UNCORRECTED PROOF YPHRS 1577 1–9 Pharmacological Research xxx (2006) xxx–xxx Propionyl-l-carnitine prevents the progression of cisplatin-induced cardiomyopathy in a carnitine-depleted rat model 3 4 Abdulhakeem A. Al-Majed, Mohamed M. Sayed-Ahmed ∗ , Abdulaziz A. Al-Yahya, Abdulaziz M. Aleisa, Salim S. Al-Rejaie, Othman A. Al-Shabanah 5 6 Department of Pharmacology, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia 7 Accepted 16 December 2005 8 Abstract 9 This study has been initiated to investigate whether endogenous carnitine depletion and/or carnitine deficiency is a risk factor during development of cisplatin (CDDP)-induced cardiomyopathy and if so, whether carnitine supplementation by propionyl-l-carnitine (PLC) could offer protection against this toxicity. To achieve the ultimate goal of this study, a total of 60 adult male Wistar albino rats were divided into six groups. The first three groups were injected intraperitoneally with normal saline, PLC (500 mg kg -1 ), and d-carnitine (500 mg kg -1 ) respectively, for 10 successive days. The 4th, 5th, and 6th groups were injected intraperitoneally with the same doses of normal saline, PLC and d-carnitine, respectively, for 5 successive days before and after a single dose of CDDP (7 mg kg -1 ). On day 6 after CDDP treatment, animals were sacrificed, serum as well as hearts were isolated and analyzed. CDDP resulted in a significant increase in serum creatine phosphokinase isoenzyme (CK-MB) and lactate dehydrogenase (LDH), thiobarbituric acid reactive substances (TBARS) and total nitrate/nitrite (NO(x)) and a significant decrease in reduced glutathione (GSH), total carnitine, and adenosine triphosphate (ATP) content in cardiac tissues. In the carnitine-depleted rat model, CDDP induced dramatic increase in serum cardiomyopathy enzymatic indices, CK-MB and LDH, as well as progressive reduction in total carnitine and ATP content in cardiac tissue. Interestingly, PLC supplementation resulted in a complete reversal of the increase in cardiac enzymes, TBARS and NO x , and the decrease in total carnitine, GSH and ATP, induced by CDDP, to the control values. Moreover, histopathological examination of cardiac tissues confirmed the biochemical data, where PLC prevents CDDP-induced cardiac degenerative changes while d-carnitine aggravated CDDP-induced cardiac tissue damage. In conclusion, data from this study suggest for the first time that carnitine deficiency and oxidative stress are risk factors and should be viewed as mechanisms during development of CDDP-related cardiomyopathy and that carnitine supplementation, using PLC, prevents the progression of CDDP-induced cardiotoxicity. 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 © 2005 Published by Elsevier Ltd. 26 Keywords: Cisplatin; Carnitine deficiency; Cardiomyopathy; d-carnitine; Proionyl-l-carnitine 27 28 1. Introduction 29 Cisplatin, cis-diamminedichloroplatinum II (CDDP), is an 30 inorganic platinum compound with a broad-spectrum antineo- 31 plastic activity against various types of animal and human 32 tumours [1]. Unfortunately, the optimal usefulness of CDDP as 33 an important anticancer drug is usually limited secondary to its 34 dose related nephrotoxicity [2,3]. It is well known that CDDP- 35 induced nephrotoxicity is the most important dose-limiting fac- 36 tor in cancer chemotherapy [2,3]. 37 ∗ Corresponding author. Tel.: +966 506065734; fax: +966 1 467 7200. E-mail address: mmsayedahmed@hotmail.com (M.M. Sayed-Ahmed). Earlier studies have reported that CDDP therapy is usually 38 associated with cardiotoxicity [4,5]. Cardiac events, reported in 39 many case reports, may include electrocardiographic changes, 40 arrythmias, myocarditis, cardiomyopathy and congestive heart 41 failure [6–8]. CDDP-induced cardiotoxicity was reported to be 42 due to its disposition in the sinoatrial-node area, which may lead 43 to bradycardia [9]. Combinations of CDDP with other anticancer 44 drugs as methotrexate, 5-fluorouracil, bleomycin and doxoru- 45 bicin are associated with lethal cardiomyopathy [10–13]. 46 CDDP is a well-known renal tubular toxin, leading to 47 increased excretion of a number of vital endogenous substances 48 including l-carnitine [14,15]. Under normal physiological con- 49 ditions, l-carnitine is highly conserved since 90% of the filtered 50 l-carnitine is reabsorbed at the proximal tubular level [16]. It 51 has been reported that CDDP inhibited carnitine reabsorption 52 1 1043-6618/$ – see front matter © 2005 Published by Elsevier Ltd. 2 doi:10.1016/j.phrs.2005.12.005