PLA2 Mediated Arachidonate Free Radicals: PLA2 Inhibition and Neutralization of Free Radicals by Anti-Oxidants – A New Role as Anti-Inflammatory Molecule

Abstract

PLA2 enzyme catalyses the hydrolysis of cellular phospholipids at the sn-2 position to liberate arachidonic acid and lysophospholipid to generate a family of pro-inflammatory eicosanoids and platelet activating factor. The generation of pro-inflammatory eicosanoids involves a series of free radical intermediates with simultaneous release of reactive oxygen species (superoxide and hydroxyl radicals). Reactive oxygen species formed during arachidonic acid metabolism generates lipid peroxides and the cytotoxic products such as 4-hydroxy nonenal and acrolein, which induces cellular damage. Thus PLA2 catalyzes the rate-limiting step in the production of pro-inflammatory eicosanoids and free radicals. These peroxides and reactive oxygen species in turn activates PLA2 enzyme and further attenuates the inflammatory process. Therefore scavenging these free radicals and inhibition of PLA2 enzyme simultaneously by a single molecule such as antioxidants is of great therapeutic relevance for the development of anti-inflammatory molecules. PLA2 enzymes have been classified into calcium dependent cPLA2 and sPLA2 and calcium independent iPLA2 forms. In several inflammatory diseases sPLA2 group IIA is the most abundant isoform identified. This isoform is therefore targeted for the development of anti-inflammatory molecules. Many secondary metabolites from plants and marine sponges exhibit both anti-inflammatory and antioxidant properties. Some of them include flavonoids, terpenes and alkaloids. But in terms of PLA2 inhibition and antioxidant activity, the structural aspects of flavonoids are well studied rather than terpenes and alkaloids. In this line, molecules having both anti-oxidant and PLA2 inhibitions are reviewed. A single molecule with dual activities may prove to be a powerful anti-inflammatory drug.

Calcium-independent phospholipases A2 and their roles in biological processes and diseases

“…Modulation of the islet ␤ -cell-delayed rectifi er potassium channel, Kv2.1, by AA amplifi es Ca 2+ infl ux into the ␤ -cells and enhances glucose-stimulated insulin secretion ( 142,228 ). While AA itself manifests biological activity, the accompanying lysolipids and metabolites of AA, or eicosanoids, signifi cantly impact various cellular processes to promote a multitude of effects ( 229,230 ).…”

Macrophages: An elusive yet emerging therapeutic target of atherosclerosis

“…[339][340][341] Besides NADPH oxidase activation, PLA2 action leads to generation of cellular and membrane phospholipidderived inflammatory mediators such as arachidonic acid, platelet-activating factor (PAF), and prostaglandins, all demonstrated to be central in both the initiation and propagation of the inflammatory response. 340,342 Activation of iPLA2 results in release of choline lysophospholipids from endothelial cells. These metabolites may contribute to the initiation of ventricular arrhythmias following myocardial ischemia as a direct result of incorporation into the myocyte sarcolemma.…”

Anti-inflammatory and antioxidant activities ofJungia paniculata

“…Many secondary metabolites from plants and marine sponges exhibit both anti-inflammatory and antioxidant properties. In this way, extracts with dual activities may prove to be powerful anti-inflammatory drugs (Nanda et al, 2007). Only the MeOH50 extract of Jungia paniculata significantly inhibited PLA 2 enzyme activity (82.3 ± 2.6%) with an efficacy comparable to that of SCA (83.8 ± 5.1%) ( Table 2).…”