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

Abstract

Azaspiranes are cationic amphiphilic compounds that are active in a number of models of autoimmune disease and transplantation. Repeated administration of cationic amphiphiles induces phospholipid accumulation in a variety of species. The present study was conducted to explore the mechanism of phospholipid accumulation in rats caused by treatment with the novel azaspirane, SK&F 106615 (atiprimod). Atiprimod inhibited the activities of partially purified 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 increased the contents of arachidonate-containing molecular species within plasmalogen subclasses of hepatic phosphatidylcholine and phosphatidylethanolamine. In contrast, diacyl-linked species were not affected, indicating a selective effect upon an hepatic plasmalogen-selective phospholipase A(2). Taken together, the data suggest that the beneficial effects of atiprimod in autoimmune diseases may involve inhibition of phospholipase A(2) and C activities. Further, the data suggest that atiprimod is a selective inhibitor of plasmalogen-selective phospholipase A(2) in vivo.

• Authors: J A Handler, A Badger, C A Genell, A M Klinkner, S Kassis, C R Waites, P J Bugelski
• Journal: Toxicology and applied pharmacology (Toxicol Appl Pharmacol) Vol. 159 Issue 1 Pg. 9-17 (Aug 15 1999) ISSN: 0041-008X [Print] United States
• PMID: 10448120 (Publication Type: Journal Article)
• Copyright: Copyright 1999 Academic Press.

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Phosphatidylcholines
• Phosphatidylethanolamines
• Phospholipids
• Spiro Compounds
• azaspirane
• Arachidonic Acid
• Phospholipases

Topics

• Animals
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
• Arachidonic Acid (metabolism)
• Binding, Competitive
• In Vitro Techniques
• Macrophages, Alveolar (metabolism)
• Male
• Phosphatidylcholines (metabolism)
• Phosphatidylethanolamines (metabolism)
• Phospholipases (antagonists & inhibitors, classification)
• Phospholipids (metabolism)
• Rats
• Rats, Sprague-Dawley
• Spiro Compounds (pharmacology)