الفهرس 
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Abstract
Nephrotoxicity is a kidney-specific feature in which excretion does not go smoothly, and due to the relatively large blood flow of the kidney and its ability to extract and concentrate hydrosoluble toxic molecules, the kidney is prone to drug induced damage. One of these drugs is gentamicin, an aminoglycoside antibiotic that is widely used in the treatment of various Gram-negative bacterial infections. Nephrotoxicity represents a major adverse effect of gentamicin therapy that appears clinically in 10-25% of all patients. Several mechanisms appear to contribute to the pathogenesis of GM nephrotoxicity including impairment of cell membrane integrity, inhibition of mitochondrial oxidative phosphorylation, intracellular release of hydrolase enzymes and excess production of ROS. Although its adverse effects on the kidney, gentamicin remains a first-line antibiotic for many severe infections as in addition to clinical effectiveness the rates of resistance remain low and it is inexpensive. Accordingly, the urgency to develop reno-protective strategies stimulates extensive research in this area.
Curcumin is the major active compound isolated from the ground rhizome of Curcuma longa and has been used for centuries as a spice, coloring agent and in traditional medicine. CC has therapeutic potential due to its anti-oxidant and anti-inflammatory actions. In fact, it has been reported that CC exerts both direct and indirect antioxidant effects by scavenging ROS and inducing the expression of cytoprotective and anti-oxidant proteins. Moreover, CC blocks overexpression of inflammatory mediators such as TNF-α and interleukin 1β.
N-acetyl cysteine is the acetylated form of the amino acid L-cysteine. It has been used clinically for several decades in several disorders including drug or heavy metal induced toxicity, renal and hepatic toxicity, COPD and cancer. The wide range of uses for NAC is due to its antioxidant and anti-inflammatory effects. It acts by increasing intracellular GSH synthesis, being an analogue and a precursor of intracellular GSH, and also by the direct scavenging of ROS. The anti-inflammatory action of NAC manifests by inhibition of many pro-inflammatory cytokines activity including IL-8, IL-6 and TNF-α.
Based on the suggested role of oxidative stress and inflammation in the pathogenesis of GM-induced renal injury, the present study was designed to investigate the protective and curative effects of NAC and CC, given alone and in combination, on GM-induced nephrotoxicity.
The present study was performed on 54 adult male albino rats weighing 200-250 g. Animals were divided randomly into nine groups, with 6 rats in each group. In study I, the preventive effects of CC and NAC were evaluated. In this study, the rats were treated as follows: group I: the rats received the vehicles only for 10 days, group IIA (GM group): the rats received vehicles only for 4 days followed by GM (80 mg/kg/day intraperitoneally) for 6 days , group III (CC+GM group): the rats received CC (200 mg/kg/day orally) for 4 days followed by CC+GM for the subsequent 6 days, group IV(NAC+GM group): the rats received NAC (40 mg/kg/day intraperitoneally) for 4 days followed by NAC+GM for the subsequent 6 days and group V ((CC+NAC)+GM group):the rats in this group were treated with the two drugs followed by concomitant administration of GM as in groups III and IV.
In study II, the curative effects of CC and NAC were evaluated. In this study, the rats were treated as follows: group IIB (GM group): the rats received GM (80 mg/kg/day intraperitoneally) for 6 days followed by vehicles only for 10 days, group VI (GM+CC group): the rats received GM for 6 days followed by CC(200 mg/kg/day orally) for the subsequent 10 days, group VII (GM+NAC group): the rats received GM for 6 days followed by NAC (40 mg/kg/day intraperitoneally) for the subsequent 10 days and group VIII (GM+ (CC+NAC) group):the rats in this group were treated with GM followed by concomitant administration of and the two agents (CC and NAC) as in groups VI and VII. Twenty-four hours after the last dose of drug treatment, the rats were sacrificed, blood samples were collected for determination of:
- Urea concentration.
- Creatinine concentration.
Immediately after blood collection the kidneys of the rats were quickly excised, washed with ice cold saline, blotted dry on filter paper and weighed, the left kidney was preserved at -80 °C for determination of kidney tissue:
- Lactate.
- Tumor necrosis factor-alpha (TNF- α) level.
- Reduced glutatione.
- Superoxide dismutase (SOD) activity.
- Malondialdehyde (MDA) level.
The right kidney was fixed in 10% neutral-buffered formalin, dehydrated, embedded in paraffin and 4μm section were cut, stained with hematoxylin and eosin, and subjected to histopathological examination by light microscopy.
The results of the present study clearly demonstrated that renal oxidative stress and inflammation play a key role in the pathogenesis of nephrotoxicity induced by GM. This toxic effect was evaluated histopathologically by light microscopy and biochemically by measuring the concentrations of serum creatinine and urea and the levels of GSH, MDA, lactate, TNF-α and SOD activity in renal tissue.
The findings of this study showed that CC and NAC possess preventive and curative properties against gentamicin-induced nephrotoxicity in rats. The present study demonstrated that treatment of rats with CC, NAC or CC+NAC before and simultaneously with GM administration prevented the development of GM-induced nephrotoxicity. Our results also showed that GM-administered rats, when left untreated for 10 days after the 6-day period of GM-administration, showed partial recovery of some of the manifestations of the induced nephrotoxicity. However, post-treatment of GM-administered rats with CC, NAC or CC+NAC for 10 days after stopping GM administration markedly ameliorated the residual effects of the induced nephrotoxicity as compared to the control GM-administered rats treated with the vehicle.
In conclusion, CC and NAC had protective and curative effects against GM-induced nephrotoxicity in rats as evidenced by markedly ameliorating GM-induced renal oxidative stress and inflammation with a noticeable improvement of renal structural and functional abnormalities. With the combined treatment, CC and NAC seemed to act co-operatively to potentiate the activity of each other through scavenging and neutralizing oxidative free
radicals and modulating tubular cells inflammatory response with a resultant marked amelioration of GM-induced renal injury. Similarly, post-treatment of GM-administered rats with CC plus NAC showed almost normal serum and renal tissue biochemical parameters with a greater curative effect on kidney histoarchitecture as compared to post-treatment with either agents alone in GM-administered rats. In the former group, the GM-damaged renal tissue was almost totally improved by the combination of CC and NAC since no evidence of tubular necrosis was detected in kidney sections of CC+NAC post-treated GM-administered rats. Our study also demonstrated for the first time that pre- and post-treatment with CC+NAC resulted in comparatively a greater improvement of the renal histopathological abnormalities associated with GM administration than did by treatment with either agent alone.