7B-7D) compared with the control group. The immunohistochemical staining for caspase-3 was quantified, and the results are summarised in Fig. 7E. This immunohistochemical finding was confirmed by spectrophotometric measurement of caspase-3 activity in cardiac tissues. Caspase-3 activity increased in response to clozapine treatment at the significance level p < 0.05 with 10 mg/kg, p < 0.01 with 15 mg/kg and p < 0.001 with the dose 25 mg/kg after 21 days of treatment (Fig. 7F). Approximately 30% of individuals diagnosed with schizophrenia suffer from treatment-resistant or refractory schizophrenia. The gold standard for treatment of refractory

schizophrenia is clozapine [8]. However, a significant number of patients cease clozapine therapy. The main cause is drug-induced check details adverse effects, most notably including myocarditis and cardiomyopathy [7]. The exact mechanisms of clozapine-induced cardiac toxicity are not yet fully understood. Existing selleck screening library evidence points to a multitude of molecular mechanisms involved in clozapine-induced

cardiotoxicity. In this study, we investigated possible mechanisms of clozapine cardiotoxicity and the cause of sudden death observed in many patients during the course of clozapine therapy. Because most of the reported cases of clozapine cardiotoxicity were in young patients, we performed this study in young (3-4 weeks old) rats treated with clozapine for 21 days. In the present study, all animals treated with clozapine appeared sedated, lethargic and sick for at least 1 h after clozapine injection, which may reflect the lethargy reported in some patients that has been related to clozapine cardiotoxicity [27]. Clinically, patients receiving clozapine should be regularly monitored by echocardiography during treatment; FS and EF are

considered the standard indicators of LV function used for diagnosis of cardiotoxicity. Because clinical cardiac changes were difficult to interpret by echocardiography in short-term studies like this one, we therefore also measured myocardial functional parameters (LVEDP) by hemodynamic analysis to further strengthen our findings on cardiac changes after clozapine treatment. Clozapine -treated animals showed dose-related decreases in FS and EF but increases in LVEDP, LVDd and LVDs, indicating LV dysfunction consistent with cardiomyopathy. Previous Nintedanib (BIBF 1120) studies showed that the potential cardiotoxicity of clozapine may be in the form of myocarditis and cardiomyopathy [28], [29] and [30]. In addition, our results showed that treatment with clozapine in the tested doses induced marked dose-related inflammatory and cardiotoxic effects, with the highest incidence in response to 25 mg/kg clozapine. Inflammatory lesions were observed in both the left and right ventricles, mainly in the myocardium below the endocardium of the left ventricle, in the posterior papillary muscle of the left ventricle and in the septum.