Comparison of systemic and local eosinophil recruitment induced by PAF or immune challenge in the rat: Modulation by drugs

Abstract

The chapter presents a study on kadsurenone and other related lignans as antagonists of platelet-activating factor (PAF) receptor. The chapter describes the chemistry and pharmacology of kadsurenone and other lignan derivatives. PAF is a highly potent ether-linked phospholipid (1-O-alkyl-2-acetyl-sn-glycerol-3-phosphorylcholine), which activates platelets as well as modulates the function of leukocytes and other target cells. Interaction of PAF with a specific membrane recognition site coupled to phosphatidylinositol metabolism produces the biological actions of the phospholipid. A number of specific reversible and irreversible PAF receptor antagonists have been developed using both in vitro (platelet aggregation; binding studies) and in vivo (hypotension; bronchoconstriction) screening methods. Some of these antagonists include PAF analogs, for example, CV-3989, ONO-6248, SR-63441, natural products, for example, kadsurenone, tetrahydrofuran lignans and their synthetic analogs, ginkgolide B (BN 52021), benzodiazepine derivatives, and other synthetic structures. Kadsurenone is a specific, potent, and reversible inhibitor of the binding of [3H]PAF to its membrane receptor and PAF-induced aggregation of platelets. It also inhibits PAF-induced aggregation and degranulation of neutrophils. In the rat, kadsurenone inhibits PAF-induced foot edema and the shock syndromes, acute hypotension, neutropenia, extravasation, and secretion of lysosomal enzymes, induced by endotoxin, soluble immune complex or PAF.