Protection against cyclosporin-induced nephrotoxicity: 1. Effect of a PAF antagonist, BN50726.
The clinical usefulness of cyclosporin A (CsA) in organ transplantation is limited by its intrinsic nephrotoxicity, the mechanisms of which have not yet been completely elucidated. Various processes could be responsible for the CsA-induced nephrotoxicity including an interaction with glutathione metabolism, a lipoperoxidative process, or an interaction with platelet-activating factor (PAF). Therefore, the aim of this study was to assess the potential role of PAF in CsA-induced nephrotoxicity using a new PAF antagonist, BN50726. CsA alone provoked a significant increase in serum urea, urinary gamma-glutamyl transferase activity and oxidized glutathione level of kidney cortex in the rat. In contrast, when rats were treated with CsA plus BN50726, urinary gamma-glutamyltransferase activity was similar to that of controls and oxidized glutathione was significantly lower than that measured in rats treated with CsA alone. However, serum urea remained increased as it was in the CsA group. Our results suggest that BN50726 is able to prevent the damage of renal membranes probably by an antiperoxidative activity. These data indicate the potential therapeutic capacity of a PAF antagonist, BN50726, in reducing CsA nephrotoxicity and suggest interactions between PAF and CsA in the mechanism of renal injury.
Massicot
F
F
Laboratoire de Toxicologie (E.A. 207), Faculté de Pharmacie, Paris, France.
Warnet
J M
JM
Dutertre-Catella
H
H
Martin
C
C
Braquet
P
P
Claude
J R
JR
D000818:Animals; D001381:Azepines / Q000627:therapeutic use*; D003404:Creatinine / Q000097:blood; D016572:Cyclosporine / Q000633:toxicity*; D004347:Drug Interactions; D005978:Glutathione / Q000378:metabolism; D007672:Kidney Cortex / Q000187:drug effects / Q000378:metabolism; D007674:Kidney Diseases / Q000139:chemically induced* / Q000517:prevention & control*; D008297:Male; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D058924:Thienopyridines; D014508:Urea / Q000097:blood
D001381:Azepines; D010972:Platelet Activating Factor; D058924:Thienopyridines; C061327:BN 50726; D016572:Cyclosporine; D014508:Urea; D003404:Creatinine; D005978:Glutathione