title: Clozapine-Induced Cardiotoxicity: Role of Oxidative Stress, Tumour Necrosis Factor Alpha and NF-κβ.
abstract: Safety concerns have been raised about clozapine-induced cardiotoxicity particularly in young patients. The exact mechanism of clozapine cardiotoxicity has not yet been thoroughly studied. This study aimed to investigate the possible mechanisms of clozapine-induced cardiotoxicity in a rat model. Young male Wistar rats were treated with clozapine (10, 15 and 25 mg/kg/day, i.p.) for 21 days. Haemodynamic and echocardiographic studies were performed for assessment of cardiac functions. Heart sections were studied histopathologically and immunohistochemically. Serum and cardiac markers of cardiotoxicity, oxidative stress, inflammation and apoptosis were evaluated. Heart sections of clozapine-treated animals showed increased cardiac inflammation that correlated with the clozapine dose. Serum levels of CK-MB and LDH levels increased, as did cardiac levels of TNF-α, MDA, NO, myeloperoxidase, 8-OHdG, caspase-3 and NF-κB p65. In contrast, GSH levels and GSH-Px activity decreased. Furthermore, immunohistochemical examination of the heart sections showed positive immunostaining for both 3-nitrotyrosine and caspase-3 in all clozapine-treated groups. Clozapine, particularly in relatively high doses, has a clear cardiotoxic effect. This cardiotoxicity is accompanied by increased myocardial oxidative stress, inflammatory cytokines, DNA damage and apoptosis with attenuation in antioxidant defences, thus explaining the previously reported myocarditis and pericarditis during clozapine therapy in clinical studies.
authors.affiliation: Department of Pharmacology, College of Medicine, Assiut University, Assiut, Egypt. basel_post@msn.com.|Department of Pharmacology, College of Medicine, Najran University, Najran, Saudi Arabia. basel_post@msn.com.
authors.forename: Basel A
authors.initials: BA
authors.lastname: Abdel-Wahab
authors.affiliation: Department of Forensic Medicine and Toxicology, College of Medicine, Suez Canal University, Ismailia, Egypt.|Department of Forensic Medicine and Toxicology, College of Medicine, Najran University, Najran, Saudi Arabia.
authors.forename: Metwally E
authors.initials: ME
authors.lastname: Metwally
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D051017:Apoptosis Regulatory Proteins / Q000097:blood; D015415:Biomarkers / Q000097:blood; D003024:Clozapine; D004249:DNA Damage; D004195:Disease Models, Animal; D006331:Heart Diseases / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D018836:Inflammation Mediators / Q000378:metabolism*; D008297:Male; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism*; D018384:Oxidative Stress; D017208:Rats, Wistar; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D000975:Antioxidants; D051017:Apoptosis Regulatory Proteins; D015415:Biomarkers; D018836:Inflammation Mediators; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D003024:Clozapine
keywords: Cardiotoxicity; Caspase-3; Clozapine; DNA damage; NF-κB p65; Oxidative stress; TNF-α