Brexpiprazole induces acute cardiotoxicity via disrupting calcineurin/NFAT and calcium signaling pathway: A validation from biochemical, echocardiographic, histological, and computational analysis.

Brexpiprazole (BPZ) is a third-generation atypical antipsychotic drug that is reported to induce various organ toxicity in non-target organisms. The current investigation was conducted to explore the dose-dependent toxicity of BPZ on cardiac tissues. Thirty-six rats were divided into four groups including control, BPZ (3 mg/kg), BPZ (10 mg/kg), and BPZ (30 mg/kg) treated group. BPZ intoxication compromised mRNA expressions of Calcineurin/NFAT and Calcium Signaling Pathway as evidenced by increased expression of protein phosphatase 3 catalytic subunit alpha (PPP3CA), nuclear factor of activated T cells, cytoplasmic 3 (NFATC3), regulator of calcineurin 1 (RCAN1), and phospholamban (PLN) while downregulating the expression of Ryanodine receptor 2 (RYR2), calcium voltage-gated channel subunit alpha c (CACNA1C), ATPase sarcoplasmic/endoplasmic reticulum Ca transporting 2 (SERCA2). Oxidative stress was clearly observed given the level of reactive oxygen species (ROS) and malondialdehyde (MDA) was markedly elevated coupled with significant inhibition of endogenous antioxidant enzymes including, heme oxygenase-1 (HO-1), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GSR), reduced glutathione (GSH) and glutathione S-transferase (GST) after BPZ intoxication. Functional cardiac impairment was further corroborated by significant changes occurring in echocardiographic parameters of myocardial impairment and ventricular dysfunction following the exposure of BPZ. Consistently, BPZ administration provoked the levels of creatine phosphokinase (CPK), B-type natriuretic peptide (BNP), N-terminal pro-B-type natriuretic peptide (NT-proBNP), C-reactive protein (CRP), lactate dehydrogenase (LDH), creatine kinase-myocardial band (CK-MB), cardiac troponin I (cTnI) and cardiac troponin T (cTnT). Higher BPZ doses (10 and 30 mg/kg) triggered apoptotic imbalance, i.e., an increase in Cysteine-aspartic acid protease-3 (Caspase-3), Cysteine-aspartic acid protease-9 (Caspase-9), Bcl-2-associated X protein (Bax), while a significant reduction in the levels of B cell lymphoma-2 (Bcl-2). Histopathological evaluation showed severe myocardial damage in cardiac morphology following the intoxication of BPZ. In silico analyses supported these results showing binding affinity of BPZ with important key regulatory proteins. Collectively, the obtained data suggest that long-term exposure to BPZ results in cardiotoxicity mediated by oxidative stress, inflammation, apoptosis, and functional cardiac dysfunction.