Nitric oxide and oxidative stress in brain and heart of normal rats treated with doxorubicin: role of aminoguanidine.
Doxorubicin (DOX) is a potent antitumor antibiotic drug known to cause severe cardiac toxicity. Moreover, its adverse effects were found to be extended to the cerebral tissue. Several mechanisms for this toxicity have been ascribed. Currently, one of the most accepted mechanisms is through free radicals; however, the exact role of nitric oxide (NO) is still unclear. Accordingly, a NO-synthase inhibitor with some antioxidant property, aminoguanidine (AG), was selected to examine its potential protective effect against DOX-induced toxicity. Male Wistar albino rats (150-200 g) were allocated into a normal control group, DOX-induced toxicity group, and DOX + AG-treated group. DOX was injected i.p. at a dose of 10 mg/kg divided into four equal injections over a period of 2 weeks. AG was injected i.p. at a dose of 100 mg/kg 1 h before each DOX injection. The animals were sacrificed 24 h after the last DOX injection and the following parameters were measured: serum lactate dehydrogenase (LDH) and creatine phosphokinase (CPK) activities, cardiac and cerebral contents of malondialdehyde (MDA), conjugated diene (CD), glutathione (GSH), NO, and cytosolic calcium, as well as superoxide dismutase (SOD) and glutathione peroxidase (GSHP(X)) activities. Cardiotoxicity was manifested by a marked increase in serum LDH and CPK in addition to the sharp increase in MDA reaching eightfolds the basal level. This was accompanied by significant increase in CD, NO, cytosolic calcium, SOD, and GSHP(X) content/activity by 69, 85, 76, 125, and 41% respectively as compared to normal control. On the other hand, GSH was significantly depressed. In brain, only significant increase in MDA and GSHP(X) and decrease in GSH were obtained but to a lesser extent than the cardiac tissue. AG treatment failed to prevent the excessive release of cardiac enzymes; however, it alleviated the adverse effects of DOX in heart. AG administration resulted in marked decrease in the elevated levels of MDA, NO, SOD, and GSHP(X), however, MDA level was still pathological. The altered parameters in brain were restored by AG. It is concluded that, AG could not provide complete protection against DOX-induced toxicity. Therefore, it is recommended that, maintenance of the endogenous antioxidant, GSH, and regulation of calcium homeostasis must be considered, rather than NO formation, to guard against DOX-induced toxicity.
Abd El-Gawad
Hanan M
HM
Biochemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt. hananabdelgawad@hotmail.com
El-Sawalhi
Maha M
MM
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D004317:Doxorubicin / Q000633:toxicity*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D006146:Guanidines / Q000494:pharmacology; D006321:Heart / Q000187:drug effects*; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052247:Nitric Oxide Synthase Type II; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar
D000903:Antibiotics, Antineoplastic; D004791:Enzyme Inhibitors; D006146:Guanidines; D009569:Nitric Oxide; D008315:Malondialdehyde; D004317:Doxorubicin; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D005978:Glutathione; C004479:pimagedine