TNF-α can trigger iNOS expression in macrophages and cardiac myocytes. The overproduction of NO by proinflammatory cytokines may depress myocyte contractility [48]. Excessive production of ROS and RNS in myocardial cells leads to the exhaustion of cellular GSH stores and dysregulation of antioxidant enzymes as GSH-Px, thereby leading to the impairment of antioxidant defences (Solaini et al., 2005). These effects were reflected in our results in the form of decreases in the GSH level and GSH-Px activity in cardiac tissues in clozapine–treated animals. Clinical and
experimental investigations suggested that increased oxidative stress associated with an impaired antioxidant defence status initiates a cascade of reactions responsible for clozapine-induced cardiotoxicity [49]. The increase in free radical formation and the attenuation check details of antioxidant defences by clozapine,
can lead to oxidative damage to cellular lipids, proteins and DNA [44]. This can explain the observed increase in both serum and cardiac levels of 8-OHdG the biomarker of DNA damage and the increase in the expression of NF-κB p65, the nuclear factor that contributes in inflammatory response and cell apoptosis. Moreover, the results showed selleck chemicals llc increased expression of caspase-3 in cardiac tissues of clozapine-treated animals. Caspase-3 is an important marker of apoptosis, and this finding indicates that the clozapine-induced cardiotoxicity can lead to apoptosis of cardiac cells. This can be attributed to the observed increase
in oxidative stress with attenuation of antioxidant defences and the consequent cellular and DNA damage. Over the long term, these changes can lead to the development of myocarditis and cell apoptosis in cardiac muscle and to profound cardiac injury and cardiomyopathy [14]. In conclusion, clozapine-induced cardiotoxicity is a serious and potentially lethal complication during the course of clozapine therapy for schizophrenia. Increased myocardial 4��8C oxidative stress, inflammatory cytokines, cellular and DNA damage and apoptosis with attenuation in antioxidant defences are all contributing factors. This necessitates a high degree of clinical care through the course of clozapine therapy. The use of echocardiographic monitoring as a routine periodical check during the course of clozapine therapy, and biohumoral investigation if any signs of cardiotoxicity starts to appear is recommended. Interruption of the clozapine treatment or combination with other drugs that can modulate the above-mentioned pathogenesis in susceptible patients requires further studies. [50] This work was financially supported by Najran University Program for Health and Medical Research Grants, Grant No. (NU 3/10). This study was carried out in the College of Medicine, Najran University, Najran, Saudi Arabia. “
“Antiepileptic drugs, which are also referred to as anticonvulsants, are used in the treatment and prophylaxis of epileptic seizures.