Abstract
Platelet activating factor (PAF) is an inflammatory lipid mediator released by ischemic brain. Our objectives were to use an inhibitor of PAF that does not readily cross the blood-brain barrier, WEB 2170, to study the role of intravascular PAF on brain swelling and subsequent brain atrophy in a neonatal rat model of hypoxic-ischemic brain injury. We injured the right cerebral hemisphere of 7-d-old rats by ligating the right common carotid artery and exposing the rats to 8% oxygen for 2.25 h. Forty-two rats received saline or the PAF antagonist WEB 2170, 1 h before hypoxia. We found that WEB 2170 pretreatment reduced swelling by 64% (p = 0.003). In contrast, treatment immediately after hypoxic-ischemic injury did not reduce swelling. In two additional experiments involving 103 rats, we found that pretreatment or repeated doses of PAF antagonist before and after hypoxic-ischemic injury did not reduce atrophy. We also found that the brain-penetrating PAF antagonist, BN 52021, did not prevent atrophy in our Wistar rat model. In conclusion, we were unable to reduce long-term brain injury with either PAF antagonist. WEB 2170 pretreatment reduced brain swelling by 64% without reducing atrophy. This suggests that although brain swelling may accompany cerebral infarction, it does not contribute to the pathogenesis of infarction and subsequent atrophy in the neonatal rat. The ability to reduce early postischemic brain swelling without reducing atrophy may be particularly unique to the immature animal with a compliant skull.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
Abbreviations
- PAF:
-
platelet activating factor
- P7:
-
7-day old rats
- HI:
-
hypoxic-ischemic
References
Palmer C 1995 Hypoxic-ischemic encephalopathy: therapeutic approaches against microvascular injury, and role of neutrophils, PAF, and free radicals. Clin Perinatol 22: 481–517
Vannucci RC, Christensen MA, Yager JY 1993 Nature, time-course, and extent of cerebral edema in perinatal hypoxic-ischemic brain damage. Pediatr Neurol 9: 29–34
Satoh K, Yoshida H, Imaizumi TA, Koyama M, Takamatsu S 1995 Production of platelet-activating factor by porcine brain microvascular endothelial cells in culture. Thromb Haemost 74: 1335–1339
Bratton D, Henson PM 1989 Cellular origin of PAF. In: Barnes PJ, Page CP, Henson PM (eds) Platelet Activating Factor in Human Disease. Blackwell Scientific, London, pp 23–57
Humphrey DMN, McManus LM, Hanahan DJ, Pinckard RN 1984 Morphologic basis of increased vascular permeability induced by acetyl glyceryl ether phosphorylcholine. Lab Invest 50: 16–25
Maki N, Hoffman DR, Johnston JM 1988 Platelet activating factor acetylhydrolase activity in maternal, fetal and newborn rabbit plasma during pregnancy and lactation. Proc Natl Acad Sci U S A 85: 728–732
Francescangeli E, Goracci G 1989 The de novo biosynthesis of platelet-activating factor in rat brain. Biochem Biophys Res Commun 161: 107–112
Sogos V, Bussolino F, Pilia E, Torelli S, Gremo F 1990 Acetylcholine-induced production of platelet-activating factor by human fetal brain cells in culture. J Neurosci Res 27: 706–711
Predescu D, Ihida K, Predescu S, Palade GE 1996 The vascular distribution of the platelet-activating factor receptor. Eur J Cell Biol 69: 86–98
Bito H, Honda Z, Nakamura M, Shimizu T 1994 Cloning, expression and tissue distribution of rat platelet-activating factor receptor cDNA. Eur J Biochem 221: 211–218
Spinnewyn B, Blavet N, Clostre F, Bazan N, Braquet P 1987 Involvement of platelet-activating factor (PAF) in cerebral post-ischemic phase in mongolian gerbils. Prostaglandins 34: 337–349
Lindsberg PJ, Hallenbeck JM, Feuerstein G 1991 Platelet-activating factor in stroke and brain injury. Ann Neurol 30: 117–129
Yue TL, Gleason MM, Gu JL, Lysko PG, Hallenbeck J, Feuerstein G 1991 Platelet-activating factor (PAF) receptor-mediated calcium mobilization and phosphoinositide turnover in neurohybrid NG108–15 cells: studies with BN 50739, a new PAF antagonist. J Pharmacol Exp Ther 257: 374–381
Liu XH, Eun BL, Silverstein FS, Barks JDE 1996 The platelet-activating factor antagonist BN 52021 attenuates hypoxic-ischemic brain injury in the immature rat. Pediatr Res 40: 797–803
Faden AI, Tzendzalian PA 1992 Platelet-activating factor antagonists limit glycine changes and behavioral deficits after brain trauma. Am J Physiol 263: R909–R914
Rice JE, Vannucci RC, Brierley JB 1981 The influence of immaturity on hypoxic-ischemic brain damage in the rat. Ann Neurol 9: 131–141
Palmer C, Towfighi J, Roberts RL, Heitjan DF 1993 Allopurinol administered after inducing hypoxia-ischemia reduces brain injury in 7-day-old rats. Pediatr Res 33: 405–411
Gidday JM, Fitzgibbons JC, Shah AR, Park TS 1994 Neuroprotection from ischemic brain injury by hypoxic preconditioning in the neonatal rat. Neurosci Lett 168: 221–224
Anderson BO, Poggetti RS, Shanley PF, Bensard DD, Pitman JM, Nelson DW, Whitman GJ, Banerjee A, Harken AH 1991 Primed neutrophils injure rat lung through a platelet-activating factor dependent mechanism. J Surg Res 50: 510–514
Zhou W, McCollum MO, Levine BA, Olson MS 1992 Inflammation and platelet-activating factor production during hepatic ischemia/reperfusion. Hepatology 16: 1236–1240
Vannucci RC, Christensen MA, Yager JY 1993 Nature, time-course and extent of cerebral edema in perinatal hypoxic-ischemic brain damage. Pediatr Neurol 9: 29–34
Rumpel H, Nedelcu J, Aguzzi A, Martin E 1997 Late glial swelling after acute cerebral hypoxia ischemia in the neonatal rat: a combined magnetic resonance and histochemical study. Pediatr Res 42: 54–59
Lehr HA, Seemuller J, Hubner C, Menger MD, Messmer K 1993 Oxidized LDL-induced leukocyte/endothelium interaction in vivo involves the receptor for platelet-activating factor. Arterioscler Thromb 13: 1013–1018
Domingo MT, Spinnewyn B, Chabrier PE, Braquet P 1994 Changes in [3H]PAF binding and PAF concentrations in gerbil brain after bilateral common carotid artery occlusion: a quantitative autoradiographic study. Brain Res 640: 268–276
Kornecki E, Ehrlich YH 1988 Neuroregulatory and neuropathological actions of the ether-phospholipid platelet-activating factor. Science 240: 1792–1794
Matsuo Y, Kihara T, Ikeda M, Ninomiya M, Onodera H, Kogure K 1996 Role of platelet-activating factor and thromboxane A2 in radical production during ischemia and reperfusion of the rat brain. Brain Res 709: 296–302
Palmer C, Roberts RL 1997 Deferoxamine starch conjugate provides partial protection from hypoxic-ischemic brain injury in neonatal rats. Pediatr Res 41: 294Aabstr
Palmer C, Roberts RL, Young P 1996 The reduction of hypoxic-ischemic brain injury in the 7-day old rat with PEG-SOD. Pediatr Res 39: 379Aabstr
Bradbury M 1979 The barrier to drugs, neurotransmitters and metabolites. In: Bradbury M (ed) The Concept of a Blood-Brain Barrier. John Wiley & Sons, Chichester, pp 323–350
Weber KH, Heuer H 1989 Structure-activity relationships and effects of platelet-activating factor antagonists in the hetrazepine series. Int Arch Allergy Appl Immunol 88: 82–87
Duverger D, MacKenzie ET 1988 The quantification of cerebral infarction following focal ischemia in the rat: influence of strain, arterial pressure, blood glucose concentration, and age. J Cereb Blood Flow Metab 8: 449–461
Acknowledgements
The authors thank Michael S. Caplan, M.D., Department of Pediatrics, Evanston Hospital, North Western University Medical School, Chicago, IL, U.S.A., for his assistance in this study.
Author information
Authors and Affiliations
Additional information
Supported by National Institutes of Health grants NS29704 and HD31704 to C.P.
Rights and permissions
About this article
Cite this article
Viswanath, M., Palmer, C. & Roberts, R. Reduction of Hypoxic-Ischemic Brain Swelling in the Neonatal Rat with PAF Antagonist WEB 2170: Lack of Long-Term Protection. Pediatr Res 48, 109–113 (2000). https://doi.org/10.1203/00006450-200007000-00019
Received:
Accepted:
Issue date:
DOI: https://doi.org/10.1203/00006450-200007000-00019
This article is cited by
-
Loss of PAFR prevents neuroinflammation and brain dysfunction after traumatic brain injury
Scientific Reports (2017)
