Protective effect of cysteine and vitamin E, Crocus sativus and Nigella sativa extracts on cisplatin-induced toxicity in rats.

Cisplatin [cis-dichlorodiammineplatinum (II)] is a widely used chemotherapeutic drug that is toxic to the kidney. Concurrent administration of cysteine together with vitamin E, Crocus sativus and Nigella sativa reduced the toxicity of cisplatin in rats. When administered i.p. for 5 alternate days with 3 mg/kg cisplatin, cysteine (20 mg/kg) together with vitamin E (2 mg/rat) an extract of Crocus sativus stigmas (50 mg/kg) and Nigella sativa seed (50 mg/kg) significantly reduced blood urea nitrogen (BUN) and serum creatinine levels as well as cisplatin-induced serum total lipids increases. In contrast, the protective agents given together with cisplatin led to an even greater decrease in blood glucose than that seen with cisplatin alone. The serum activities of alkaline phosphatase, lactate dehydrogenase, malate dehydrogenase, aspartate aminotransferase and alanine aminotransferase of cisplatin-treated rats were significantly decreased, whereas the activities of glutathione reductase and isocitrate dehydrogenase were significantly increased. Addition of cysteine and vitamin E, Crocus sativus and Nigella sativa in combination with cisplatin partially prevented many changes in the activities of serum enzymes. In cisplatin-treated rats, the liver activities of isocitrate dehydrogenase and aspartate aminotransferase were significantly increased, whereas much greater changes were found in the kidneys, with increased activity of glucose-6-phosphate dehydrogenase and decreased activities of alkaline phosphatase, isocitrate dehydrogenase, malate dehydrogenase, aspartate aminotransferase, alanine aminotransferase, sorbitol dehydrogenase and gamma-glutamyl transferase, as well as a decreased phosphorylation to oxidation ratio in the mitochondria, indicating reduced adenosine triphosphate production. Also, administration of cysteine and vitamin E, Crocus sativus and Nigella sativa together with cisplatin partially reversed many of the kidney enzymes changes induced by cisplatin. Cysteine together with vitamin E, Crocus sativus and Nigella sativa tended to protect from cisplatin-induced falls in leucocyte counts, haemoglobin levels and mean osmotic fragility of erythrocytes and also prevented the increase in haematocrit. The results of this study indicate a basis for the toxic effects of cisplatin, and suggest a possible way of counteracting the toxicity by introducing protective agents such sulphydryl compounds, other antioxidants and extracts of natural products. It also appears that cells adapt to the effects of cisplatin through the induction of systems that produce NADPH, which in turn compensates the decrease of free sulphydryl groups. We conclude that cysteine and vitamin E, Crocus sativus and Nigella Sativa may be a promising compound for reducing cisplatin-toxic side effects including nephrotoxicity.

Effect of methimazole and fish oil treatment on gentamicin nephrotoxicity in rats.

Gentamicin, a nephrotoxic aminoglycoside antibiotic, was injected into adult male albino rats, alone or together with methimazole and fish oil. The effects on renal and liver functions and renal thiol status were studied. Gentamicin was administered as two i.p. injections (40 mg/kg body weight) for 3, 7 and 10 consecutive days. The animals were sacrificed 12 hours after the last injection. In gentamicin-treated rats, for 7 and 10 days, blood urea nitrogen (BUN) and serum creatinine concentrations and urinary N-acetyl-beta-D-glucosaminidase (NAG) activity were significantly increased compared with saline-treated controls. Administration of methimazole (20 mg/kg) and fish oil (5 ml/kg) together with gentamicin partially protected against the nephrotoxicity induced by gentamicin by returning the urea and creatinine concentrations and urinary NAG activity to normal levels, despite having higher kidney gentamicin concentrations, especially with methimazole. Rats given gentamicin alone for 3 days exhibited no elevation of BNU, serum creatinine and urinary NAG values. However, these rats exhibited an increase in nonprotein disulfide concentrations and a decrease in renal protein thiol and protein disulfide concentrations, as opposed to rats given gentamicin and methimazole and rats given gentamicin and fish oil. These results show that methimazole and fish oil were effective antagonists of gentamicin-induced nephrotoxicity. Methimazole did not inhibit gentamicin renal uptake but may protect against gentamicin-induced nephrotoxicity by acting as an antioxidant within the kidneys. On the other hand, fish oil may protect against gentamicin-induced nephrotoxicity by counteracting the biochemical alterations induced by the drug in the renal cortex. We conclude that methimazole and fish oil may be compounds for reducing gentamicin-toxic side effects, including nephrotoxicity, without compromising its antibiotic activity.

Influence of acute and chronic morphine or stadol on the secretion of adrenocorticotrophin and its hypothalamic releasing hormone in the rat.

The effects of acute and chronic treatment with morphine and stadol on the functional activity of the hypothalamo-pituitary-adrenocortical (HPA) system in the rat were studied by investigating their effects on the secretion of adrenocorticotrophin (ACTH) by the pituitary gland and corticotrophin-releasing hormone (CRH) by the hypothalamus. The acute injection of morphine or stadol (3.5 mg/100 g body weight i.p.) caused a rise at 5 and 25 min followed by a fall at 90 and 120 min in the concentrations of ACTH in the plasma and adenohypophysis and in hypothalamic CRH content. It appears that, in the rat, the response of HPA system to acute morphine or stadol administration could change depending upon the time of courses. In addition, chronic morphine or stadol (0.5 mg/100 g body weight i.p. daily) administration for a period of 7 days have little effect on plasma and adenohypophysis ACTH concentrations and hypothalamic CRH content. This may indicate that drug tolerance might have developed. Conversely, repeated daily doses of morphine or stadol (2 mg/ 100 g body weight i.p.) for 7 days cause a significant lowering of plasma and pituitary ACTH concentrations and hypothalamic CRH content. These data suggest that the effect of both drugs is dose related. Overall, the present results are consistent with an increased release of pro-opiomelanocortin-derived peptides after acute morphine or stadol treatment for a short-term, and with a decreased release of these peptides in chronic treatment. However, the results indicate that morphine and stadol change HPA activity by acting on specific receptors in the hypothalamus and raise the possibility that opioid peptides and their receptors are physiologically important in the control of the secretion of CRH.