Reduction of hypoxic-ischemic brain swelling in the neonatal rat with PAF antagonist WEB 2170: lack of long-term protection.
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.
Viswanath
M
M
Department of Pediatrics, Section of Newborn Medicine, Pennsylvania State University College of Medicine, Hershey 17033, USA.
Palmer
C
C
Roberts
R L
RL
D000818:Animals; D000831:Animals, Newborn; D001284:Atrophy; D001381:Azepines / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D001929:Brain Edema / Q000209:etiology* / Q000517:prevention & control; D005260:Female; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D014230:Triazoles / Q000494:pharmacology*; D015430:Weight Gain / Q000187:drug effects
D001381:Azepines; D010972:Platelet Activating Factor; D010975:Platelet Aggregation Inhibitors; D014230:Triazoles; C063964:bepafant