title: Synthetic and natural inhibitors of phospholipases A2: their importance for understanding and treatment of neurological disorders.
abstract: Phospholipases A2 (PLA2) are a diverse group of enzymes that hydrolyze membrane phospholipids into arachidonic acid and lysophospholipids. Arachidonic acid is metabolized to eicosanoids (prostaglandins, leukotrienes, thromboxanes), and lysophospholipids are converted to platelet-activating factors. These lipid mediators play critical roles in the initiation, maintenance, and modulation of neuroinflammation and oxidative stress. Neurological disorders including excitotoxicity; traumatic nerve and brain injury; cerebral ischemia; Alzheimer's disease; Parkinson's disease; multiple sclerosis; experimental allergic encephalitis; pain; depression; bipolar disorder; schizophrenia; and autism are characterized by oxidative stress, inflammatory reactions, alterations in phospholipid metabolism, accumulation of lipid peroxides, and increased activities of brain phospholipase A2 isoforms. Several old and new synthetic inhibitors of PLA2, including fatty acid trifluoromethyl ketones; methyl arachidonyl fluorophosphonate; bromoenol lactone; indole-based inhibitors; pyrrolidine-based inhibitors; amide inhibitors, 2-oxoamides; 1,3-disubstituted propan-2-ones and polyfluoroalkyl ketones as well as phytochemical based PLA2 inhibitors including curcumin, Ginkgo biloba and Centella asiatica extracts have been discovered and used for the treatment of neurological disorders in cell culture and animal model systems. The purpose of this review is to summarize information on selective and potent synthetic inhibitors of PLA2 as well as several PLA2 inhibitors from plants, for treatment of oxidative stress and neuroinflammation associated with the pathogenesis of neurological disorders.
authors.affiliation: †Department of Anatomy, National University of Singapore, Singapore 119260, Singapore.
authors.forename: Wei-Yi
authors.initials: WY
authors.lastname: Ong
authors.affiliation: ‡Department of Molecular and Cellular Biochemistry, Ohio State University, Columbus, Ohio 43210, United States.
authors.forename: Tahira
authors.initials: T
authors.lastname: Farooqui
authors.affiliation: §Laboratory of Organic Chemistry, Department of Chemistry, University of Athens, Panepistimiopolis, Athens 15771, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Kokotos
authors.affiliation: ‡Department of Molecular and Cellular Biochemistry, Ohio State University, Columbus, Ohio 43210, United States.
authors.forename: Akhlaq A
authors.initials: AA
authors.lastname: Farooqui
mesh_terms: D000818:Animals; D001927:Brain Diseases / Q000188:drug therapy / Q000201:enzymology; D006801:Humans; D001523:Mental Disorders / Q000188:drug therapy / Q000201:enzymology; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000201:enzymology; D064801:Phospholipase A2 Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D064801:Phospholipase A2 Inhibitors
keywords: Phospholipase A2 inhibitors; eicosanoids; lipid mediators; lipids; neurodegeneration; neuroinflammation; neurological disorders; oxidative stress