Memantine, an NMDA receptor antagonist, attenuates cardiac remodeling, lipid peroxidation and neutrophil recruitment in heart failure: A cardioprotective agent?

Abstract

In addition to their role in the central nervous system (CNS), N-methyl-d-aspartate (NMDA) receptors activation contributes to myocardial pathogenesis. This study sought to determine the potential cardioprotective effects of pre-treatment with memantine, an NMDA receptor antagonist, in heart failure (HF). A subcutaneous injection of isoproterenol (5 mg/kg/day) for 14 days was used for the induction of heart failure in rats. Memantine was injected intraperitoneally (ip) at doses of 5 and 20 mg/kg one week before isoproterenol injection for 21 days (n = 8 each group). Then, hemodynamic, electrocardiogram and histopathological changes as well as lipid peroxidation, myeloperoxidase (MPO) and adenosine monophosphate-activated protein kinase (AMPK) activity were evaluated. Histopathological analysis showed a marked attenuation of myocyte necrosis and fibrosis in memantine 20 mg/kg pre-treated group (p < 0.001) in comparison to HF group. Pre-treatment with memantine 20 mg/kg significantly reduced myocardial edematous, MPO activity and malondialdehyde (MDA) levels in comparison to HF group (p < 0.05, p < 0.05 and p < 0.001 respectively). Memantine had no significant effect on hemodynamic parameters and AMPK activity but improved the electrocardiogram (ECG) pattern. Our results for the first time showed cardioprotective effects of memantine in HF through reduction in cardiac remodeling, lipid peroxidation and neutrophil infiltration. In addition these effects are through an AMPK-independent pathways.

Keywords: AMPK; Cardiac remodeling; Heart failure; Isoproterenol; Lipid peroxidation; Memantine; Neutrophil.