A New Generation of Arachidonic Acid Analogues as Potential Neurological Agent Targeting Cytosolic Phospholipase A2

Abstract

Cytosolic phospholipase A2 (cPLA2) is an enzyme that releases arachidonic acid (AA) for the synthesis of eicosanoids and lysophospholipids which play critical roles in the initiation and modulation of oxidative stress and neuroinflammation. In the central nervous system, cPLA2 activation is implicated in the pathogenesis of various neurodegenerative diseases that involves neuroinflammation, thus making it an important pharmacological target. In this paper, a new class of arachidonic acid (AA) analogues was synthesized and evaluated for their ability to inhibit cPLA2. Several compounds were found to inhibit cPLA2 more strongly than arachidonyl trifluoromethyl ketone (AACOCF3), an inhibitor that is commonly used in the study of cPLA2-related neurodegenerative diseases. Subsequent experiments concluded that one of the inhibitors was found to be cPLA2-selective, non-cytotoxic, cell and brain penetrant and capable of reducing reactive oxygen species (ROS) and nitric oxide (NO) production in stimulated microglial cells. Computational studies were employed to understand how the compound interacts with cPLA2.

Small-molecule inhibitors as potential therapeutics and as tools to understand the role of phospholipases A2

“…Recently, a new generation of AA analogues was developed as potential neurological agents targeting GIVA cPLA 2 [43]. Among these compounds, inhibitor 10 ( Fig.…”

Pre-clinical Pharmacokinetic and Metabolomic Analyses of Isorhapontigenin, a Dietary Resveratrol Derivative

“…Moreover, a pro-inflammatory role of cadaverine was observed in a recent in vivo study ( Fan et al, 2012 ). Similarly, arachidonic acid is a polyunsaturated fatty acid which plays an important role in mediation of a variety of inflammation responses and initiation of oxidative stress via serving as the precursor for the synthesis of eicosanoids and prostanoids ( Ng et al, 2017 ). In this study, 1-week ISO intervention was found to downregulate plasma levels of both cadaverine and arachidonic acid.…”

Differentiation of Promonocytic U937 Cells to Monocytes Is Associated with Reduced Mitochondrial Transport of Ascorbic Acid

“…Finally, we also obtained evidence of increased phospholipase A 2 activity [ 25 ], readily detected in terms of arachidonic acid release after stimulation with 10 μ M A23187 or 200 μ M peroxynitrite ( Figure 1(d) ). AACOCF 3 , a well-established inhibitor of cytosolic phospholipase A 2 [ 36 ], suppressed arachidonic acid release detected under both circumstances.…”