Showing papers by "Farzad Kobarfard published in 2006"

Lysosomal Oxidative Stress Cytotoxicity Induced by Dacarbazine and It’s Pyridine Derivative in Hepatocytes

Abstract: Dacarbazine (DTIC) is a synthetic chemical antitumor agent which is used to treat malignant melanoma and Hodgkin’s disease. DTIC is a prodrug which is converted to an active form undergoing demethylation by liver enzymes. The active form prevents the progress of disease via alkylation of DNA strand. In the structure of this drug, the imidazole ring, a triazen chain and carboxamide group exist. Based on the literature, the ring and carboxamide group do not have a key role in antitumor activity of the drug. On the other hand, imidazole ring has a unique tautomerization which may participate in the mechanism of action of DTIC and carboxamide group may determine the rich guanine pieces in DNA strand. In order to investigate the mechanistic role of imidazole group and its known tautomerization in DTIC cytotoxicity, derivative of DTIC with a pyridine ring (3-(3,3-dimethyl-1triazenyl)pyridine, (compound I) instead of imidazole ring was synthesized. In the following, the cellular and molecular mechanism of cytotoxicity induced by DTIC and its pyridine derivative toward the isolated rat hepatocytes were studied and compared. Hepatocyte reactive oxygen species (ROS) generation was significantly increased by both DTIC and compound B before cytotoxicity ensued. In addition, DTIC and compound I induced lysosomal damage and hepatocyte protease activation. Endocytosis inhibitors, lysosomotropic agents or lysosomal protease inhibitors also prevented both DTIC and compound B induced hepatocytes cytotoxicity. Furthermore desferoxamine (a ferric chelator), antioxidants or ROS scavengers (catalase, mannitol or dimethylsulfoxide) prevented both DTIC and compound I cytotoxicity. It is concluded that H 2 O 2 reacts with lysosomal Fe 2+ to form hydroxyl radical which (Haber-Weiss reaction) causes lysosomal membrane disruption, proteases and other digestive enzymes release and finally the cell death.

Sex differences and role of gonadal hormones in development of tolerance to morphine analgesia and glutamate level in the nucleus accumbens of rats: A microdialysis study

Abstract: Introduction: Sex differences are observed in the development of tolerance to antinociceptive effect of opioid drugs such as morphine, but the underlying mechanisms remain unclear. Critical role of glutamate in the development and maintenance of opioid tolerance has been reported by many investigators. There are also evidences about interaction between gonadal hormones and neuromodulatory systems including opioidergic and glutamatergic systems. The present study examined the sex differences and role of gonadal hormones on the glutamate level in the nucleus accumbens in morphine tolerant rats using in vivo microdialysis. Methods: Intact, gonadectoized and sham-operated male and female rats were used. Morphine (7 mg/kg/day, SC) was administered for 8 days. Response to thermal noxious stimuli were measured by tail-flick test. Tolerance was defined as the response which was not significantly different from baseline. Results: The results showed that after chronic morphine administration, antinociceptive tolerance in male rats was significantly greater than females (P<0.05). Sex differences in morphine tolerance disappeared with gonadectomy of animals. There was also significant sex difference in glutamate level in nucleus accumbens of morphine tolerant rats (P<0.05), Glutamate level was decreased after ovariectomy of female rats (P<0.05), but gonadectomy had not significantly effect on glutamate level in males. Conclusion: Results of this study provide evidence of sex differences in development of tolerance to morphine in rats and mediatory roles of gonadal hormones and glutamate levels in these differences.