Does clozapine induce myocarditis, myocardial oxidative stress and DNA damage in rats?

Abstract

Clozapine is an atypical antipsychotic drug selectively effective in the treatment of refractory schizophrenia. However, myocarditis, as a serious cardiotoxic effect, has in several case reports been associated with clozapine therapy. Ani increase in the free radical production and ischemia, probably induced by clozapine-induced release of catecholamines, have been hypothesized to trigger an inflammatory response that leads to the clinically observed cardiomyopathy and sudden death even in young patients. The aim of this work is to study the role of oxidative stress in clozapine-induced myocarditis and myocardial DNA damage in a rat model. Methods: Male Wistar rats, age ∼6 weeks, were administered 5, 10 or 25 mg/kg clozapine daily for 21 days; saline-treated rats served as the control. Heart sections were stained with hematoxylin and eosin for histopathological examination. Plasma CK-MB, LDH and TNF-α concentrations were determined. Myocardial oxidative stress (MDA and NO), antioxidant (GSH and GSH-Px) parameters, and the marker of oxidative DNA damage (8-OHdG) were determined. Results: Clozapine treatment resulted in significant dose-related increases in myocardial inflammation with increased plasma TNF-α, CK-MB and LDH levels. Myocardial MDA, NO and serum and cardiac 8-OHdG levels increased while GSH level and GSH-Px activity decreased with the highest significance seen with the largest tested dose (25 mg/kg) of clozapine. Conclusions: Clozapine, in relatively large doses induced myocarditis consistently with increased myocardial oxidative stress, DNA damage and inflammatory cytokines in rat a model.

Keywords

• Clozapine
• Myocarditis
• Oxidative stress
• TNF-α
• DNA damage