Levetiracetam elicits sub-chronic cardiotoxicity via modulating TLR4/MyD88 and NF-κB signaling axis: Mechanistic...

Levetiracetam (LTM) is a commonly used anti-epileptic medication, however its possible cardiovascular (CV) risks are poorly characterized. The present study aimed to investigate the dose-dependent cardiac toxicity induced by LTM in Sprague-Dawley (SD) rats through the assessment of inflammatory signaling, oxidative stress, apoptosis, functional impairment and structural damage. Thirty-six male albino SD rats were randomly distributed into four groups (n = 9) namely the control, LTM (25 mg/kg), LTM (50 mg/kg), and LTM (150 mg/kg). LTM administration significantly increased the expressions of toll-like receptor-4 (TLR4) signaling cascade, as indicated by significant upregulation of myeloid differentiation factor-88 (MyD88), interleukin-1 receptor-associated kinase-4 (IRAK4) and tumor necrosis factor receptor-associated factor-6 (TRAF6). Similarly, there was a paradoxical increase in the expression of nuclear factor kappa B inhibitor alpha (IκBα) in parallel with enhanced activation of nuclear factor-kappa B (NF-κB) which culminated in increased production of pro-inflammatory mediators such as tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), interleukin 1 beta (IL-1β), and cyclooxygenase-2 (COX-2). Oxidative stress was marked, as shown by higher levels of reactive oxygen species (ROS), malondialdehyde (MDA) with inhibition of antioxidant enzymes such as heme oxygenase-1 (HO-1), catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GSR) and glutathione-S-transferase (GST) following LTM exposure. LTM intoxication promoted the concentrations of serum creatine phosphokinase (CPK), creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH), troponin I, troponin T, B-type natriuretic peptide (BNP), N-terminal pro-B-type natriuretic peptide NT proBNP and C-reactive protein (CRP) in a dose-dependent manner. Moreover, LTM intoxication altered echocardiographic parameters including reduced ejection fraction (EF), heart rate (HR), dilation of left ventricle, and increased ventricular diameter. The levels of Bcl-2 associated X protein (Bax), cysteine-aspartic proteases-3 (caspase-3) and cysteine-aspartic proteases-9 (caspase-9) were increased, accompanied by reduced levels of B-cell lymphoma-2 (Bcl-2) in response to all the tested doses of LTM. Collectively, these findings show that LTM induces cardiotoxicity through modulation of the TLR4/NF-κB-mediated inflammation, oxidative stress, and apoptosis in a dose-dependent manner.