Effect of Spirulina on Cyclosporine (CsA)-Induced Changes in Lipid Peroxidation (MDA) and Activities of Antioxidant Enzymes

Parameter Control Spirulina

Kidney tissue MDA (nm/mg protein) 2.56 ± 0.18 2.48 ± 0.18

Glutathione peroxidase U/mg protein 0.53 ± 0.09 0.51 ± 0.04

CsA + Spirulina

1.87 ± 0.19** 2.87 ± 0.51** 2.32 ± 0.20** 0.29 ± 0.05** 0.55 ± 0.03**

Values are expressed as mean ± SD (n = 7). *p < .05 vs. control; **p < .05 vs. CsA.

oxalate crystal deposition in the kidney. C-phycocyanin has also been shown to protect against the oxalate-mediated renal injury in rats.129 Experimental observations reveal that C-phycocyanin administration causes a significant restoration in the thiol content of the renal tissue and red blood cells (RBCs) through the elevation of the GSH levels, a marked decrease in the extent of lipid peroxidation (MDA) in the plasma, and a significant enhancement of the activities of antioxidant enzymes (catalase and glucose-6-phosphate dehydrogenase) in the RBCs of oxalate-treated animals, suggesting that C-phycocyanin not only ameliorates oxidative stress but also acts as a free radical scavenger.129

Collectively, various studies have confirmed that Spirulina offers protection against the drug- and chemical-induced renal toxicity. Gentamycin, an aminoglycoside antibiotic used in the treatment of Gram-negative infections, has been shown to enhance the generation of oxidants including the superoxide anion, peroxynitrite, hydrogen peroxide, and hydroxyl radical in the renal cortical mitochondria.130,131 Recent studies have established that Spirulina fusiformis, significantly and dose dependently, protects against the gentamycin-induced oxidative stress, renal histological alterations, and renal dysfunction in rats.132 Reports have been made on the characteristic morphological changes such as tubular necrosis, tubular regeneration, and tubulointestinal mononuclear cell filtration in the kidneys of the gentamycin-treated rats, which are significantly attenuated by Spirulina, further supporting the active role of antioxidants and ^-carotene present in Spirulina in such protection.104,133 An enhanced generation of NO by the inducible NOS (iNOS) is shown to cause injury to the kidney through several mechanisms. Elevated levels of NO leads to the depletion of cellular ATP through inactivation of the enzymes of the Krebs cycle and mitochondrial electron transport chain.134 Gentamicin has been observed to enhance glomerular NO production.135 Spirulina has been noticed to significantly and dose dependently attenuate the gentamycin-induced nitrosative stress and this probably is due to the inhibition of the iNOS activity.132

The involvement of heavy metals has been emphasized in a variety of pathological states such as hypertension and renal, neural and hepatic disorders.136 MDA provides an index of lipid peroxidation of cell membranes. Spirulina has been reported to effectively decrease the extent of lipid peroxidation and restore the levels of various

Nephrotoxic drugs (e.g. Cisplatin, cyclosporine)

Nephrotoxic drugs (e.g. Cisplatin, cyclosporine)

SCHEMA 1 Proposed mechanism of protection against drug-induced nephrotoxicity protection by Spirulina and its antioxidants. Drugs entering the kidney cells undergo metabolism by the drug-metabolizing enzymes and get transformed into their respective metabolites. Either the parent drugs (e.g., cisplatin and cyclosporine) or their metabolites activate molecular oxygen through oxygenases such as the xanthine oxidase or the mitochondrial electron transport system into the ROS, which cause oxidative stress. The ROS thus formed induce intracellular oxidative stress involving lipid peroxidation, protein oxidation, and DNA damage. The oxidative stress also triggers activation of the stress-activated kinases (p38 MAPK and JNK), which in turn activate caspase-3 and down-regulate Bcl-2. These signaling cascades induce the renal cell toxic events including necrosis and apoptosis thus resulting in the nephrotoxicity. Spirulina and its antioxidants have been shown to inhibit the formation of ROS, attenuate oxidative stress, and inhibit the activation of signaling cascades and the resultant necrosis and apoptosis in the cells of the kidney exposed to the nephrotoxic drugs. Alternatively, the ability of Spirulina and its antioxidants to modulate the drug-metabolism and drug-induced enzymatic activation of molecular oxygen is also proposed as a possible mechanism of protection against the drug-induced nephrotoxicity.

endogenous antioxidants in several organs such as the kidney, liver, heart, lung, and brain of the experimental animals.82,106,132 Reports have been made that Spirulina restores the activities of various membrane-bound enzymes including the Na+-K+ -ATPase, Ca++-ATPase and Mg++-ATPase and several lipids in the vital organs such as the liver, kidney, heart, and lung of rats exposed to lead.106 Rats fed with Spirulina have shown amelioration of the kidney damage from cadmium toxicity.137 The induction of oxidative stress by heavy metals in a wide variety of systems is also established. Therefore, from these studies it is conceivable to deduce that Spirulina offers a protective antioxidant effect against the renal injury (nephrotoxicity) caused by various toxicants, heavy metals, and drugs including the anticancer chemothera-peutic agents (Schema 1). Nevertheless, the molecular mechanisms behind protection of the chemical- and drug-induced nephrotoxicity by Spirulina through the mitigation of the oxidant reactions, modulation of the antioxidant enzymes, and the inhibition of apoptosis need to be thoroughly investigated and established in both in vitro and in vivo systems.

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