EFFECT OF THE PLATELET-ACTIVATING-FACTOR ANTAGONIST BN-50739 AND ITS DILUENTS ON MITOCHONDRIAL RESPIRATION AND MEMBRANE-LIPIDS DURING AND FOLLOWING CEREBRAL-ISCHEMIA

Recent evidence suggests that platelet-activating factor plays a role in ischemia-induced neural injury. The Pulsinelli-Brierley four-vessel occlusion model was used to study the effect of a synthetic platelet- activating factor antagonist, BN 50739, and its solvents, either dimet hyl sulfoxide or hydroxypropyl-beta-cyclodextrin, on cerebral ischemia -reperfusion. Rats were subjected to either 30 min of ischemia or 30 m in of ischemia followed by 60 min of recirculation. Changes in the bra in mitochondrial free fatty acid pool size, fatty acyl composition of phospholipids, and respiratory function were monitored. When the BN 50 739 (2 mg of BN 50739/kg of body weight i.v.) was administered at the onset of recirculation, it significantly reversed the ischemia-induced accumulation of mitochondrial free fatty acids and loss of polyunsatu rated fatty acyl chains from phosphatidylcholine and phosphatidylethan olamine while simultaneously improving mitochondrial respiration. Dime thyl sulfoxide alone decreased the mitochondrial level of malonyldiald ehyde and total free fatty acid pool size, but there was no improvemen t in mitochondrial respiration. Hydroxypropyl-beta-cyclodextrin was re ported to be pharmacologically inactive and capable of dissolving BN 5 0739. However, hydroxypropyl-beta-cyclodextrin alone also caused a sig nificant increase in content of cerebral mitochondrial membrane free f atty acids and hydrolysis of phosphatidylcholine in normoxic control a nimals. The overall effect of BN 50739 on mitochondrial structure and energy metabolism supports the hypothesis that platelet-activating fac tor may play a key role in ischemia-induced cerebral injury.