Recently, interest has been focused on the role of platelet-activating factor (PAF) in neurological injury. Originally isolated from stimulated basophils,8,9,33,50 PAF can be produced by a variety of cells such as neutrophils, platelets, monocytes, macrophages, and endothelial cells; it has also been suggested as a mediator of inflammation, platelet and neutrophil activation, plasma extravasation, and anaphylactic shock.12 Platelet-activating factor is synthesized by the sequential activities of the phospholipase A2 and acetyl transferase, which depends on cell activation and the presence of calcium;55 PAF is inactivated by acetylhydrolase and acyltransferase, which is independent of cell stimulation. Alkyl-acyl glycerophosphocholine, which is stored in cell membranes, is not only the end-product of the cellular metabolism of PAF, it is also the potential precursor of PAF as well as of arachidonic acid.
The involvement of PAF in the pathophysiology of central nervous system (CNS) disorders has been suggested in several studies. Platelet-activating factor increases the BBB permeability42 and reduces cerebral blood flow (CBF) in the cortex presumably by constriction of cerebral vessels.2,39 Beneficial effects of PAF antagonists have been shown repeatedly in various models of cerebral ischemia. Thus, pretreatment as well as postischemic administration of the PAF antagonist BN 52021 resulted in reduction of edema formation and improved neurological outcome following global ischemia in the gerbil.56 In the same model, administration of a PAF antagonist upon reperfusion resulted in improved cerebral microcirculation in the phase of hypoperfusion;48 furthermore, the pathological postischemic accumulation of free fatty acids was reduced by PAF inhibition. These effects were not associated with any alterations of tissue phosphoinositides or diacylglycerol,10 suggesting that the phospholipase A2 might be an important mediator of PAF-related effects. Additional support for the potential role of PAF in mediation of brain damage can be drawn from recent findings showing the existence of PAF in brain tissue57 and elevated PAF levels following electroconvulsive disorders.42
Previous reports on the interaction of the neodymium:yttrium-aluminum-garnet (Nd:YAG) laser with nervous tissue indicated the eventual usefulness of this laser for production of highly reproducible focal cortical lesions.6,21,45,62 Edema, BBB disruption, selective neuronal necrosis (which develop beyond the boundary of the edematous zone), and the evolution of the histopathological picture suggest that Nd:YAG laser-induced brain lesions may be appropriate for studying mechanisms of secondary brain damage following traumatic brain injury. The present study has been designed to further characterize the evolution of widespread brain injury in response to focal trauma and to investigate the potential role of PAF in this process.
The authors thank Mrs. Vicky Guthrie for technical assistance in preparing the histological sections. We also express our gratitude to Dr. W. van deMerwe and Mr. M. Smith of the Center of Lasers and Biophysics, Uniformed Services University of the Health Sciences.
Kornecki ELenox RHHardwick DHet al: Interactions of the alkyl-ether-phospholipid, platelet-activating factor (PAF) with platelets, neural cells, and the psychotropic drugs triazolobenzodiazepinesEhrlich YHLenox RHKornecki Eet al: Molecular Mechanisms of Neuronal Responsiveness. New York: Plenum Press1987477–488Molecular Mechanisms of Neuronal Responsiveness.
Panetta TMarcheselli VLBraquet Pet al: Effects of a platelet activating factor antagonist (BN 52021) on free fatty acids, diacylglycerols, polyphosphoinositides and blood flow in the gerbil brain: inhibition of ischemiareperfusion induced cerebral injury. Biochem Biophys Res Commun 149:580–5871987Biochem Biophys Res Commun 149:
Pinckard RNFarr RSHanahan DJ: Physiochemical and functional identity of rabbit platelet-activating factor (PAF) released in vivo during IgE anaphylaxis with PAF released in vitro from IgE sensitized basophils. J Immunol 123:1847–18571979in vivo during IgE anaphylaxis with PAF released in vitro from IgE sensitized basophils. J Immunol 123:
Snyder F: Biochemistry of platelet-activating factor: a unique class of biologically active phospholipids (42839). Proc Soc Exp Biol Med 190:125–1351989Snyder F: Biochemistry of platelet-activating factor: a unique class of biologically active phospholipids (42839). Proc Soc Exp Biol Med 190:
Wirthmueller UDe Weck ALDahinden CA: Platelet-activating factor production in human neutrophils by sequential stimulation with granulocyte-macrophage colony-stimulating factor and the chemotactic factors C5A or formyl-methionyl-leucyl-phenylalanine. J Immunol 142:3213–32181989J Immunol 142:
Stereotactic instrument manufactured by David Knopf Instruments, Tujunga, California.
CL40 laser manufactured by Surgical Laser Technologies, Malvern, Pennsylvania.
BN 50739 was kindly provided by Professor P. Braquet, Institute Henri Beaufour, Paris, France.
Endoscopic flow probe P436 manufactured by TSI, Inc., St. Paul, Minnesota.
Blood perfusion monitor BPM 403a was manufactured by TSI, Inc., St. Paul, Minnesota.
Chemical balance M3 obtained from Mettler Instrument Corp., Hightstown, New Jersey.
Desiccator oven OV-8A obtained from Blue M Electric Company, Blue Island, Illinois.
This work was supported in part by Grant GM9229 from the Uniformed Services University of the Health Sciences, Bethesda, Maryland, and by Grant G19249 from the Institute Henri Beaufour, Paris, France.
This paper was presented in part at the 15th International Joint Conference on Stroke and Cerebral Circulation, Orlando, Florida, in 1990.