Contents lists available at ScienceDirect Chemico-Biological Interactions journal homepage: www.elsevier.com/locate/chembioint Studies on the interaction of NMDA receptor antagonist memantine with cell membranes: A mini-review Pablo Zambrano a,* , Mario Suwalsky a , Malgorzata Jemiola-Rzeminska b,c , Kazimierz Strzalka b,c a Faculty of Chemical Sciences, University of Concepción, Concepción, Chile b Malopolska Centre of Biotechnology, Jagiellonian University, Kraków, Poland c Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland ABSTRACT Memantine is an NMDA receptor antagonist clinically used for the treatment of moderate to severe Alzheimer's disease. Currently, it is the only NMDA receptor antagonist drug marketed against this disease. Despite the large number of publications regarding its clinical and therapeutic use, studies related to its mechanism of action are still inconclusive. Knowledge of drug interactions with cell membranes may lead to the development of novel drugs for neurodegenerative diseases. The present mini-review aims to give an overview of the latest findings regarding the interaction of memantine with cell membranes, specifically with that of the human erythrocyte. 1. Introduction Alzheimer's disease (AD) is one of the most common neurodegen- erative pathologies for which no effective cure has been found. In the United States approximately 5 million people over 65 years of age suffer from this disease [1]. It is expected that by the year 2050 about one million new cases will appear each year and the estimated total pre- valence may reach 13.8 millions of affected patients [2]. The AD etiology is multifactorial and includes genetic and environmental components. There are many theories that describe the pathogenesis of AD. Among the most accepted is the intraneuronal accumulation of Ca 2+ resulting in neurodegeneration and cellular apoptosis [3–5]. NMDA receptors are a subtype of glutamate receptors that are involved in regulating synaptic neuroplasticity and the intracellular influx of calcium, playing an important role in memory and learning [6–9]. NMDA receptors contribute to the intracellular Ca 2+ homeostasis and modulate the oxygen supply to the peripheral tissues. Any alteration of the activity of this receptor by an agonist or antagonist causes an al- teration of the ion flow through the channel. Therefore, uncontrolled activation of the receptor results in a transient accumulation of in- tracellular Ca 2+ inducing cellular contraction and alteration in in- tracellular pH [10]. Memantine (3,5-dimethyladamantan-1-amine, Fig. 1) is an NMDA receptor antagonist clinically used for the treatment of moderate to severe AD. This drug is thought to function by preferentially blocking reversibly open NMDA channels [11,12]. Several randomized studies have been conducted to determine the efficacy of memantine in AD [13–15]. According to the main results, memantine monotherapy sig- nificantly improves various aspects of the disease such as behavior, activities of daily living and global function. However, it has been found that the efficacy of the drug is small and there is limited evidence of its clinical benefit[16,17]. Despite the large number of clinical studies on the use of memantine in AD, data on its interaction with human cell membranes are scarce. Previous studies have proposed qualitative models on the reaction kinetics and molecular orientation in lipid bilayers [18]. On the other hand, studies have been carried out on the deformability of the red blood cell membrane in experimental an- imals with inconclusive results [19,20]. The objective of this mini-re- view is to report the existing information regarding the interaction of memantine with cell membranes, and its effect on the human ery- throcyte membrane. 2. Interaction of memantine with NMDA receptor NMDA receptors are not only present in neural membranes, they also exist in other cell types such as erythrocytes [21]. This receptor is activated in the presence of glutamate, which is the main excitatory substance of the central nervous system. However, glutamate does not act individually as the presence of glycine is required to activate the NMDA receptor [22–24]. Despite the variety of reports and structural https://doi.org/10.1016/j.cbi.2018.01.022 Received 10 August 2017; Received in revised form 15 January 2018; Accepted 26 January 2018 * Corresponding author. E-mail address: pzambranol@udec.cl (P. Zambrano). Abbreviations: NMDA, n-methyl-d-aspartate; DPPC, dipalmitoylphosphatidylcholine; DPPG, dipalmitoylphosphatidylglycerol; DMPC, dimyristoylphosphatidylcholine; DMPE, dimyr- istoylphosphatidylethanolamine; SEM, scanning electron microscopy; DSC, differential scanning calorimetry; MLV, multilamellar liposome Chemico-Biological Interactions 283 (2018) 47–50 0009-2797/ © 2018 Elsevier B.V. All rights reserved. T