Curcumin alleviates colistin-induced nephrotoxicity and neurotoxicity in rats via attenuation of oxidative stress, inflammation and apoptosis
Introduction
Colistin, also known as polymyxin E, is a glycopeptide antibiotic produced by Bacillus polymixa var colistinus [1]. It was discovered by Koyama in 1947, and since 1959, it has been utilized in the treatment of infections caused by multidrug-resistant (MDR) gram-negative bacteria [2,3]. Colistin induces bactericidal effects via the interaction of its cationic polypeptides with the anionic lipopolysaccharide (LPS) molecule of the gram-negative bacterial membrane, leading to displacement of Ca2+ and Mg+ of LPS; these changes in turn disturb membrane stability and increase membrane permeability, causing leakage of cell contents and ultimately cell death. It also binds to the endotoxin of gram-negative bacteria, the lipid A portion of the LPS molecule, and neutralizes it [1,2,4,5].
Colistin was efficacious and had good results in the treatment of infections caused by Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumonia, Acinetobacter baumannii, Salmonella sp., Enterobacter sp., Haemophilus influenza, and Shigella sp. The resistance of these bacteria against the drug was extremely low. In 1970, it was reported that colistin had nephrotoxic and neurotoxic side effects; thus, its use was temporarily stopped [6,7]. Renal toxicity is the most common side effect associated with colistin administration, because colistin is excreted primarily via the kidneys, and elevated blood levels may deteriorate renal function (Lewis and Lewis, 2004). Furthermore, neurological symptoms, such as confusion, dizziness, vertigo, seizures, and facial/peripheral paresthesia, and less common fatal effects, including respiratory muscle weakness, apnea, and ataxia, were recorded in colistin-treated patients [8,9]. Clearly, identification of nephroprotective and neuroprotective agents that can be co-administered with colistin has the potential to allow the clinical application of this essential drug.
A potential nephroprotective and neuroprotective candidate is curcumin, a compound found within the bright yellow spice turmeric, obtained from the rhizome of Curcuma longa Linn [10]. It has an outstanding safety profile and a number of pleiotropic actions, including anti-inflammatory [[11], [12], [13]], antioxidant and radical scavenging [14], cytotoxic and anti-apoptotic activities [[15], [16], [17]]. Additionally, it has hepatoprotective [[18], [19], [20]] and nephroprotective effects [[21], [22], [23]]. Notably, curcumin can cross the blood-brain barrier, suggesting a possible usage as a neuroprotective substance [[24], [25], [26], [27]].
The spread of infections caused by MDR gram-negative bacteria and the lack of new antibiotics to fight them have led to a revival in colistin use [1]. Therefore, there is an urgent need to alleviate colistin-induced nephrotoxicity and neurotoxicity, as this would increase the therapeutic index of colistin, and thereby permit the administration of higher doses. Natural ingredients have been used to ameliorate the side effects of colistin [[28], [29], [30]]. Thus, the main aim of this work was to assess the mechanism by which colistin induces nephrotoxic and neurotoxic effects, and to determine whether curcumin can protect against colistin side effects via its antioxidant, anti-inflammatory and anti-apoptotic properties.
Section snippets
Materials and methods
Colistin (Colomycin®) vials were produced by Forest Laboratories UK, Ltd. Each vial contains 1 million IU colistimethate sodium powder for injection. Crystalline 99% extra pure curcumin was purchased from Loba Chemie Pvt Ltd-India. Colistin and curcumin were dissolved in sterile normal saline solution.
Effects of curcumin on several biochemical parameters of colistin-treated rats
Table 1 shows that rats treated only with colistin had significantly higher levels of serum creatinine (0.86 mg/dl), uric acid (4.32 mg/dl) and urea (27.97 mg/dl) as well as brain GABA (0.204 ng/ml) in comparison to control rats (0.58 mg/dl, 3.45 mg/dl, 18.83 mg/dl and 0.105 ng/ml, respectively). However, rats that were co-administered with both curcumin and colistin were intermediate in terms of all markers between colistin-only and control rats, for both renal function (creatinine 0.72 mg/dl,
Discussion
The emergence of MDR gram-negative bacteria has renewed interest in colistin use, which had fallen out of favor because of reports of nephrotoxicity and neurotoxicity [43]. Amelioration of these side effects would increase the therapeutic appeal of colistin and permit administration of higher doses of colistin. Oxidative stress plays a pivotal role in many diseases and in a variety of drug-induced hepatic, cardiac, renal and neurotoxicities [[44], [45], [46], [47]]. Increased production of ROS
Conclusion
To our knowledge, this is the first in vivo study that assessed the protective effects of curcumin on colistin-induced nephrotoxicity and neurotoxicity. We revealed the involvement of oxidative stress, inflammation and apoptosis in colistin-induced toxicities. Our findings are consistent with a beneficial effect of curcumin administration in ameliorating these adverse effects via its antioxidant, anti-inflammatory and anti-apoptotic activities. Therefore, curcumin could represent a promising
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