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Progression of cyclophosphamide-induced acute renal metabolic damage in carnitine-depleted rat model

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Abstract

Background

Little information is available regarding the mechanism of cyclophosphamide (CP)-induced renal damage. Therefore, this study examined whether carnitine deficiency constitutes a risk factor in and should be viewed as a mechanism during development of CP-induced nephrotoxicity and explored whether carnitine supplementation, using propionyl-l-carnitine (PLC), could offer protection against this toxicity.

Methods

Experimental rats were assigned to one of six groups; the first three groups were injected intraperitoneally with normal saline, PLC (250 mg/kg/day) or d-carnitine (250 mg/kg/day) + Mildronate (200 mg/kg/day), respectively, for 10 successive days. The 4th, 5th and 6th groups received the same doses of normal saline, PLC or d-carnitine + Mildronate, respectively, for 5 successive days before and after a single dose of CP (200 mg/kg).

Results

CP significantly increased serum creatinine, blood urea nitrogen (BUN), intramitochondrial acetyl-coenzyme A (CoA) and thiobarbituric acid reactive substances, significantly decreased total carnitine, intramitochondrial CoA-SH, adenosine triphosphate (ATP) and ATP/adenosine diphosphate (ADP) and reduced glutathione in kidney tissues. In carnitine-depleted rats, CP resulted in dramatic increase in serum nephrotoxicity indices and acetyl-CoA and induced progressive reduction in total carnitine, CoA-SH and ATP as well as severe histopathological lesions in kidney tissues. Interestingly, PLC completely reversed the biochemical and histopathological changes induced by CP to normal values.

Conclusions

Oxidative stress is not involved in CP-induced renal injury in this model. Carnitine deficiency and energy starvation constitute risk factors in and should be viewed as a mechanism during CP-induced nephrotoxicity. PLC prevents development of CP-induced nephrotoxicity by increasing intracellular carnitine content, intramitochondrial CoA-SH/acetyl-CoA ratio and energy production.

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Acknowledgments

Author of this study are grateful to Dr. Zaven Orfalin, Sigma-Tau Pharmaceuticals, Pomezia, Italy, for providing PLC, d-carnitine and Mildronate. The present work was supported by an operating grant from the Research Center, College of Pharmacy, King Saud University (CPRC080144).

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  1. Department of Pharmacology, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh, 11451, Kingdom of Saudi Arabia

    Mohamed M. Sayed-Ahmed

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Correspondence to Mohamed M. Sayed-Ahmed.

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Sayed-Ahmed, M.M. Progression of cyclophosphamide-induced acute renal metabolic damage in carnitine-depleted rat model. Clin Exp Nephrol 14, 418–426 (2010). https://doi.org/10.1007/s10157-010-0321-0

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