Selective inhibition of phospholipases by atiprimod, a macrophage targeting antiarthritic compound

Azaspiranes are cationic amphiphilic compounds that are active in a number of models of autoimmune disease and transplantation. Repeated administratio n of cationic amphiphiles induces phospholipid accumulation in a variety of species. The present study was conducted to explore the mechanism of phosp holipid accumulation in rats caused by treatment with the novel azaspirane, SK&F 106615 (atiprimod). Atiprimod inhibited the activities of partially p urified phospholipases A(2) and C, but not D, in a noncompetitive manner in vitro. Treatment of rats for 28 days with 10 mg/kg/day of atiprimod increa sed the contents of arachidonate-containing molecular species within plasma logen subclasses of hepatic phosphatidylcholine and phosphatidylethanolamin e. In contrast, diacyl-linked species were not affected, indicating a selec tive effect upon an hepatic plasmalogen-selective phospholipase A(2). Taken together, the data suggest that the beneficial effects of atiprimod in aut oimmune diseases may involve inhibition of phospholipase A(2) and C activit ies. Further, the data suggest that atiprimod is a selective inhibitor of p lasmalogen-selective phospholipase A(2) in vivo. (C) 1999 Academic Press.