Phospholipase A2 and its molecular mechanism after spinal cord injury

Abstract

Phospholipases A(2) (PLA(2)s) are a diverse family of lipolytic enzymes which hydrolyze the acyl bond at the sn-2 position of glycerophospholipids to produce free fatty acids and lysophospholipids. These products are precursors of bioactive eicosanoids and platelet-activating factor which have been implicated in pathological states of numerous acute and chronic neurological disorders. To date, more than 27 isoforms of PLA(2) have been found in the mammalian system which can be classified into four major categories: secretory PLA(2), cytosolic PLA(2), Ca(2+)-independent PLA(2), and platelet-activating factor acetylhydrolases. Multiple isoforms of PLA(2) are found in the mammalian spinal cord. Under physiological conditions, PLA(2)s are involved in diverse cellular responses, including phospholipid digestion and metabolism, host defense, and signal transduction. However, under pathological situations, increased PLA(2) activity, excessive production of free fatty acids and their metabolites may lead to the loss of membrane integrity, inflammation, oxidative stress, and subsequent neuronal injury. There is emerging evidence that PLA(2) plays a key role in the secondary injury process after traumatic spinal cord injury. This review outlines the current knowledge of the PLA(2) in the spinal cord with an emphasis being placed on the possible roles of PLA(2) in mediating the secondary SCI.

Fig. 1

PLA₂ mediates the production of lipid mediators. PLA₂ hydrolyzes the membrane phospholipids to produce a free fatty acid such as arachidonic acid (AA) and a lysophospholipid such as lysophosphatidylcholine (Lyso-PC). AA can give rise to eicosanoids via cyclooxygenases (COX), 5-lipoxygenase (5-LO), and 15-lipoxygenase (15-LO) enzymes. Eicosanoids such as thromboxanes (TX), prostaglandins (PG), and leukotrienes (LT) are potent mediators of inflammation which can increase vascular permeability and induce chemotaxis of immune cells. Lipoxin is also an AA-derived lipid mediator. However, in contrast to above eicosanoids, it has an anti-inflammatory effect. In addition, platelet-activating factor (PAF) is biosynthesized from Lyso-PC and acetyl CoA by enzyme Lyso-PC acetyltransferase. Lyso-PC is a myelinolytic agent and can act as a chemoattractant for immune cells. PAF is a potent phospholipid activator and a mediator of many leukocyte functions, including platelet aggregation, inflammation, and anaphylaxis. 5-HPETE 5-hydroperoxyeicosatetraenoic acid, PGH₂ prostaglandin H₂

Fig. 2

Possible mechanisms underlying PLA₂-mediated secondary spinal cord injury. Acute traumatic SCI triggers a secondary injury process mediated by multiple injury inducers including inflammatory cytokines, free radicals, and excitatory amino acids; all these inducers may activate PLA₂. Over-activation of PLA₂ may enhance membrane phospholipid hydrolysis, arachidonic acid release, oxygen free radical generation, eicosanoids production, and ultimately lead to neuronal death