Protective effects of alpha lipoic acid versusN-acetylcysteine on ifosfamide-induced nephrotoxicity

Abstract

Ifosfamide (IFO) is a highly effective chemotherapeutic agent for treating a variety of pediatric solid tumors. However, its use is limited due to its serious side effect on kidneys. The side-chain oxidation of IFO in renal tubular cells produces a reactive toxic metabolite that is believed to be responsible for its nephrotoxic effect. Therefore, this study was carried out to investigate the possible underlying mechanisms that may be involved in IFO-induced nephrotoxicity, including free radical generation and the possible role of alpha lipoic acid (ALA) versus N-acetylcysteine (NAC) in protection against this toxicity. Male albino rats were injected intraperitoneally with saline, IFO (50 mg/kg daily for 5 days), IFO + ALA (100 mg/kg daily for 8 days) and IFO + NAC (200 mg/kg daily for 8 days). Kidney malondialdehyde, nitric oxide and glutathione contents and serum biochemical parameters and histopathological analysis were determined. Both ALA and NAC markedly reduced the severity of renal dysfunction induced by IFO. NAC was more nephroprotective than ALA. This study suggests that oxidative stress is possibly involved in the IFO-induced nephrotoxicity in rats. The study also suggests the potential therapeutic role for ALA and NAC against IFO-induced nephrotoxicity.

N-acetylcysteine suppresses colistimethate sodium-induced nephrotoxicity via activation of SOD2, eNOS, and MMP3 protein expressions

“…It is known that the dose of colistin given to rats intraperitoneally, which is 150 000 IU/kg/day, is the maximum therapeutic dose used for humans [ 8 ]. In previous studies that examine whether nephrotoxic effects of drugs such as vancomycin and gentamicin are prevented by NAC, it was seen that NAC was used at a dose of 10–200 mg/kg/day intraperitoneally and these doses could prevent histological renal damage [ 30–34 , 41 ]. In two studies performed previously, high doses of NAC such as 500 mg/kg/day were used [ 42 , 43 ].…”

The effects ofN-acetyl-l-cysteine on the female reproductive performance and nephrotoxicity in rats

“…N-Acetylcysteine (NAC) is the possible role of in protection against IF toxicity in male rats. 24 N-acetylcysteine is an ideal candidate for replenishing tissue GSH levels through two major protective mechanisms: it acts as precursor for GSH synthesis (sulfhydryl source for GSH synthesis) 66 and nucleophile that scavenges reactive oxygen species such as O2 , H2O2 and OH 67 and conjugates with reactive metabolites rendering them less toxic. 68 The underlying mechanisms governing the tissue-specific effects of NAC on SOD protein expression might be due to tissue-specific effectiveness of NAC in reducing the production of superoxide.…”

Drug Conjugation Affects Pharmacokinetics and Specificity of Kidney-Targeted Peptide Carriers

“…Lipoic acid has strong antioxidative properties, and its reduced form, dihydrolipoic acid, enables scavenging of free radicals. In various studies, lipoic acid was used to prevent nephrotoxicity of different compounds toxic to tubular cells, such as cisplatin, ifosfamide, or gentamicin. − Consequently, lipoic acid is a nontoxic model compound used as a radical scavenger to protect cells stressed by chemotherapy-induced low glutathione levels. , In spite of its low molecular mass, its highly lipophilic character (log P of 2.25, calculated using software from ) causes a heavy load for the polar targeting peptides. To avoid premature cleavage of conjugated drug, a stable amide bond was used as linkage between the N-terminus of the peptides and lipoic acid.…”