Evaluation of efficacy of natural astaxanthin and vitamin E in prevention of colistin-induced nephrotoxicity in the rat model

doi:10.1016/j.etap.2014.03.004

Environmental Toxicology and Pharmacology

Volume 37, Issue 3, May 2014, Pages 960-966

https://doi.org/10.1016/j.etap.2014.03.004 Get rights and content

Highlights

•
Colistin is an efficient antibiotic. However, nephrotoxicity is the major adverse effect that impedes its administration in high doses.
•
Recently, oxidative stress is considered to play a key role in colistin-induced nephrotoxicity.
•
Moreover, An attention was focused on the role of some antioxidants in offering therapeutic opportunities.
•
The co-treatment with vit E or ASX plus CMS restored biochemical (GGT, MDA, SOD, CAT, GPx) and histopathological damage.
•
This nephrotoxicity might be due to oxidant stress. Reno-protection could be due to antioxidant effects of ASX and vit E.

Abstract

Objective

We evaluated the effect of astaxanthin (ASX) and vitamin E (vit E) on colistin methanesulfonate (CMS) induced-nephrotoxicity in rats.

Methods

Animals were treated with sterile saline, 300 000 or 450 000 IU/kg/day of CMS, CMS + ASX (20 mg/kg), CMS + vit E (100 mg/kg), or CMS + 1 ml/kg olive oil (OO) for 7 days. The plasma/urine creatinine (Cr) level, urine γ-glutamyl-transferase (GGT) level, and renal tissue activities in malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and reductase (GSH), as well as renal histology were performed.

Results

CMS induced a tubular damage, increased the GGT and MDA levels, and decreased the activities of SOD, CAT, GPx and GSH. Co-treatment with ASX or vit E restored all biochemical parameters cited above and improved the histopathological damage.

Conclusion

Nephrotoxicity induced by CMS might be due to oxidative damage. The improvement by ASX or vit E seems to be related to their antioxidant properties.

Introduction

Colistin methanesulfonate (CMS), a clinical form of colistin, is one of the few remaining therapeutic options available for the treatment of life-threatening infections caused by multidrug-resistant gram-negative bacteria, in particular Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae (Falagas and Kasiakou, 2005, Li et al., 2006). Notwithstanding its efficiency, nephrotoxicity is the major adverse effect that impedes the ability to administer high doses of CMS. Renal toxicity due to CMS is reported to be dose dependent and mainly present as acute tubular necrosis (Falagas and Kasiakou, 2006). Recent studies in rats suggest that oxidative stress can play a key role in CMS-induced nephrotoxicity and an attention has been focused on the role of some antioxidants in offering therapeutic opportunities (Ozyilmaz et al., 2010, Yousef et al., 2011, Yousef et al., 2012).

Vitamin E (vit E) is an essential nutrient that functions as a non-enzymatic antioxidant. It is an important biological free radical scavenger which can readily cross cell membranes and exerts its effect both on cells and membranes (Halliwell and Gutteridge, 1999). Various experimental studies in rats and mice have shown promising effect of vit E against gentamicin (Abdel-Naim et al., 1999), vancomicyn (Naghibi et al., 2006) and cisplatin (Ajith et al., 2007) induced nephrotoxicity and kidney oxidative damage.

Astaxanthin (ASX) is a red-orange carotenoid naturally found in a wide variety of aquatic organisms, such as microalgae, fishes and crustaceans such as shrimps. This pigment is known for its potent role in human health (Kidd, 2011). ASX has some pharmacological proprieties, including antioxidant and anti-inflammatory (Guerra et al., 2012, Pashkow et al., 2008). It can effectively scavenge lipid radicals and destroy peroxides, thereby protecting fatty acids and biological membranes from oxidative damage (Kurashige et al., 1990). In the context of kidney pathology, ASX has revealed a beneficial protection against diabetes nephropathy in mice (Naito et al., 2004) and HgCl₂ induced nephrotoxicity in rats (Augusti et al., 2008).

Given their numerous health benefits and potential antioxidant properties, the present study was performed to evaluate, and for the first time, the nephroprotective effect of natural ASX and vit E on CMS-induced nephrotoxicity in rats.

Section snippets

Chemical products

•
Colistin was administered as colistin methanesulfonate (CMS) obtained from Aventis-France (1 million IU/vial). CMS is an inactive pro-drug that is converted in vivo into colistin, the antibacterial and toxic entity (Bergen et al., 2006).
•
Vitamin E (α-tocopherol acetate) was purchased from Sigma (St. Louis, MO, USA).
•
Natural astaxanthin (Fig. 1) was obtained according to Sila et al. (2012).

Animals

Male Wistar rats weighing 250 ± 20 g were purchased from the breeding centre of the Central Pharmacy (SIPHAT). All

Evaluation of the plasma Cr and urine GGT levels

Plasma Cr showed no change between all experimental groups. GGT level increased (p < 0.01) only in the 450 000 IU/kg/day group, compared to the control. The co-treatment with ASX or vit E plus CMS attenuated its level (p < 0.01), compared to the CMS group (Table 1).

Lipid peroxidation product in the renal tissues

The CMS at 300 000 or 450 000 UI/kg/day increased the MDA levels in renal tissues (p < 0.05 and p < 0.01, respectively), compared to the control. The co-treatment with ASX or vit E plus CMS attenuated the lipid peroxidation in renal tissue,

Discussion

Nephrotoxicity is the major adverse effect limiting the dose and duration of treatment with CMS (Michalopoulos and Falagas, 2008). Current studies on rats report that renal toxicity due to CMS could be related to oxidative injury and might be prevented by the use of some antioxidants (Ozyilmaz et al., 2010, Yousef et al., 2012).

In this study, the treatment with CMS at 300 000 IU/kg/day led to a slight focal tubular dilatation. The severity of renal damage seems to be more prominent in kidneys of

Conflict of interest

The authors declare that there are no conflicts of interest.

Transparency document

Acknowledgement

The authors are grateful to Professor Bou Yahia Moufida for assistance in writing this article.

References (40)

A.B. Abdel-Naim et al.
Protective effects of vitamin E and probucol against gentamicin-induced nephrotoxicity in rats
Pharm. Res.
(1999)
H. Aebi
Catalase in vitro
Methods Enzymol.
(1984)
T.A. Ajith et al.
Ascorbic acid and alpha-tocopherol protect anticancer drug cisplatin induced nephrotoxicity in mice: a comparative study
Clin. Chim. Acta
(2007)
T.A. Ajith et al.
Co-supplementation of single and multi doses of vitamins C and E ameliorates cisplatin-induced acute renal failure in mice
Exp. Toxicol. Pathol.
(2009)
P.R. Augusti et al.
Effect of astaxanthin on kidney function impairment and oxidative stress induced by mercuric chloride in rats
Food Chem. Toxicol.
(2008)
C. Beauchamp et al.
Superoxide dismutase: improved assays and an assay applicable to acrylamide gel
Anal. Biochem.
(1971)
M. Bradford
A rapid and sensitive method for the quantification of microgram quantities of protein utilizing the principle of protein dyes binding
Anal. Biochem.
(1976)
R.T. Dean et al.
Free radical damage to proteins: the influence of the relative localization of radical generation, antioxidants and the target proteins
Free Radic. Biol. Med.
(1991)
H.H. Draper et al.
Malondialdehyde determination as index of lipid peroxidation
Methods Enzymol.
(1990)
G.L. Ellman
Tissue sulfhydryl groups
Anal. Biochem.
(1959)

B.A. Guerra et al.

Carbonyl stress and a combination of astaxanthin/vitamin C induce biochemical changes in human neutrophils

Toxicol. in Vitro

(2012)

J. Li et al.

Colistin: the re-emerging antibiotic for multidrug-resistant gram-negative bacterial infections

Lancet Infect. Dis.

(2006)

J.M. Lopez-Novoa et al.

New insights into the mechanism of aminoglycoside nephrotoxicity: an integrative point of view

Kidney Int.

(2011)

P. Mardones et al.

α-Tocopherol metabolism is abnormal in scavenger receptor class B type I (SR-BI)-deficient mice

J. Nutr.

(2002)

H.P. McNulty et al.

Differential effects of carotenoids on lipid peroxidation due to membrane interactions

X-ray Diffr. Anal.

(2007)

A.S. Michalopoulos et al.

Colistin and polymyxin B in critical care

Crit. Care Clin.

(2008)

A. Sila et al.

Isolation and characterisation of carotenoproteins from deep-water pink shrimp processing waste

Int. J. Biol. Macromol.

(2012)

P.J. Bergen et al.

Colistin methanesulfonate is an inactive prodrug of colistin against Pseudomonas aeruginosa

Antimicrob. Agents Chemother.

(2006)

H.D. Choi et al.

Effects of astaxanthin on oxidative stress in overweight and obese adults

Phytother. Res.

(2011)

S. Cuzzocrea et al.

A role for superoxide in gentamicin-mediated nephropathy in rats

Eur. J. Pharmacol.

(2002)

Cited by (50)

Prostaglandin F2α analogue, bimatoprost ameliorates colistin-induced nephrotoxicity
2023, Biomedicine and Pharmacotherapy
Colistin (polymyxin E) is an antibiotic that is effective against multidrug-resistant gram-negative bacteria. However, the high incidence of nephrotoxicity caused by colistin limits its clinical use. To identify compounds that might ameliorate colistin-induced nephrotoxicity, we obtained 1707 compounds from the Korea Chemical Bank and used a high-content screening (HCS) imaging-based assay. In this way, we found that bimatoprost (one of prostaglandin F2α analogue) ameliorated colistin-induced nephrotoxicity. To further assess the effects of bimatoprost on colistin-induced nephrotoxicity, we used in vitro and in vivo models. In cultured human proximal tubular cells (HK-2), colistin induced dose-dependent cytotoxicity. The number of terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL)-positive cells, indicative of apoptosis, was higher in colistin-treated cells, but this effect of colistin was ameliorated by cotreatment with bimatoprost. The generation of reactive oxygen species, assessed using 2,7-dichlorodihydrofluorescein diacetate, was less marked in cells treated with both colistin and bimatoprost than in those treated with colistin alone. Female C57BL/6 mice (n = 10 per group) that were intraperitoneally injected with colistin (10 mg/kg/12 hr) for 14 days showed high blood urea nitrogen and serum creatinine concentrations that were reduced by the coadministration of bimatoprost (0.5 mg/kg/12 hr). In addition, kidney injury molecule-1 (KIM1) and Neutrophil gelatinase-associated lipocalin (NGAL) expression also reduced by bimatoprost administration. Further investigation in tubuloid and kidney organoids also showed that bimatoprost attenuated the nephrotoxicity by colistin, showing dose-dependent reducing effect of KIM1 expression. In this study, we have identified bimatoprost, prostaglandin F2α analogue as a drug that ameliorates colistin-induced nephrotoxicity.
Dexmedetomidine may reduce the risk of acute kidney injury development in critically ill patients during colistin therapy
2023, Journal of Infection and Chemotherapy
Colistin is considered as a last resort therapy for multidrug-resistant gram-negative organisms. It is widely used despite the significant risk of nephrotoxicity. Experimental studies showed the nephroprotective effect of dexmedetomidine, a sedative agent, against colistin toxicity. This study was performed to show the possible nephroprotective effect of dexmedetomidine among critically ill patients who received colistin.
Adult (>17 years) patients who were admitted to our surgical and medical intensive care unit (ICU) from March 2018 through March 2021, and who received colistin were included. Patients who receive Colistin therapy or intensive care unit follow-up of <72 h (discharge or death) and Acute kidney injury (AKI) or need hemodialysis prior to colistin therapy at the same hospitalization were excluded. AKI risk factors were examined by grouping patients with and without AKI. Patients, receiving colistin concomitantly with dexmedetomidine were also evaluated.
Of the 139 patients included, 27 (17.8%) patients received dexmedetomidine. Sixty-five patients (47%) had AKI, at a median 5 (4-7) days after the initiation of colistin. Older age, lower baseline estimated glomerular filtration rate, and vasopressor use were associated with a higher risk of AKI, while dexmedetomidine use was associated with a lower risk. In the multivariate regression model, dexmedetomidine use was independently associated with a lower risk of AKI development (OR 0.20 95% CI 0.07–0.59, p = 0.003).
In respect to these findings, dexmedetomidine may provide protection against AKI during colistin therapy in critically ill patients.
A new autophagy-driven protective pathway of Haematococcus astaxanthin against chemical damage in wistar rats with gentamicin-induced acute kidney injury
2023, Algal Research
Astaxanthin was established to conserve kidney function and subcellular structure through anti-oxidation and/or the free radical scavenging system, yet little research linked a new protective effect to autophagy or lysosomes. We pre-fed Wistar rats with natural astaxanthin, β-carotene, or placebo and induced acute kidney injury using gentamicin, before examining renal tissues and measuring physiological indices. Qualitative evidence from histopathological and subcellular images, along with quantitative evidence showing treatment effects on blood urea nitrogen and serum creatinine (p < 0.01), indicated that esterified Haematococcus astaxanthin surpassed β-carotene at effectively counteracting chemical damage and protecting the kidneys from injury. Proliferation of enlarged lysosomes and mediation analysis results revealing enhanced lysosomal acid phosphatase activity were consistent with the hypothesized autophagy-lysosomal pathway being up-regulated by astaxanthin intake (p < 0.05). In conclusion, the protective effect of astaxanthin against acute kidney injury exerted through the autophagy-lysosomal detoxification pathway, which totally different from the anti-oxidation and/or conventional SOD-dependent free radical scavenging system, was demonstrated with strong evidence. In light of the pandemic outbreak of novel coronavirus pneumonia associated with a virus preferentially targeting the renal tubular cells, dietary astaxanthin may help bring down incidence rate of coronavirus disease, cases of acute kidney injury secondary to the disease, and mortality rate from acute kidney injury, especially when a standard of care treatment for the infectious disease is pending.
Genome-wide gene expression analysis reveals molecular insights into the drug-induced toxicity of nephrotoxic agents
2022, Life Sciences
Drug-induced nephrotoxicity is frequently reported. However, the mechanisms underlying nephrotoxic medications and their overlapping molecular events, which might have therapeutic value, are unclear. We performed a genome-wide analysis of gene expression and a gene set enrichment analysis to identify common and unique pathways associated with the toxicity of colistin, ifosfamide, indomethacin, and puromycin. Rats were randomly allocated into the treatment or control group. The treatment group received a toxic dose once daily of each investigated drug for 1 week. Differentially expressed genes were found in the drug-treated kidney and liver compared to the control, except for colistin in the liver. Upregulated pathways were mainly related to cell death, cell cycle, protein synthesis, and immune response modulation in the kidney. Cell cycle was upregulated by all drugs. Downregulated pathways were associated with carbon metabolism, amino acid metabolism, and fatty acid metabolism. Indomethacin, colistin, and puromycin shared the most altered pathways in the kidney. Ifosfamide and indomethacin affected molecular processes greatly in the liver. Our findings provide insight into the mechanisms underlying the renal and hepatic adverse effects of the four drugs. Further investigation should explore the combinatory drug therapies that attenuate the toxic effects and maximize the effectiveness of nephrotoxic drugs.
Nephroprotective potential of Panduratin A against colistin-induced renal injury via attenuating mitochondrial dysfunction and cell apoptosis
2022, Biomedicine and Pharmacotherapy
Colistin is a last-resort polypeptide antibiotic widely used to treat against multidrug-resistant Gram-negative bacterial infections. However, this treatment is associated with nephrotoxicity. The aim of this study was to examine the potential protective effect of panduratin A, a bioactive compound of Boesenbergia rotunda, on colistin-induced nephrotoxicity in both in vivo and in vitro models. Intraperitoneal injection of 15 mg/kg colistin for 7 days markedly promoted renal tubular degeneration, increased blood urea nitrogen (BUN) levels, and upregulated the expression of renal injury biomarker and apoptosis proteins. In addition, treatment with colistin increased oxidative stress and apoptosis in mice kidney tissues. Interestingly, these defects were attenuated when co-administered of colistin with panduratin A (2.5 or 25 mg/kg). The underlying mechanisms of panduratin A attenuating colistin toxicity was investigated in human renal proximal tubular cells (RPTEC/TERT1). The mechanisms by which colistin-triggered cytotoxicity was determined by analysis of cell death, reactive oxygen species (ROS) levels, mitochondria function as well as the expression of proteins related to apoptosis pathway. Colistin treatment (200 µg/ml) significantly increased cell apoptosis, elevated ROS production, reduced mitochondrial membrane potential, and decreased anti-apoptotic protein (Bcl-2) expression. These effects were notably suppressed by co-treatment with panduratin A (5 μM). Collectively, panduratin A exerts as a novel nephroprotective agent to protect against colistin-induced renal injury by attenuating mitochondrial damage and renal cell apoptosis.
Delineation of the molecular mechanisms underlying Colistin-mediated toxicity using metabolomic and transcriptomic analyses
2022, Toxicology and Applied Pharmacology
The mechanisms underlying colistin-induced toxicity are not fully understood. This study used untargeted metabolomics and transcriptomics to elucidate the molecular processes occurring in the liver and kidney of rats after treatment with colistin methanesulfonate (CMS). Rats were treated with 50 mg/kg CMS (high-dose), 25 mg/kg CMS (low-dose), or vehicle control, either as a single dose or once daily for 1 or 4 weeks. We found that metabolic alterations were dose- and treatment duration-dependent in the kidney, whereas mild changes were noted in the liver. Metabolic profiles in the high-dose, low-dose, and control groups of both tissues could be classified using partial least-squares discriminant analysis. Metabolic alterations were associated with the citric acid cycle and related processes, disrupted balance between pro-oxidants and antioxidants, inflammatory responses, and amino acid and nucleic acid metabolism. Gene expression profiles further showed that high-dose treatment was associated with disrupted metabolism, oxidative stress, and proinflammatory signals in the kidney. The expression levels of genes related to the cell cycle, DNA replication, and programmed cell death were also predominantly upregulated. These findings suggested that high-dose treatment was associated with a dramatic increase in cellular kidney injury, while only minor effects were observed in the low-dose group. Almost no significant gene expression was changed in the liver, even with high-dose CMS. In conclusion, untargeted metabolomics and transcriptomics provided better insights into the biological mechanisms underlying colistin-induced nephrotoxicity.

View all citing articles on Scopus

View full text

Evaluation of efficacy of natural astaxanthin and vitamin E in prevention of colistin-induced nephrotoxicity in the rat model

Highlights

Abstract

Objective

Methods

Results

Conclusion

Introduction

Section snippets

Chemical products

Animals

Evaluation of the plasma Cr and urine GGT levels

Lipid peroxidation product in the renal tissues

Discussion

Conflict of interest

Transparency document

Acknowledgement

Pharm. Res.

Methods Enzymol.

Clin. Chim. Acta

Exp. Toxicol. Pathol.

Food Chem. Toxicol.

Anal. Biochem.

Anal. Biochem.

Free Radic. Biol. Med.

Methods Enzymol.

Anal. Biochem.

Toxicol. in Vitro

Lancet Infect. Dis.

Kidney Int.

J. Nutr.

X-ray Diffr. Anal.

Crit. Care Clin.

Int. J. Biol. Macromol.

Colistin methanesulfonate is an inactive prodrug of colistin against Pseudomonas aeruginosa

Antimicrob. Agents Chemother.

Effects of astaxanthin on oxidative stress in overweight and obese adults

Phytother. Res.

A role for superoxide in gentamicin-mediated nephropathy in rats

Eur. J. Pharmacol.