Biochemical Insights into the Effects of a Small Molecule Drug Candidate on Imatinib-Induced Cardiac Inflammation

Szabó, Renáta and Börzsei, Denise and Nagy, András Levente and Kiss, Viktória Mónika and Virág, Zoltán and Karcsúné Kis, Gyöngyi and Almási, Nikoletta and Török, Szilvia and Veszelka, Médea and Bagyánszki, Mária and Bódi, Nikolett and Barta, Bence Pál and Neuperger, Patricia and Szebeni, Gábor and Varga, Csaba (2025) Biochemical Insights into the Effects of a Small Molecule Drug Candidate on Imatinib-Induced Cardiac Inflammation. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 26 (14). No. 6661. ISSN 1661-6596

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Abstract

BGP-15, a poly(ADP-ribose) polymerase-1 (PARP-1) inhibitor exerts cardioprotective effects; however, the underlying mechanisms remain unclear. Therefore, our study aimed to investigate the effects of BGP-15 on the imatinib (Imtb)-induced cardiac inflammation at the biochemical level. Male rats were divided to control, Imtb-treated (60 mg/kg/day for 14 days), and Imtb + BGP-15-treated animals. In this group Imtb was co-administered with BGP-15 at the dose of 10 mg/kg/day. At the end of the experiment, nuclear factorkappa B/p65 (NF-κB/p65), nuclear transcription factor erythroid-2 related factor (Nrf2), heme oxygenase-1 (HO-1), high mobility group box 1 (HMGB1), and myeloperoxidase (MPO) were measured by Western blot. Chemokine and interleukins (ILs) were determined by Legendplex. Additionally, cardiac specific changes were visualized by immunohistochemistry. We demonstrated that Imtb increased NF-κB/p65, IL-6, IL-1β, IL-18, MCP-1, HMGB1, as well as the expression and activity of MPO. Conversely, the expressions of antioxidant Nrf2 and HO-1 were decreased. Administration of BGP-15 effectively mitigated these inflammatory alterations by significantly reducing pro-inflammatory cytokines and MPO activity, while simultaneously restoring and enhancing the levels of Nrf2 and HO-1, thereby promoting antioxidant defenses. The immunohistochemical staining further supported these biochemical changes. Our study provides new and comprehensive biochemical insight for managing Imtb-induced inflammatory responses via BGP-15-induced PARP1 inhibition.

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