Progression of cisplatin-induced nephrotoxicity in a carnitine-depleted rat model.
BACKGROUND
This study has been initiated to investigate whether endogenous carnitine depletion and/or carnitine deficiency is an additional risk factor and/or a mechanism in cisplatin-induced nephrotoxicity and to gain insights into the possibility of a mechanism-based protection by L-carnitine against this toxicity.


METHODS
60 male Sprague-Dawley rats were divided into six groups of 10 animals each and received one of the following treatments: The first three groups were injected intraperitoneally with normal saline, L-carnitine (500 mg/kg), and D-carnitine (750 mg/kg), respectively, for 10 successive days. The 4th, 5th, and 6th groups were injected intraperitoneally with the same doses of normal saline, L-carnitine and D-carnitine, respectively, for 5 successive days before and after a single dose of cisplatin (7 mg/kg). Six days after cisplatin treatment, the animals were sacrificed, and serum as well as kidneys were isolated and analyzed.


RESULTS
A single dose of cisplatin resulted in a significant increase in blood urea nitrogen (BUN), serum creatinine, malondialdehyde (MDA) and nitric oxide (NO) and a significant decrease in total carnitine, reduced glutathione (GSH) and adenosine triphosphate (ATP) content in kidney tissues. Interestingly, L-carnitine supplementation attenuated cisplatin-induced nephrotoxicity manifested by normalizing the increase of serum creatinine, BUN, MDA and NO and the decrease in total carnitine, GSH and ATP content in kidney tissues. In the carnitine-depleted rat model, cisplatin induced a progressive increase in serum creatinine and BUN as well as a progressive reduction in total carnitine and ATP content in kidney tissue. Histopathological examination of kidney tissues confirmed the biochemical data, i.e. L-carnitine supplementation protected against cisplatin-induced kidney damage, whereas D-carnitine aggravated cisplatin-induced renal injury.


CONCLUSIONS
Data from this study suggest that: (1) oxidative stress plays an important role in cisplatin-induced kidney damage; (2) carnitine deficiency should be viewed as an additional risk factor and/or a mechanism in cisplatin-induced renal dysfunction, and (3) L-carnitine supplementation attenuates cisplatin-induced renal dysfunction.
Sayed-Ahmed
Mohamed M
MM
Pharmacology Unit, Cancer Biology Department, National Cancer Institute, Fum El-Khalig, Kasr El-Aini Street, Cairo, Egypt. mmsayedahmed@hotmail.com
Eissa
Maha A
MA
Kenawy
Sanaa A
SA
Mostafa
Nadia
N
Calvani
Menotti
M
Osman
Abdel-Moneim M
AM
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D002331:Carnitine / Q000172:deficiency* / Q000378:metabolism; D002945:Cisplatin / Q000633:toxicity*; D004195:Disease Models, Animal; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced*; D008297:Male; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D012307:Risk Factors
D000970:Antineoplastic Agents; D002945:Cisplatin; D002331:Carnitine