Varenicline as a cardioprotective agent against doxorubicin-induced toxicity: A study on apoptotic, TLR4/NF-κB, and inflammasome/caspase-1/IL-1β pathway modulation in a rat model

Doxorubicin-induced cardiotoxicity represents a significant challenge in oncology, impacting treatment efficacy and patient quality of life. The search for cardioprotective agents that preserve anticancer efficacy remains ongoing. Varenicline, a prescription medication commonly used to treat smoking addiction, showed promising outcomes in modulating inflammatory responses, indicating a potential protective role against doxorubicin-induced cardiac injury. This study investigates varenicline's cardioprotective effects on doxorubicin-induced cardiotoxicity, focusing on inflammatory and apoptotic signaling pathways.

In this study, rats were divided into five experimental groups: control (Saline), a varenicline-only group (100 μg/kg/day), a doxorubicin-only group (2.5 mg/kg every 48 h for eight doses), and two combination groups receiving doxorubicin with either a high (100 μg/kg/day) or low (50 μg/kg/day) dose of varenicline, over 18 days.

ECG analysis indicated that doxorubicin treatment caused significant disruptions, including ST-segment elevation and prolonged QT intervals, along with elevated levels of cTnT and CK-MB, signifying cardiac injury. Doxorubicin treatment also significantly increased pro-inflammatory and apoptotic markers such as TLR4, Bax, TNF-α, NF-κB, TRAF-6, IL-1β, and IL-6, while activating inflammasome components like NLRP3 and elevating the Bax/Bcl-2 ratio and caspase-3 activity along with decreasing the expression of α7-nAchR. In contrast, varenicline co-treatment improved ECG parameters, reduced TLR4 and NF-κB levels, attenuated pro-apoptotic markers, and increased α7-nAchR expression, highlighting its potential as a therapeutic agent for mitigating doxorubicin-induced cardiotoxicity.

In conclusion, varenicline demonstrates protective effects by modulating inflammatory and apoptotic pathways, improving cardiac function and electrical stability. Therefore, we suggest that varenicline may be a potential therapeutic agent for mitigating doxorubicin-induced cardiotoxicity.