Investigation of the protective effects of dabrafenib- receptor interacting protein kinase 3 inhibitor- against necroptosis induced by doxorubicin cardiotoxicity

Aim: It was aimed to examine the protective effects of dabrafenib- a selective RIP3 inhibitor- against doxorubicin induced cardiotoxicity and to compare it with necrostatin-1, which is a RIP1 inhibitor and has a proven protective effect against necroptosis. Materials and Methods: 48 Sprague Dawley male rats were divided into 9 groups and intraperitoneally injected for seven days: Control group (saline 1ml every day); Dox group (a single dose of 10 mg/kg Dox); Dox+Dab group (single dose of 10 mg/kg Dox and 10mg/kg Dab daily); Dox+Nec group (a single dose of 10 mg/kg Dox and 1.65 mg/kg Nec-1 daily); Dab group (10 mg/kg /day Dab); Nec group (1.65 mg/kg/day Nec-1). After seven days in all groups, the hearts of the rats were isolated and cannulated from the aorta and perfused with Krebs-Henseleit solution by using Langendorff system. Coronary perfusion pressure was recorded by MP30 (Biopac systems) and heart rates were measured by electrodes attached to the heart. In heart tissues mondialdehyde (MDA) levels were determined and protein expression levels of RIP1, RIP3, CaMKII, CypD were examined by western blotting. Besides that, heart tissues were fixed by formaldehyde and histopathologically examined Results: In the Dox group, increased perfusion pressure, heart rate, MDA levels and expression levels of necroptotic proteins were significantly decreased by dabrafenib administration (p<0.05). In addition, while the protective effects of dabrafenib was compared with necrostatin-1 it was observed that dabrafenib was significantly more effective against necroptosis (p<0.05). Conclusion: It was found that dabrafenib had a protective effect against necroptosis occurred in doxorubicin induced cardiotoxic injury, and it was more effective than necrostatin-1.