Document Type : Original research articles
Authors
1
Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Assiut University, Assiut, Egypt
2
Department of Medical Physiology, Faculty of Medicine, Assiut University, Assiut, Egypt & Department of Physiology, College of Medicine, Qassim University, Buraidah, Saudi Arabia
3
Department of Medical Pharmacology, Faculty of Medicine, Assiut University, Assiut, Egypt
4
Department of Histology, Faculty of Medicine, Assiut University, Assiut, Egypt
5
Undergraduate Medical Student, Faculty of Medicine, Assiut University, Assiut, Egypt
6
Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Assiut University, Assiut, Egypt & Department of Basic medical science, Badr University, New Naser city, west of Assiut, Assiut, Egypt
Abstract
Background: Clozapine (CLZ) is an effective choice for the treatment of resistant schizophrenia; however, there is a risk of clozapine-induced cardiotoxicity. Connexin-43 (CX43) and Vimentin are intracellular structural-functional proteins involved in cardiac pathophysiology.
Objectives: The current investigation aimed to assess the cardioprotective mechanisms of beta1-adrenergic blockade by atenolol (ATN) against clozapine (CLZ) induced cardiotoxicity, focusing on the implications for gap junction and intermediate filament proteins.
Materials and methods: Thirty-two male rats were divided into four equal groups: control, clozapine-induced myocarditis (dose 25 mg/kg/day) i.p., myocarditis, and treated with oral ATN with dosage of 5 and 10 mg/kg), for 3 weeks. Biomarkers of cardiac injury, oxidative stress, inflammation (IL1β & TNFα), apoptosis, the levels of vimentin & CX43 expression & CD86 were determined via chemical, ELISA, RT-PCR, histopathological, and immunohistochemical investigations.
Results: Clozapine-treated rats exhibited increased cardiac injury biomarkers, cardiac oxidative stress indices (NO and TBARS), proinflammatory cytokines, and increased expression of caspase-3, vimentin, CX43, and CD86, along with suppression of antioxidants (GSH and GSH-Px). Atenolol showed dose-dependent suppression of the biochemical and histopathological disturbances related to clozapine-induced cardiotoxicity and significant downregulation the expression of vimentin and CX43.
Conclusion:The cardioprotective novel role of ATN in clozapine-induced myocarditis is linked to its selective β1-adrenergic blockade and its ability to repair myocardial proteins vimentin & CX43 by reversing the inflammatory response, oxidative damage, and cellular apoptosis.
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