The Neuropharmacological Basis for the Use of Memantine in the Treatment of Alzheimer's Disease

Abstract

Memantine has been demonstrated to be safe and effective in the symptomatic treatment of Alzheimer's disease (AD). While the neurobiological basis for the therapeutic activity of memantine is not fully understood, the drug is not a cholinesterase in-hibitor and, therefore, acts differently from current AD therapies. Memantine can interact with a variety of ligand-gated ion channels. However, NMDA receptors appear to be a key target of memantine at therapeutic concentrations. Memantine is an uncompetitive (channel blocking) NMDA receptor antagonist. Like other NMDA receptor antagonists, memantine at high concentrations can inhibit mechanisms of synaptic plasticity that are believed to underlie learning and memory. However, at lower, clinically relevant concentrations memantine can under some circumstances promote synaptic plasticity and preserve or enhance memory in animal models of AD. In addition, memantine can protect against the excitotoxic destruction of cholinergic neurons. Blockade of NMDA receptors by memantine could theoretically confer disease-modifying activity in AD by inhibiting the "weak" NMDA receptor-dependent excitotoxicity that has been hypothesized to play a role in the progressive neuronal loss that underlies the evolving dementia. Moreover, recent in vitro studies suggest that memantine abrogates â-amyloid (Aâ) toxicity and possibly inhibits Aâ production. Considerable attention has focused on the investigation of theories to explain the better tolerability of memantine over other NMDA receptor antagonists , particularly those that act by a similar channel blocking mechanism such as dis-sociative anesthetic-like agents (phencyclidine, ketamine, MK-801). A variety of chan-275 nel-level factors could be relevant, including fast channel-blocking kinetics and strong voltage-dependence (allowing rapid relief of block during synaptic activity), as well as reduced trapping (permitting egress from closed channels). These factors may allow memantine to block channel activity induced by low, tonic levels of glutamate-an action that might contribute to symptomatic improvement and could theoretically protect against weak excitotoxicity-while sparing synaptic responses required for normal be-havioral functioning, cognition and memory.

Dimebon enhances hippocampus-dependent learning in both appetitive and inhibitory memory tasks in mice

“…the concentrations used in this study, which correspond to sub-threshold levels for receptor activation via a mono-target mechanism, are only able to evoke physiological effects by synergistic activation of several neurotransmitter systems (Youdim and Buccafusco, 2005;Cavalli et al, 2008). The memory-enhancing effects of dimebon may indicate simultaneous activity toward AMPA, NMDA, dopamine and serotonin receptors, all of which have been involved in inhibitory and appetitive hippocampus-dependent learning (Ungerer et al, 1998;Orsetti et al, 2001;Rogawski and Wenk, 2003;LaLumiere et al, 2003;Lynch and Gall, 2006;Balschun et al, 2006;Da Silva Costa et al, 2009;Benchenane et al, 2010). In particular, it has been hypothesised that dimebon's activity as a positive modulator of AMPA receptors and low affinity non-competitive blocker of NMDA receptors via a multi-drug mechanism, can explain the pro-cognitive action of this compound (Grigorev et al, 2003;Grigoriev 2009).…”

Rapid, concurrent alterations in pre- and postsynaptic structure induced by naturally-secreted amyloid-β protein

“…Two strategies already used clinically to enhance cognitive function in AD involve partial blockade of NMDA receptors using memantine (Rogawski and Wenk, 2003) or enhancement of cholinergic transmission using acetylcholinesterase inhibitors (Lleo, et al, 2006). The precise molecular targets of these pathways remain unknown, and AD-related studies in simple model systems present a complex picture.…”

Ketamine, But Not Phencyclidine, Selectively Modulates Cerebellar GABAAReceptors Containing α6 and δ Subunits

“…Binding and electrophysiological studies have demonstrated that PCP and MK-801 are superior noncompetitive inhibitors of, and have markedly higher affinity for, NMDA receptors than ketamine (Chen et al, 1959;Johnstone et al, 1959;Chen, 1965;McCarthy et al, 1965;Wong et al, 1986;MacDonald et al, 1991;Rogawski and Wenk, 2003). In addition, MK-801 block can occur across different membrane potentials, whereas PCP and ketamine inhibit NMDA receptors predominately at depolarized potentials (Halliwell et al, 1989;Dravid et al, 2007).…”

“…It has been established that dissociative anesthetics are noncompetitive inhibitors of NMDA excitatory ligand-gated ion channels (Lodge and Anis, 1982;Anis et al, 1983;MacDonald et al, 1987MacDonald et al, , 1991ffrench-Mullen and Rogawski, 1989;Rogawski and Wenk, 2003). These drugs also modulate the activity of nicotinic acetylcholine, muscarinic, and opioid receptors, and voltage-gated ion channels, but at significantly higher concentrations than needed to block NMDA receptors (Finck and Ngai, 1982;Ramoa et al, 1990;Hustveit et al, 1995;Hirota and Lambert, 1996;Scheller et al, 1996;Brau et al, 1997;Furuya et al, 1999;Flood and Krasowski, 2000;Yamakura et al, 2000;Schnoebel et al, 2005).…”