α-lipoic acid: An inhibitor of secretory phospholipase A2 with anti-inflammatory activity

A biophysical approach to phospholipase A2 activity and inhibition by anti-inflammatory drugs

“…Each NSAID was studied individually regarding its ability to modify the enzyme's secondary structure. The binding of ligands can affect the structure of enzymes and it has been previously reported the ability of inhibitors to change PLA 2 conformation through the increase or decrease in the α-helical content [3,32,33]. It is visible that PLA 2 CD spectra after addition of the NSAIDs show minor differences comparing with that from the enzyme alone, indicating lack of major changes in the secondary structure (Fig.…”

“…Arachidonic acid (AA) is among the free fatty acids released representing a possible store of energy [2] and being involved in the biosynthesis of prostaglandins, prostacyclins, thromboxanes and interleukins -eicosanoids, known as mediators of inflammation and signal transduction [2][3][4]. Plants, mammals, snakes and bee venoms can be the source of PLA 2 and according to their cellular location, these enzymes can be classified as cytosolic (cPLA 2 ), calcium independent (iPLA 2 ) and secretory (sPLA 2 ) [5].…”

“…Plants, mammals, snakes and bee venoms can be the source of PLA 2 and according to their cellular location, these enzymes can be classified as cytosolic (cPLA 2 ), calcium independent (iPLA 2 ) and secretory (sPLA 2 ) [5]. Considering the three types of PLA 2 mentioned, studies revealed that sPLA 2 is deeply involved in the inflammatory process of several conditions [3,6] such as rheumatoid arthritis, atherosclerosis, respiratory distress syndrome and septic shock [4,5,7]. Most precisely, sPLA 2 leads to the formation of lipid inflammatory mediators through its lipolytic activity and also by activation of iPLA 2 [7].…”

“…For instance, it has been shown that indomethacin and alminoprofen inhibit rat peritoneal and snake venom PLA 2 , respectively [17]. Other molecules, like α-lipoic acid (ALA), inhibit several sPLA 2 s from human serum and also from snake venoms [3]. Although the mechanism for this inhibition is still unclear, it seems that while some molecules change the membrane biophysical properties, blocking the passage and the contact of PLA 2 with the membrane [3], others have a direct contact with the enzyme and can also form complexes with it, as demonstrated in studies involving ALA [3] and oxyphenbutazone [1].…”

“…Other molecules, like α-lipoic acid (ALA), inhibit several sPLA 2 s from human serum and also from snake venoms [3]. Although the mechanism for this inhibition is still unclear, it seems that while some molecules change the membrane biophysical properties, blocking the passage and the contact of PLA 2 with the membrane [3], others have a direct contact with the enzyme and can also form complexes with it, as demonstrated in studies involving ALA [3] and oxyphenbutazone [1]. In view to this, the experiments presented in this work have first the purpose to study the PLA 2 activity and inhibition by the NSAIDs tested, and second, to determine the factor(s) that contribute to that inhibition which might include: (i) the drug induced biophysical changes occurring at the interface where PLA 2 activity takes place; (ii) the direct interaction between the drug and enzyme and/or the drug induced disturbance in the binding of PLA 2 to the substrate.…”