have been investigated in a sheep model of asthma [65].…”

“…Although Eli Lilly and Shionogi developed a series of very potent sPLA 2 inhibitors, such as LY-311727 (10), LY-315920 (14) and indoxam (15), no inhibition data have been presented with the classical anti-inflammatory in vivo test systems such as the carrageenan-induced paw oedema model of the rat, the adjuvant-induced arthritis model of the rat and the phorbolester (TPA)-induced mouse ear oedema assay [5,6,72]. Boehringer Mannheim (now Roche Diagnostics) could only achieve inhibition of the carrageenan oedema with their sPLA 2 -IIA inhibitors, while these compounds were totally inactive in the chronic adjuvant arthritis model [63]. Glaxo Wellcome (now GlaxoSmithKline) decided to abandon sPLA 2 as a molecular target for development of anti-inflammatory drugs since sPLA 2 inhibitors developed by this company had only modest activities in the carrageenan oedema model, even after optimisation of the pharmacokinetic parameters and the metabolic stability of the compounds [67].…”

“…In the in vivo studies published ip. administration or high oral doses are necessary to get a therapeutic effect [63][64][65][66]130,[134][135][136][137]. One reason for this may be that the substantial lipophilicity of the compounds, which is probably necessary for binding to the enzyme, may result in low oral resorption or high protein binding [6].…”