1. It is well documented that cisplatin (CDDP) treatment increases the expression of adenosine A(1) receptors in both kidney and testes. However, the effect of adenosine at these receptors is controversial. Adenosine A(1) receptors have been documented to be involved in either cytoprotection or aggravation of nephrotoxicity. The aim of the present study was to examine the effect of the non-selective adenosine receptor inhibitor theophylline and the phosphodiesterase inhibitor pentoxifylline on CDDP-induced renal and testicular toxicity. 2. Male Wister rats were divided into six groups. Two control groups received plain drinking water and a third control group received theophylline 0.8 mg/mL in the drinking water for 2 weeks. One group of animals drinking plain water was injected intraperitoneally (i.p.) with pentoxifylline 50 mg/kg per day for 2 weeks. The remaining groups were treated in the same manner and received single dose of CDDP 7 mg/kg, i.p., 1 week after starting theophylline and pentoxifylline treatment and all animals were killed 1 week after CDDP treatment. 3. Rats treated with CDDP developed nephrotoxicity, as demonstrated by increased kidney and testes weight as a percentage of total bodyweight, blood urea nitrogen and serum creatinine levels and decreased serum calcium and albumin levels. In addition, CDDP treatment resulted in an increase in the production of malondialdehyde (MDA) and decreases in total nitrate/nitrite levels, as well as depletion of reduced glutathione (GSH) content and glutathione peroxidase (GPX) activity in both the kidney and testes. Administration of theophylline in the drinking water to CDDP-treated rats resulted in exacerbation of the indices of nephrotoxicity, depletion of GSH content and GPX activity levels, with increased MDA production and platinum accumulation in both the kidney and testes. However, pentoxifylline administration reduced CDDP-induced biochemical changes and reduced platinum accumulation in both organs. Histopathological examination of the kidney revealed that CDDP treatment produced multifocal tubular atrophy, atypical reparative changes of the tubular epithelium and marked tubular necrosis. Animals treated with the theophylline/CDDP combination showed extensive widespread damage with intratubular calcification. However, pentoxifylline treatment ameliorated the overt changes induced by CDDP treatment. 4. Theophylline exacerbates the deleterious effects of CDDP on rat kidney and testes. However, pentoxifylline alleviates CDDP-induced renal and testicular toxicity.
The higher incidence of cardiotoxicity of doxorubicin (DOX)/paclitaxel (PTX) combination compared with DOX alone remains to be a major obstacle against effective chemotherapeutic treatment. We investigated the effect of sequence and time interval between administration of both drugs on the severity of cardiotoxicity of the combination. Male Wistar rats were divided into seven groups. DOX was administered intraperitoneally (i.p.) at a single dose of 5 mg x kg(-1) every other 2 days, 2 doses per week for a total cumulative dose of 20 mg x kg(-1). PTX was administered by an i.p. route at a dose of 20 mg x kg(-1) every other 2 days. Both drugs were injected either alone or sequentially in combination. In one case, DOX preceded PTX by 30 min and 24 h and in the other case, PTX preceded DOX by 30 min and 24 h. Cardiotoxicity was evaluated by both biochemical and histopathological examination, 48 h after the last DOX dose. DOX-induced cardiotoxicity was manifested by abnormal biochemical changes including marked increases in serum creatine phosphokinase isoenzyme (CK-MB), lactate dehydrogenase (LDH), glutathione peroxidase (GSH-Px), and aspartate aminotransferase (AST) activity levels. Myocardial tissue from DOX-treated rats showed significant increases in malondialdehyde (MDA) production and total nitrate/nitrite (NOx) levels, parallel with depletion of "endogenous antioxidant reserve," including GSH contents and GSH-Px activity level. PTX treatment produced significant changes in the biochemical parameters measured by a lower magnitude than those changes produced by DOX alone. Combination of both drugs resulted in aggravation of DOX-induced cardiotoxicity regardless the sequence and time interval between administration of either drug. Administration of PTX 30 min and 24 h after DOX treatment showed exaggeration of combination-induced cardiotoxicity compared with the reverse sequence. This exacerbation was manifested by much more pronounced changes in serum and cardiac tissue parameters measured. Histopathological examination of ventricles of rat's heart revealed that DOX treatment produced myo-cytolysis and myocardial necrosis. Administration of PTX following DOX treatment showed extensive myocardial necrosis compared with those rats treated with either DOX alone or the reverse sequence of administration. Moreover, rats treated with PTX 24 h after DOX treatment showed exaggeration of the combination-induced cardiotoxicity. In conclusion, PTX might synergistically aggravate DOX-induced cardiotoxicity. The effect might be much more pronounced with those rats treated with PTX 24 h after DOX treatment.
Background: Nitric oxide (NO) has been shown to play a role in maintaining normal renal function. However, the role of NO in cisplatin (CDDP)-induced nephrotoxicity is still unclear. The aim of the present work was to examine the effect of the NO synthase (NOS) inhibitor, 2-amino-4-methylpyridine, on the severity of CDDP-induced nephrotoxicity. Methods: Male Wistar rats were divided into six groups. Three control groups received plain drinking water or water containing 1.5% L-arginine. One of the two groups receiving plain water was treated with an intraperitoneal injection of 2-amino-4-methylpyridine (1 mg/kg in normal saline), and the other two control groups were injected intraperitoneally with normal saline. Another three groups were treated in the same manner and injected with CDDP (6 mg/kg, i.p.). CDDP was injected 1 h after 2-amino-4-methylpyridine treatment. Rats were sacrificed 7 days after CDDP treatment, and serum as well as kidneys were isolated and analysed. Results: CDDP-treated rats showed increases in the kidney weight as a percentage of the total body weight and serum creatinine and urea levels and decreases in serum albumin and calcium levels. Also, CDDP treatment induced reductions in the kidney total nitrate/nitrite (NOx), reduced glutathione (GSH) and glutathione peroxidase activity (GSH-Px) levels and an increase in the kidney malondialdehyde (MDA) production level. In contrast, 2-amino-4-methylpyridine treatment 1 h prior to CDDP injection induced marked exacerbation of CDDP-induced nephrotoxicity, as manifested by severe aggravation of the indices of nephrotoxicity. Also, 2-amino-4-methylpyridine plus CDDP-treated rats showed exaggeration of the reduction in the kidney total NOx content and GSH-Px activity and elevation of the kidney platinum accumulation level with normalization of the kidney MDA production level and rebound in the kidney GSH content. Histopathologically, CDDP-treated rats showed marked interstitial nephritis, tubular atrophy and tubular necrosis. However, treatment with 2-amino-4-methylpyridine 1 h prior to CDDP injection revealed marked exacerbation of CDDP-induced histopathological changes. Conclusions: The present findings suggest that NO plays a role in CDDP-induced nephrotoxicity. Administration of 2-amino-4-methylpyridine, an NOS inhibitor, exacerbates CDDP-induced nephrotoxicity.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.