Alogliptin mitigates doxorubicin-induced cardiotoxicity in rats: Implications of SIRT3/NRF2 pathway and miRNA-133a.

Abstract

Doxorubicin (DOX) is an anticancer antibiotic that is widely utilized. Nevertheless, this therapeutic potential is hampered by its cardiotoxicity. Alogliptin (ALO), an antidiabetic, recently is being repurposed for the management of various organs ailments owing to its discovered biological activities as an antioxidant, anti-inflammatory, anti-apoptotic and antifibrotic through multiple pathways. This study is directed to evaluate the possible protective effect of ALO against DOX-induced cardiac molecular and histopathological alterations. Twenty-four adult Wistar rats were grouped into control in addition to ALO (20 mg/kg, p.o, 21 days), DOX (18 mg/kg, i.p; six equal divided doses on alternative days starting at day 8), and Dox + ALO treated groups. On the 21st day, blood samples are collected to assess cardiac biomarkers. Additionally, the hearts of all rats were separated and processed for histological evaluation, ultrastructural examination, and collagen content determination by Masson Triciumus staining, and biochemical studies. The DOX group had pronounced deleterious histological and ultrastructural disorganization accompanied with abundant collagen disposition. Biochemically, DOX group demonstrated significant elevation of cardiomyocytes content of MDA, NF-κB, TNF-α, IL-6, BAX, and TGF-β1 which mirrored as significantly elevated serum LDH, CKMB, and cTnI levels. However, SOD and CAT activities as well as GSH, BCL-2, SIRT3 and NRF2 content along with miRNA-133a gene expression are significantly decreased. Present results proved the prophylactic ALO antioxidant, anti-inflammatory, anti-apoptotic, and anti-fibrotic influence on the DOX-induced cardiotoxicity with proposed mechanisms entailing the activation of SIRT3 pathway that may be governed by miRNA-133a. However, these results are limited by the inspection lack of echocardiography or hemodynamic alterations, gain and loss of function, caspase activation, and mitochondrial health tests. Thus, ALO has the potential to be an appropriate therapy for DOX-induced cardiotoxicity.