pregabalin and Cardiotoxicity

We investigated the antioxidant, anti-inflammatory and anti-apoptotic effects of pregabalin (PREG) on lipopolysaccharide (LPS) induced sepsis related cardiotoxicity via NF-kβ pathways. We used 24 female Wistar albino rats divided into three groups: control, LPS treated and LPS + PREG treated. Total oxidant status (TOS), total antioxidant status (TAS), oxidative stress index (OSI), tumor necrosis factor alpha (TNF-α), nuclear factor kappa beta (NF-kβ)/p65, p-NF-kβ/p65, caspase-3 (Cas-3) and cleaved Cas-3 were measured in cardiac tissues and creatine kinase MB (CKMB), aspartate aminotransferase (AST), lactate dehydrogenase (LDH) levels were measured in blood samples. Also, Cas-3, granulocyte-colony stimulating factors (G-CSF), interleukin-6 (IL-6), serum amyloid A (SAA) and inducible nitric oxide synthase (iNOS) were measured immunohistochemically in heart and aorta tissue. In the LPS group; the levels of CKMB, AST, LDH, TOS, OSI increased and TAS decreased. TNF-α, p-NF-kβ/p65 and Cas-3 protein levels also increased in the LPS group. Immunohistochemical evaluation of the heart and aorta revealed a significant increase in the levels of Cas-3, G-CSF, SAA, IL-6 and iNOS in the LPS group. PREG treatment restored all measurements to near normal. LPS induced cardiovascular toxicity was due to inflammation, oxidative stress and apoptosis. PREG ameliorated the damage by inhibition of NF-kβ phosphorylation.

Topics: Animals; Cardiotoxicity; Female; Humans; Lipopolysaccharides; NF-kappa B; Nitric Oxide Synthase Type II; Oxidative Stress; Pregabalin; Rats; Tumor Necrosis Factor-alpha

Pregabalin (PRG) possesses great therapeutic benefits in the treatment of epilepsy, neuropathic pain, and fibromyalgia. However, clinical data have reported incidence or exacerbation of heart failure following PRG administration. Experimental data exploring cardiac alterations and its underlying mechanisms are quite scarce. The aim of the present work was to investigate the effect of PRG on morphometric, echocardiographic, neurohumoral, and histopathological parameters in rats. It was hypothesized that alterations in cardiac renin angiotensin system (RAS) might be involved in PRG-induced cardiotoxicity. To further emphasize the role of RAS in the mechanism of PRG-induced cardiotoxicity, the protective potential of diminazene aceturate (DIZE), an ACE2 activator, was investigated. Results showed 44% decrease in ejection fraction and sevenfold increase in plasma N-terminal pro-brain natriuretic peptide. Histopathological examination also showed prominent vacuolar changes and edema in cardiomyocytes. In addition, PRG significantly increased angiotensin II (Ang II), angiotensin converting enzyme (ACE) and angiotensin II type 1 receptor (AT1R) levels, while decreased angiotensin 1-7 (Ang 1-7), angiotensin converting enzyme 2 (ACE2), and Mas receptor (MasR) cardiac levels. DIZE co-administration showed prominent protection against PRG-induced echocardiographic, neurohumoral, and histopathological alterations in rats. In addition, downregulation of ACE/Ang II/AT1R and upregulation of ACE2/Ang 1-7/MasR axes were noted in DIZE co-treated rats. These findings showed, for the first time, the detailed cardiac deleterious effects of PRG in rats. The underlying pathophysiological mechanism is probably mediated via altered balance between the RAS axes in favor to the ACE/Ang II/AT1R pathway. Accordingly, ACE2 activators might represent promising therapeutic agents for PRG-induced cardiotoxicity.

Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme 2; Animals; Biomarkers; Cardiotoxicity; Cyclic AMP-Dependent Protein Kinases; Heart Diseases; Male; Myocytes, Cardiac; Natriuretic Peptide, Brain; Peptide Fragments; Peptidyl-Dipeptidase A; Phosphatidylinositol 3-Kinase; Pregabalin; Proto-Oncogene Mas; Proto-Oncogene Proteins; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Receptors, G-Protein-Coupled; Renin-Angiotensin System; Signal Transduction; Stroke Volume; Ventricular Function, Left