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Protection against doxorubicin cardiomyopathy in rats: role of phosphodiesterase inhibitors type 4.
J Pharm Pharmacol 2004; 56(6):757-68JP

Abstract

Selective cardiotoxicity of doxorubicin (DOX) remains a significant and dose-limiting clinical problem. The mechanisms implicated are not yet fully defined but may involve the production of reactive oxygen species or expression of cytokines. Although patients with advanced congestive heart failure express elevated circulating levels of tumour necrosis factor-alpha (TNFalpha), little is known about the prognostic importance and regulation of TNF in the heart in cardiac disease states. Here we tested whether the expression of TNFalpha, along with oxidative stress, is associated with the development of DOX-induced cardiomyopathy (DOX-CM) and whether concurrent treatment with taurine (Taur), an antioxidant, or rolipram (Rolp), a TNFalpha inhibitor, offer a certain protection against DOX cardiotoxic properties. DOX (cumulative dose, 12 mg kg(-1)) was administered to rats in six equal (intraperitoneal) injections over a period of 6 weeks. Cardiomyopathy was evident by myocardial cell damage, which was characterized by a dense indented nucleus with peripheral heterochromatin condensation and distorted mitochondria, as well as significant increase in serum levels of creatine kinase and lactate dehydrogenase. DOX also induced an increment (P<0.001) in serum TNF and plasma nitric oxide levels. The extent of left ventricular (LV) superoxide anion, lipid peroxide measured as malondialdehyde, catalase and calcium content were markedly elevated, whereas superoxide dismutase, total and non-protein-bound thiol were dramatically decreased in DOX-treated rats. Exaggeration of DOX-CM was achieved by intraperitoneal injection of lipopolysaccharide (LPS) (1 mg kg(-1)) 18 h before sampling and evaluated by highly significant increase in heart enzymes (P<0.001), oxidative stress biomarkers and TNFalpha production. Pre- and co-treatment of DOX or DOX-LPS rats with Taur (1% daily supplemented in drinking water, 10 days before and concurrent with DOX) or Rolp (3 mg kg(-1), intraperitoneally, one dose before DOX administration then every 2 weeks throughout the experimental period) ameliorated the deleterious effect of both DOX and LPS on the aforementioned parameters. Meanwhile, it is noteworthy that Rolp exhibited a more preferable effect on serum TNFalpha level. Taur and rolipram also restored the myocardial apoptosis induced by DOX. In conclusion, a cumulative dose of DOX affected free radical and TNFalpha production in the heart of an experimental cardiomyopathy animal model. The current results suggest that down-regulation of these radicals and cytokines could be maintained by using the free radical scavenger Taur or, more favourably, the TNFalpha inhibitor Rolp.

Authors+Show Affiliations

Department of Biochemistry, Faculty of Pharmacy, Zagazig University, Egypt. hodael_sayed@yahoo.com

Pub Type(s)

Journal Article

Language

eng

PubMed ID

15231041

Citation

Mohamed, Hoda E., et al. "Protection Against Doxorubicin Cardiomyopathy in Rats: Role of Phosphodiesterase Inhibitors Type 4." The Journal of Pharmacy and Pharmacology, vol. 56, no. 6, 2004, pp. 757-68.
Mohamed HE, Asker ME, Ali SI, et al. Protection against doxorubicin cardiomyopathy in rats: role of phosphodiesterase inhibitors type 4. J Pharm Pharmacol. 2004;56(6):757-68.
Mohamed, H. E., Asker, M. E., Ali, S. I., & el-Fattah, T. M. (2004). Protection against doxorubicin cardiomyopathy in rats: role of phosphodiesterase inhibitors type 4. The Journal of Pharmacy and Pharmacology, 56(6), pp. 757-68.
Mohamed HE, et al. Protection Against Doxorubicin Cardiomyopathy in Rats: Role of Phosphodiesterase Inhibitors Type 4. J Pharm Pharmacol. 2004;56(6):757-68. PubMed PMID: 15231041.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Protection against doxorubicin cardiomyopathy in rats: role of phosphodiesterase inhibitors type 4. AU - Mohamed,Hoda E, AU - Asker,Mervat E, AU - Ali,Sousou I, AU - el-Fattah,Tamer M Abd, PY - 2004/7/3/pubmed PY - 2004/11/13/medline PY - 2004/7/3/entrez SP - 757 EP - 68 JF - The Journal of pharmacy and pharmacology JO - J. Pharm. Pharmacol. VL - 56 IS - 6 N2 - Selective cardiotoxicity of doxorubicin (DOX) remains a significant and dose-limiting clinical problem. The mechanisms implicated are not yet fully defined but may involve the production of reactive oxygen species or expression of cytokines. Although patients with advanced congestive heart failure express elevated circulating levels of tumour necrosis factor-alpha (TNFalpha), little is known about the prognostic importance and regulation of TNF in the heart in cardiac disease states. Here we tested whether the expression of TNFalpha, along with oxidative stress, is associated with the development of DOX-induced cardiomyopathy (DOX-CM) and whether concurrent treatment with taurine (Taur), an antioxidant, or rolipram (Rolp), a TNFalpha inhibitor, offer a certain protection against DOX cardiotoxic properties. DOX (cumulative dose, 12 mg kg(-1)) was administered to rats in six equal (intraperitoneal) injections over a period of 6 weeks. Cardiomyopathy was evident by myocardial cell damage, which was characterized by a dense indented nucleus with peripheral heterochromatin condensation and distorted mitochondria, as well as significant increase in serum levels of creatine kinase and lactate dehydrogenase. DOX also induced an increment (P<0.001) in serum TNF and plasma nitric oxide levels. The extent of left ventricular (LV) superoxide anion, lipid peroxide measured as malondialdehyde, catalase and calcium content were markedly elevated, whereas superoxide dismutase, total and non-protein-bound thiol were dramatically decreased in DOX-treated rats. Exaggeration of DOX-CM was achieved by intraperitoneal injection of lipopolysaccharide (LPS) (1 mg kg(-1)) 18 h before sampling and evaluated by highly significant increase in heart enzymes (P<0.001), oxidative stress biomarkers and TNFalpha production. Pre- and co-treatment of DOX or DOX-LPS rats with Taur (1% daily supplemented in drinking water, 10 days before and concurrent with DOX) or Rolp (3 mg kg(-1), intraperitoneally, one dose before DOX administration then every 2 weeks throughout the experimental period) ameliorated the deleterious effect of both DOX and LPS on the aforementioned parameters. Meanwhile, it is noteworthy that Rolp exhibited a more preferable effect on serum TNFalpha level. Taur and rolipram also restored the myocardial apoptosis induced by DOX. In conclusion, a cumulative dose of DOX affected free radical and TNFalpha production in the heart of an experimental cardiomyopathy animal model. The current results suggest that down-regulation of these radicals and cytokines could be maintained by using the free radical scavenger Taur or, more favourably, the TNFalpha inhibitor Rolp. SN - 0022-3573 UR - https://www.unboundmedicine.com/medline/citation/15231041/Protection_against_doxorubicin_cardiomyopathy_in_rats:_role_of_phosphodiesterase_inhibitors_type_4_ L2 - https://onlinelibrary.wiley.com/resolve/openurl?genre=article&amp;sid=nlm:pubmed&amp;issn=0022-3573&amp;date=2004&amp;volume=56&amp;issue=6&amp;spage=757 DB - PRIME DP - Unbound Medicine ER -