REVERSAL OF CISPLATIN‐INDUCED CARNITINE DEFICIENCY AND ENERGY STARVATION BY PROPIONYL‐l‐CARNITINE IN RAT KIDNEY TISSUES

Abstract

1. The present study examined whether propionyl-L-carnitine (PLC) could prevent the development of cisplatin (CDDP)-induced acute renal failure in rats. 2. Forty adult male Wistar albino rats were divided into four groups. Rats in the first group were injected daily with normal saline (2.5 mL/kg, i.p.) for 10 consecutive days, whereas the second group received PLC (250 mg/kg, i.p.) for 10 consecutive days. Animals in the third group were injected daily with normal saline for 5 consecutive days before and after a single dose of CDDP (7 mg/kg, i.p.). Rats in the fourth group received a combination of PLC (250 mg/kg, i.p.) for 5 consecutive days before and after a single dose of CDDP (7 mg/kg, i.p.). On Day 6 following CDDP treatment, animals were killed and serum and kidneys were isolated for analysis. 3. Injection of CDDP resulted in a significant increase in serum creatinine, blood urea nitrogen (BUN), thiobarbituric acid-reactive substances (TBARS) and total nitrate/nitrite (NO(x)), as well as a significant decrease in reduced glutathione (GSH), total carnitine, ATP and ATP/ADP in kidney tissues. 4. Administration of PLC significantly attenuated the nephrotoxic effects of CDDP, manifested as normalization of the CDDP-induced increase in serum creatinine, BUN, TBARS and NO(x) and the CDDP-induced decrease in total carnitine, GSH, ATP and ATP/ADP in kidney tissues. 5. Histopathological examination of kidney tissues from CDDP-treated rats showed severe nephrotoxicity, in which 50-75% of glomeruli and renal tubules exhibited massive degenerative changes. Interestingly, administration of PLC to CDDP-treated rats resulted in a significant improvement in glomeruli and renal tubules, in which less than 25% of glomeruli and renal tubules exhibited focal necrosis. 6. Data from the present study suggest that PLC prevents the development of CDDP-induced acute renal injury by a mechanism related, at least in part, to the ability of PLC to increase intracellular carnitine content, with a consequent improvement in mitochondrial oxidative phosphorylation and energy production, as well as its ability to decrease oxidative stress. This will open new perspectives for the use of PLC in the treatment of renal diseases associated with or secondary to carnitine deficiency.

Protective effect of L-carnitine against cisplatin-induced liver and kidney oxidant injury in rats

“…Treatment with L-carnitine before the CDDP challenge could significantly prevent the depletion of the kidney and liver antioxidant systems. Similar results have been reported by Aleisa et al [14], Al-Majed et al [15], and Arafa HM [41] for kidney and liver tissues in which cisplatin and carboplatin injections caused low GSH, GSH-Px, SOD, and nitric oxide levels. Furthermore, in this study, it was observed that levels of GSH-Px and SOD for CDDP in the L-carnitine-treated groups were higher than in the CDDP group.…”

“…It is synthesized endogenously from the essential amino acids lysine and methionine. In fact, carnitine effectively inhibits mitochondrial damage induced by oxidative stress, as well as mitochondriadependent apoptosis in various types of cells [13,14]. The effects of LC on the metabolism of tissues in organs such as the heart [15], brain [16], and liver [13] have been studied widely.…”

Dose-Dependent Protective Effect of L-Carnitine on Oxidative Stress in the Livers of Hyperthyroid Rats

“…Aleisa et al [13] reported that the administration of propionyl L-carnitine at a dose of 250 mg/kg (i.p.) significantly attenuated the nephrotoxic effects of cisplatin, which manifested as a normalization of the cisplatin-induced increase in thiobarbituric acid reactive substances, such as MDA and nitric oxide, and the cisplatin-induced decrease in reduced glutathione in rat kidney tissues.…”

“…Endogenous L-carnitine is synthesized from lysine and methi- onine primarily in the liver, as well as in the kidneys and brain tissue [24]. Previous studies have indicated that L-carnitine has an important role in oxidative/antioxidative balance as well as in the transport function of long-chain fatty acids into the mitochondria in biological systems [12][13][14][15]. However, the effects of L-carnitine on specific antioxidant enzymes, such as GPX, CAT and MPO, which detoxify H 2 O 2 in water, have been reported independently in a few studies [14,25].…”

“…L-carnitine inhibits both the mitochondrial damage induced by oxidative stress and mitochondria-dependent apoptosis in various types of cells [12,13]. Recent studies suggest that L-carnitine may play an important role in oxidative/antioxidative balance and has an antiperoxidative effect on several tissues [14][15][16].…”