Platelet-activating factor antagonist BN 50730 attenuates hypoxic-ischemic brain injury in neonatal rats.
Platelet-activating factor (PAF) is a lipid derived from breakdown of cell membranes that is postulated to be a mediator of cerebral ischemic injury. PAF regulates CNS gene transcription via intracellular binding sites. To test the hypothesis that PAF mediates CNS injury in part by modulating gene transcription, we evaluated the neuroprotective efficacy of the drug BN 50730, an antagonist of the intracellular (microsomal) CNS PAF binding site, in the neonatal rat model of unilateral cerebral hypoxia-ischemia. Seven-day-old rats underwent right carotid ligation followed by a 2.5-h exposure to 8% O(2), and were then treated with BN 50730 (2.5 or 25 mg/kg per dose) or vehicle, at 0 and 2 h after the end of hypoxia. Ipsilateral cortical, striatal, and hippocampal damage was quantitated either 5 d later, or at 5 wk after the insult. Treatment with BN 50730 resulted in approximately 60- 80% reduction in ipsilateral tissue loss at both times. Learning and memory were evaluated 5 wk after insult using the Morris Watermaze place navigation task. Severity of cortical and striatal damage correlated significantly with learning and memory deficits. These results support the hypothesis that PAF is a pathogenetic mediator of hypoxic-ischemic damage in the immature brain. Accumulating evidence suggests that PAF mediates its deleterious effects in the immature CNS via multiple mechanisms.
Liu
X H
XH
Department of Pediatrics, University of Michigan Health System, Ann Arbor, Michigan 48109-0646, USA.
Eun
B L
BL
Barks
J D
JD
D000818:Animals; D000831:Animals, Newborn; D001381:Azepines / Q000494:pharmacology*; D001930:Brain Injuries / Q000209:etiology / Q000473:pathology / Q000517:prevention & control* / Q000523:psychology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology / Q000523:psychology; D002540:Cerebral Cortex / Q000187:drug effects / Q000473:pathology; D003342:Corpus Striatum / Q000187:drug effects / Q000473:pathology; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D002534:Hypoxia, Brain / Q000188:drug therapy* / Q000473:pathology / Q000523:psychology; D007858:Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D058924:Thienopyridines; D014230:Triazoles / Q000494:pharmacology*
D001381:Azepines; D010972:Platelet Activating Factor; D058924:Thienopyridines; D014230:Triazoles; C066686:BN 50730