The Roles of Platelet-Activating Factor (PAF) and its Related Signaling and Metabolism in Neurological Diseases

Platelet-activating factor (PAF, 1-O-alkyl-2-acetyl-sn-glycero- 3-phosphocholine) displays a variety of biological activities in the nervous system. It has been suggested that PAF plays important roles in neuronal physiological function via activation of its specific membranes receptors. Under certain pathological conditions, PAF acts as a potent mediator of leukocyte functions, platelet aggregation, pro-inflammatory signaling and others. Therefore, PAF has been implicated in the pathophysiology of neuronal diseases such as ischemic stroke, hemorrhagic stroke, chronic subdural hematoma after head injury, brain tumor and associated brain edema, dementia due to neurodegenerative diseases such as Parkinson’s disease and Prion diseases, and HIV-1-associated dementia. PAF is synthesized in platelet, monocytes/macrophage, neutrophils and endothelial cells in response to physiological and pathological stimuli through the de novo and remodeling pathways from cellular membrane phospholipids. PAF is thought to be a pro-inflammatory and pro-thrombotic mediator and also causes direct damage to neuronal cells. At least three types of platelet-activating factor acetylhydrolase (PAF-AH) have been identified in mammals, i.e., intracellular type I and II, and a plasma type. The type I PAF-AH hydrolyzes the sn-2 ester bound in PAF-like phospholipids with a marked preference for very short acyl chains, typically acetyl bound. On the other hand, the type II PAF-AH has its substrate specificity similar to the plasma PAF-AH. Both PAFAHs hydrolyze phospholipids with short to medium length sn-2 acyl chains including truncated ones derived from oxidative cleavage of long chain polyunsaturated fatty acyl groups. With respect to atherosclerosis it is not fully understood whether this enzyme plays an anti-atherogenic role or pro-atherogenic role. In this review, the roles of PAF, its signaling and related metabolism including PAH-AHs in a variety of pathological conditions in the central nervous system are discussed.

Keywords: platelet-activating factor (PAF), PAF acetylhydrolase (PAF-AH), PAF receptor, ischemic stroke, atherosclerosis, hemorrhagic stroke, subarachnoid hemorrhage (SAH), cerebral vasospasm, chronic subdural hematoma (CSH), meingioma, Parkinson’s disease, Prion diseases, HIV-1-associated dementia (HAD)