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  • Protective effect of captopril against clozapine-induced myocarditis in rats: role of oxidative stress, proinflammatory cytokines and DNA damage.

Protective effect of captopril against clozapine-induced myocarditis in rats: role of oxidative stress, proinflammatory cytokines and DNA damage.

Chemico-biological interactions (2014-04-09)
Basel A Abdel-Wahab, Metwally E Metwally, Mohamed M El-khawanki, Alaa M Hashim
ABSTRACT

Clozapine (CLZ) is the most effective therapeutic alternative in the treatment of resistant schizophrenia. However, the cardiotoxicity of CLZ, particularly in young patients, has raised concerns about its safety. Captopril is a well-known angiotensin-converting enzyme inhibitor with antioxidant properties effective in treating hypertension and heart failure. The aim of this study was to investigate the protective effect of captopril against clozapine-induced myocarditis in rats and the possible mechanisms behind this effect. The effect of captopril treatment [5 or 10mg/kg/d, injected intraperitoneally (i.p.) for 21days] on the cardiotoxic effect of coadministered CLZ (25mg/kg/d, i.p.) was assessed. Myocarditis was assessed histopathologically, immunohistochemically and biochemically. Frozen heart specimens were used to determine the amount of lipid peroxides product (MDA), nitric oxide (NO), reduced glutathione (GSH), glutathione peroxidase (GSH-Px) activity, proinflammatory cytokines (TNF-α and IL-10) and DNA degradation product(8-OHdG). Coadministration of captopril with the tested doses of CLZ decreased the histological hallmarks and biochemical markers (CK-MP and LDH) of myocarditis. In addition, captopril attenuated the effects of CLZ on oxidative stress parameters, NO and serum and cardiac 8-OHdG levels. Captopril significantly attenuated the effect of CLZ on all measured parameters in a dose-dependent manner. These results suggested that captopril exerts a protective action against CLZ-induced myocarditis. Multiple mechanisms contribute to this effect, including a decrease in cardiac oxidative stress and proinflammatory cytokines production, modulation of antioxidant status and protection from oxidative DNA damage. Hence, captopril may be effective in reducing the incidence and severity of CLZ-induced myocarditis in humans.

MATERIALS
Product Number
Brand
Product Description

Clozapine, European Pharmacopoeia (EP) Reference Standard
Sigma-Aldrich
2-Thiobarbituric acid, Vetec, reagent grade, ≥98%
Sigma-Aldrich
5,5′-Dithiobis(2-nitrobenzoic acid), Vetec, reagent grade, 98%
Captopril for system suitability, European Pharmacopoeia (EP) Reference Standard
Supelco
Glutathione, Pharmaceutical Secondary Standard; Certified Reference Material
Glutathione, European Pharmacopoeia (EP) Reference Standard
USP
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8-Hydroxy-2′-deoxyguanosine, ≥98% (TLC)
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2-Thiobarbituric acid, ≥98%
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Clozapine
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5,5′-Dithiobis(2-nitrobenzoic acid), ReagentPlus®, 99%
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Captopril, meets USP testing specifications
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L-Glutathione reduced, suitable for cell culture, BioReagent, ≥98.0%, powder
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Creatine, anhydrous
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Clozapine for peak identification, European Pharmacopoeia (EP) Reference Standard
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Captopril, European Pharmacopoeia (EP) Reference Standard
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