Dose-dependent administration of quetiapine induces myocardial damage associated with altered cGAS-STING-TBK1-IRF3 and Nrf-2/Keap-1 gene expression.

Quetiapine (QTP) is an atypical antipsychotic drug commonly prescribed for psychiatric illnesses, which have been linked to a range of cardiovascular side effects. However, molecular mechanisms underlying QTP-induced cardiotoxicity are not yet thoroughly understood. The current investigation was conducted to evaluate QTP-mediated cardiotoxicity at varying dose administrations. Thirty-two rats were randomly divided into four groups including the control group, QTP (20 mg/kg), QTP (55 mg/kg), QTP (100 mg/kg) by oral gavage for 28 days. Echocardiographic and electrocardiographic evaluations of cardiac function were performed and levels of cardiac injury, oxidative stress, inflammatory and apoptotic markers were determined. QTP intoxication increased the mRNA expression of MB21D1, TMEM173, TBK1, IRF3, IFNB1, and ISG15 and antioxidant responses (NFE2L2, HMOX1, NQO1, GCLC, GCLM), while decreasing KEAP1 expression, indicating transcriptional alterations in genes associated with innate immune and antioxidant defense pathways. Exposure to QTP triggered oxidative imbalances which were clearly progressive and were associated with a decrease in the activities of GST, CAT, SOD, GPx, GSR, GSH and HO-1 and increase in the levels of ROS and MDA. There was evidence of progressive impairment of LV systolic function by echocardiographic analysis characterized by elevated levels of LVEDD, LVESD, EDV and ESV. QTP intoxication induces ventricular repolarization (long QT, QTc, JT-peak, T-peak-Tend) and associated tachycardia (high heart rate). Furthermore, QTP administration provoked the levels of cTnI, cTnT, CK, CK-MB, and LDH at all the administered doses. The levels of NF-κB, TNF-α, IL-1β, IL-6 and COX-2 enhanced QTP administration. Similarly, QTP exposure augmented the levels of Bax, Caspase-9, and Caspase-3 while suppressing the levels of Bcl-2. Histopathological analysis showed dose dependent QTP-mediated myocardial degeneration, necrosis, inflammatory infiltration, edema and vascular congestion. These findings indicate that QTP administration causes dose-dependent cardiotoxicity through oxidative imbalance, innate immunity and inflammatory responses, apoptosis, electrophysiological abnormalities, functional impairment, progressive myocardial structural damage and altered expressions of key regulatory genes. Further mechanistic and pharmacokinetic investigations are needed to establish the clinical relevance of these findings.