The role of vimentin, Connexin-43 proteins, and oxidative stress in the protective effect of propranolol against clozapine-induced myocarditis and apoptosis in rats

Clozapine (CLZ) represents an effective treatment for resistant schizophrenia. However, myocarditis, recently reported in about 66% of the psychiatric patients treated with CLZ, has raised concerns about its safety. beta-blocking agents have shown to be helpful in the management of myocarditis. Moreover, Vimentin (VIM) and Connexin-43 (CX43) are important structural proteins play key roles in cytoskeletal functions and cellular communication and have complex implications in pathophysiology. The present work aimed to study the mechanisms behind the protective effect of propranolol (PRO) against CLZ-induced myocarditis and the possible involvement of VIM and CX43. The effect of PRO (5 and 10 mg/kg, oral) on the myocarditis induced by CLZ (25 mg/kg/d, i. p.) treatment for 21 days in rats, was assessed biochemically, and immunohistochemically. CLZ treatment increased the serum levels of cardiac injury (CK-MP, LDH and cTn-I) and cardiac levels of oxidative stress (TBARS and NO) markers, proinflammatory cytokines (IL-1 beta and TNF-alpha), and mRNA expression of VIM and CX43 with decreased the antioxidant defenses (GSH and GSH-Px). Immunohistochemical study showed increased cardiac expression of VIM, CX43 and caspase-3 proteins. Coadministration of PRO with CLZ, dose-dependently decreased the biochemical and immunohistochemical hallmarks of CLZ-induced myocardial injury and significantly decreased mRNA expression of VIM and CX43. Taken together, our results demonstrate that the cardioprotective effects of PRO on CLZ-induced myocarditis are related in addition to its beta-blocking activity to protection of myocardial VIM and CX43 proteins through antagonizing the CLZ-induced oxidative stress and inflammatory response, and preventing cell apoptosis.