Original article Protective effect of L-propionylcarnitine in chronic cyclosporine-a induced nephrotoxicity Nicola Origlia a , Massimiliano Migliori a , Vincenzo Panichi b , Cristina Filippi a , Aldo Bertelli c , Angelo Carpi d , Luca Giovannini a,* a Department of Neuroscience, Pharmacology section, University of Pisa, Via Roma 55, 56126 Pisa, Italy b Department of Internal Medicine, University of Pisa, Via Roma 55, 56126 Pisa, Italy c Department of Pharmacology, University of Milan, Italy d Department of Reproduction and Aging, University of Pisa, Via Roma 55, 56126 Pisa, Italy Received 9 June 2005; accepted 17 June 2005 Available online 27 December 2005 Abstract Cyclosporine (CyA) is an immunosuppressive agent used after solid organ transplantation, but its clinical use is limited by side effects, the most important of which is nephrotoxicity. In a previous work we demonstrated that L-propionylcarnitine (L-PC), a propionyl ester of L-carnitine, is able to prevent CyA-induced acute nephrotoxicity reducing lipid peroxidation in the isolated and perfused rat kidney. CyA administration was associated with a dose dependent increase in renovascular resistance prevented by a pretreatment with L-PC. The aim of the present study was to confirm L-PC protective effect, previously described in vitro, in an in vivo rat model. Chronic nephrotoxicity study was carried out for 28 days. L-PC was administered (i.p. 25 mg/kg b.w.) since the first day, while CyA treatment was performed for the last 21 days (by oral administration 25 mg/kg b.w.). We demonstrate that L-PC was able to significantly lower blood pressure in CyA treated animals and to prevent CyA induced decrease in creatinine clearance. Moreover renal tissue analysis revealed that L-PC was able to reduce lipid hydroperoxide content and morpho- logical abnormalities associated to chronic CyA administration. In conclusion our study demonstrated for the first time in vivo that L-PC protects against functional and tissue damage associated to chronic CyA administration. © 2006 Elsevier SAS. All rights reserved. Keywords: Lipid peroxidation; Hypertension; Nitric oxide 1. Introduction Cyclosporine is an immunosuppressive agent used after so- lid organ transplantation, but its clinical use is limited by side effects, the most important of which is nephrotoxicity. Chronic CyA nephrotoxicity is manifested by renal insuffi- ciency due to glomerular and vascular disease, abnormalities in tubular function and the increase in blood pressure [1]. However, the factors responsible for chronic CyA nephro- toxicity are not well understood. Indeed hemodinamic alterations are associated with high re- nal vascular resistance involving a direct constriction of intrar- enal arterioles [2]. The increase in vascular resistance may re- flect an elevated plasma creatinine concentration and the development of hypertension [1]. Structural changes associated with CyA chronic nephrotoxicity are diffuse interstitial fibrosis or stripped interstitial fibrosis with tubular atrophy, obliterate arteriolopathy and ischemic atrophy of the glomerular tuft [1,3, 4]. However, functional nephrotoxicity can cause the develop- ment of structural nephrotoxicity, and conversely, structural nephrotoxicity can lead to functional impairment involving al- tered hemodinamic and filtration. It is known that in the kidney one of the most important vasoactive factors in maintaining vascular tone is nitric oxide (NO). In addition, NO prevents http://france.elsevier.com/direct/BIOPHA/ Biomedicine & Pharmacotherapy 60 (2006) 77–81 Abbreviations: BD, Bowman’s capsule diameter; CD, glomerular capillary tuft diameter; CrCl, creatinine clearance; CyA, cyclosporine A; LOOH, lipid hydroperoxide; L-PC, L-propionylcarnitine; NO, nitric oxide; ROS, reactive oxygen species.. * Corresponding author. Tel.: +39 050 835 803; fax: +39 050 835 820. E-mail address: l.giovannini@med.unipi.it (L. Giovannini). 0753-3322/$ - see front matter © 2006 Elsevier SAS. All rights reserved. doi:10.1016/j.biopha.2005.06.014