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Protection against cyclosporin-induced nephrotoxicity: 1. Effect of a PAF antagonist, BN50726
F Massicot1, J M Warnet, H Dutertre-Catella
1Laboratoire de Toxicologie (E.A. 207), Faculté de Pharmacie, Paris, France.
Abstract:
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.
Insights
Platelet-activating factor (PAF) may play a role in cyclosporin A (CsA)-induced kidney damage. A new PAF antagonist, BN50726, reduced some markers of CsA nephrotoxicity in rats, suggesting therapeutic potential.
Area of Science:
- Nephrology
- Pharmacology
- Immunology
Background:
- Cyclosporin A (CsA) is crucial in organ transplantation but causes nephrotoxicity, limiting its clinical use.
- The exact mechanisms behind CsA-induced nephrotoxicity are not fully understood, with potential involvement of glutathione metabolism, lipoperoxidation, and platelet-activating factor (PAF).
Purpose of the Study:
- To investigate the potential role of PAF in CsA-induced nephrotoxicity.
- To evaluate the efficacy of a novel PAF antagonist, BN50726, in mitigating CsA-induced kidney damage.
Main Methods:
- Rats were treated with CsA alone or in combination with BN50726.
- Key markers of kidney injury, including serum urea, urinary gamma-glutamyl transferase (GGT) activity, and kidney cortex oxidized glutathione levels, were measured.
Main Results:
- CsA treatment significantly increased serum urea, urinary GGT activity, and oxidized glutathione levels.
- Co-administration of BN50726 with CsA normalized urinary GGT activity and significantly reduced oxidized glutathione levels compared to CsA alone.
- Serum urea levels remained elevated in rats treated with CsA plus BN50726, similar to the CsA-only group.
Conclusions:
- BN50726 demonstrates potential in preventing renal membrane damage, likely through antiperoxidative mechanisms.
- These findings suggest that PAF antagonists, such as BN50726, may have therapeutic value in reducing CsA-induced nephrotoxicity.
- The study indicates a potential interaction between PAF and CsA in the pathogenesis of renal injury.