Neuropharmacology 53 (2007) 699e723

www.elsevier.com/locate/neuropharm

Review

Memantine: a NMDA receptor antagonist that improves memory by

restoration of homeostasis in the glutamatergic system - too little
activation is bad, too much is even worse
Chris G. Parsons, Albrecht Stöffler, Wojciech Danysz*
Merz Pharmaceuticals, Eckenheimer Landstrasse 100, 60318 Frankfurt am Main, Germany
Received 30 January 2007; received in revised form 19 June 2007; accepted 17 July 2007

Abstract

The neurotransmitter glutamate activates several classes of metabotropic receptor and three major types of ionotropic receptor e a-amino-3-
hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), kainate and N-methyl-D-aspartate (NMDA). The involvement of glutamate mediated
neurotoxicity in the pathogenesis of Alzheimer’s disease (AD) is finding increasing scientific acceptance. Central to this hypothesis is the as-
sumption that glutamate receptors, in particular of the NMDA type, are overactivated in a tonic rather than a phasic manner. Such continuous,
mild, chronic activation ultimately leads to neuronal damage/death. Additionally, impairment of synaptic plasticity (learning) may result not only
from neuronal damage per se but may also be a direct consequence of this continuous, non-contingent NMDA receptor activation. Complete
NMDA receptor blockade has also been shown to impair neuronal plasticity, thus, both hypo- and hyperactivity of the glutamatergic system
leads to dysfunction.
Memantine received marketing authorization from the EMEA (European Medicines Agency) for the treatment of moderate to severe AD in
Europe and was subsequently also approved by the FDA (Food and Drug Administration) for use in the same indication in the USA. Memantine
is a moderate affinity, uncompetitive NMDA receptor antagonist with strong voltage-dependency and fast kinetics. This review summarizes
existing hypotheses on the mechanism of action (MOA) of memantine in an attempt to understand how the accepted interaction with NMDA
receptors could allow memantine to provide both neuroprotection and reverse deficits in learning/memory by the same MOA.
Ó 2007 Elsevier Ltd. All rights reserved.

Keywords: Memantine; NMDA; Alzheimer’s disease; LTP; Learning; Memory; Symptomatic

1. Introduction namely, the glutamatergic N-methyl-D-aspartate (NMDA) re-

The ability to maintain homeostasis, which assures an opti-
mal physiological balance, is a basic feature of all living organ-
isms and is normally achieved by the presence of opposing
dynamic mechanisms, e.g. antagonistic muscles or the sym-
pathetic and parasympathetic vegetative systems. Such an opti-
mal balance is particularly important for very sensitive organs
such as the central nervous system (CNS). In the present
review, the authors describe one very vivid example of such
an obligatory balance between activation and inhibition,
* Corresponding author. Tel.: þ49 69 150 35 64; fax: þ49 69 596 21 50.
E-mail address: wojciech.danysz@merz.de (W. Danysz).
ceptor (Figs. 1 and 2). It is well recognised that blockade of
NMDA receptors leads to impairment of neuronal plasticity
(learning) (Collingridge and Bliss, 1995) while their overacti-
vation leads to cell death due to calcium overload (Choi,
1992). There is however, clear evidence, that dysfunctional
overactivation of NMDA receptors may also lead to disturbances
of plasticity, even before the development of overt excitotoxicity.
Acceptance and understanding of this principle e as indicated in
the title e is crucial for understanding the cognition-improving
effects of the NMDA receptor antagonist memantine in
Alzheimer’s disease (AD).
Memantine was approved several years ago for the treat-
ment of mild-severe to severe AD (2002 EU, 2003 USA)

0028-3908/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.neuropharm.2007.07.013
700 C.G. Parsons et al. / Neuropharmacology 53 (2007) 699e723

Channel blockers Agonists Coagonists

Glutamate Glycine
M Memantine NMDA D-serine
Na+/ Ca2+
+ Mg 2+

Antagonists
SH Modulators
D-AP5
Polyamines
5,7-DCKA
Ifenprodil Zn2+
NR2B NR1
M
Histamine

+ SH Redox
N N
Pregnenolone

NR2A NR1

NR1 NR2B
K+

Fig. 1. Schematic of the topology and pharmacological recognition sites of NMDA receptors. Two major subunit families designated NR1, NR2 as well as a minor
modulatory subunit designated NR3 have been cloned. Functional receptors in the mammalian CNS are, almost certainly, only formed by tetrameric assemblies of
two NR1 and two NR2 subunits which express the glycine and glutamate recognition sites, respectively (Hirai et al., 1996; Laube et al., 1997). NR3 (NRL or Chi-1)
is expressed predominantly in the developing CNS and does not seem to form functional homomeric glutamate-activated channels but co-expression of NR3 with
NR1 and NR2 subunits decreases response magnitude (Sucher et al., 1995; Kinsley et al., 1999). There are four known subtypes of NR2 (A, B e illustrated, C and
D) and eight splice variants of NR1. Binding of agonists such as glutamate and NMDA and co-agonists such as glycine and D-serine to both recognition sites on the
receptor subunit assembly are required for receptor activation. Competitive antagonists such as D-AP5 and glycine antagonists such as 5,7-DCKA (5,7-dichloro-
kynurenic acid) bind to recognition sites, which may be distinct to the agonist recognition sites but isosterically tightly coupled in such a way as to give a com-
petitive interaction. All NMDA receptors are permeant to Ca2þ, Naþ and Kþ. The open NMDA channel is blocked by Mg2þ and uncompetitive NMDA receptor
antagonists such as memantine and (þ)MK-801 in a voltage-dependent manner although the potency, speed and voltage-dependence of this effect depends on
antagonist affinity and subunit composition. There are similarities in the channel domain of NMDA and non-NMDA receptors and mutations at the Q/R site
responsible for determining Ca2þ permeability of AMPA/kainate receptors also influence the potency of channel blockers of the NMDA receptor at the asparagine
N-site. Polyamines such as spermine and spermidine are positive modulators binding to NR2B subunits but also block the channel at higher concentrations. Ifen-
prodil is the prototypic ‘‘selective‘‘ antagonist for NR2B containing receptors. Zn2þ is a potent, voltage-independent antagonist at NR2A containing receptors. In
addition, most NMDA receptors are influenced by Zn2þ ions in a voltage-independent manner and by redox, histamine and steroids.

and since this time is on the market in Europe, USA and many
countries in the world.
Treatment with AchEIs (Acetylcholinesterase Inhibitors)
was found to be efficacious in numerous randomized con-
trolled trials (RCTs) and meta analyses but there was consen-
sus that the magnitude of effects is limited and, depending on
the response criteria used, that a considerable portion of pa-
tients do not respond (Lanctot et al., 2003; Burns et al.,
2006; Birks, 2006). If improvement of at least two points in
the Mini-Mental State Examination (MMSE) is required for
the definition of response, less than 20% of patients were clas-
sified as responders after 9 months of treatment (Raschetti
et al., 2005). With the advent of memantine a new therapeutic
treatment was offered. It is likely, that because of the different
mechanism of action (MOA) of memantine such patients
would respond to this therapy, although, this has not been sys-
tematically studied.
Memantine’s mechanism of action, which differs from the
major alternative therapies in AD which are all AchEIs, is
also a clear rationale for combination therapy. Additionally,
the most frequent side-effects of AchEIs (nausea, vomiting,
and diarrhoea) are not shared by memantine and are linked
to the actions of AchEIs on peripheral cholinergic synapses.
They may present in more than 10% of patients and may
also lead to treatment discontinuation due to tolerability
problems in clinical trials, usually with a frequency of about
twice that for placebo (for an overview see package inserts
of marketed AchEIs or Thompson et al. (2004); Takeda
et al. (2006); Birks (2006)). Combination of memantine and
AchEIs has been reported to produce enhanced therapeutic ef-
fects over AchEIs monotherapy (Hartmann and Mobius, 2003;
Tariot et al., 2004; Gauthier et al., 2005; Dantoine et al., 2006;
van Dyck et al., 2006; Cummings et al., 2006).
Memantine is an NMDA receptor channel blocker and this
MOA for an anti-dementia drug is, at first sight, not easy to
comprehend bearing in mind the accepted crucial permissive
role of NMDA receptors in synaptic plasticity (Morris et al.,
1986; Herron et al., 1986; Danysz et al., 1995; Collingridge
and Bliss, 1995). This apparent paradox can be explained by
bringing analogy to magnesium, the endogenous NMDA re-
ceptor antagonist, which is vital for normal neuronal function-
ing and for neuronal plasticity (Nowak et al., 1984; Coan
et al., 1989; Parsons et al., 1999b; Danysz and Parsons,
2003). The present review is aimed at elaborating this apparent
paradox and providing a plausible hypothesis based on our
current knowledge of memantine’s pharmacology and pharma-
cokinetics. A number of previous reviews on memantine have
been published tackling different preclinical and/or clinical
aspects (Danysz et al., 1997, 2000; Parsons et al., 1999b;
Molinuevo, 2003; Ferris, 2003; Danysz and Parsons, 2003;
 C.G. Parsons et al. / Neuropharmacology 53 (2007) 699e723 701

NR1111 NR2
NH2 NH2
S1 S2 S1 S2
N1

M M M M M M
1 3 4 1 3 4

N N
M M
2 2

P
HOOC
C2
C1 COOH
Glycine P
Glutamate

N asparagine 598 N asparagine 595/596

S1 - glycine binding site S1 - glutamate binding site

S2 - glycine binding site S2 - glutamate binding site

P Phosphorylation by PKA (serine 897)
P Phosphorylation by CaMKII (serine 1303)
and by PKC (serine 890,896)

Splices

Fig. 2. Schematic of the topology and pharmacological recognition of individual NMDA receptor subunits. NR1 and NR2 subunits have four membrane-inserted
domains. M1, M3 and M4 are all true transmembrane domains (TMD) whereas M2 makes a hairpin bend and forms the narrowest channel domain containing an
asparagine residue (N) at the Q/R/N site which determines channel permeation/block by cations. This residue is found at position 598 on NR1 subunits and position
595 or 596 on NR2 subunits and is believed to experience 80% of the transmembrane electric field. The agonist recognition site or ligand binding domain (LBD) is
formed by a ‘‘Venus fly trap’’ juxtaposition of an S1 site on the extracellular domain attached to M1 and an S2 site on the extracellular loop between M3 and M4
for both NR1 and NR2 subunits. Alternative splicing generates eight isoforms for the NR1 subfamily. The variants arise from splicing at three exons: one encodes
a 21-amino acid insert in the N-terminal domain (N1, exon 5), and two encode adjacent sequences of 37 and 38 amino acids in the C-terminal domain (C1, exon 21
and C2, exon 22). Rat NR1 variants are sometimes denoted by the presence or absence of these three alternatively spliced exons (N, C1 and C2). NR1111 has all
three exons, NR1000 has none, and NR1100 has only the N-terminal exon. The most common forbrain splice variant in the adult rat CNS is NR1011. Additionally,
receptor function/trafficking, etc., can be influenced by phosphorylation by PKA, PKC and CaMKII as well as by glycosylation.

Rogawski and Wenk, 2003; Lipton, 2006; Wenk et al., 2006;
Bullock, 2006). For aspects not covered by the present review,
e.g. details of studies related to neuroprotection or aspects out-
side of the indication dementia, readers are encouraged to use
the comprehensive reviews.
Table 1 chronologically lists milestones in the development
of our knowledge related to memantine focusing on, or sup-
portive for, symptomatological actions in AD which is the cur-
rent therapeutic label.
Since the present review discusses mechanisms of meman-
tine-induced positive (symptomatological) effects on cognition
in dementia, evidence that such an effect has indeed been
proven in placebo controlled clinical trials is crucial. The ef-
fects of memantine on cognition in AD and vascular dementia
have been investigated in more than 3000 patients. A number
of randomized controlled clinical trials in the indications of
AD and vascular dementia were performed in the last decade
that assessed cognition using standard performance-based in-
struments. Apart from a cognitive benefit, these clinical trials
also showed positive effects of memantine upon activities of
daily living and behavioural disturbances of the AD patients
as compared to placebo (Doody et al., 2004; Gauthier et al.,
2005; Cummings et al., 2006).
Cognitive performance was measured by the cognitive sub-
scale of the Alzheimer’s Disease Assessment Scale (ADAS-
cog; Rosen et al., 1984) in the studies in mild-to-moderate
AD as well as in the vascular dementia studies. In the moder-
ate-to-severe AD studies the Severe Impairment Battery (SIB;
Saxton et al., 1993; Schmitt et al., 1996) was used, which was
specifically developed to measure cognition in more advanced
stages of AD. Two vascular dementia studies (Orgogozo et al.,
2002; Wilcock et al., 2002) showed a statistically significant
better cognitive performance vs. placebo after 6 months of
treatment (while the effects on the clinical global ratings of
change were not significant).
In AD, six, 6-month Phase III trials were conducted in the
USA and Europe ((Reisberg et al., 2003; Tariot et al., 2004;
Bakchine et al., 2005; Peskind et al., 2006); for two trials,
MD-01 and MD-12, see Forest Labs, Clinical Trials Registry).
All studies showed a strong tendency for improvement by
memantine treatment over placebo, while three demonstrated
clear statistical significance, and the beneficial effects on cog-
nition were also obvious in various meta analyses (Doody
et al., 2005; McShane et al., 2006). For two of the AD trials
(Reisberg et al., 2003; Tariot et al., 2004), the cognitive effects
are reviewed in more in detail in separate papers (Schmitt
702 C.G. Parsons et al. / Neuropharmacology 53 (2007) 699e723

Table 1
Development of knowledge and concepts on memantine (focus on cognitive effect in dementia)
Year Finding References
1963 First description of memantine as part of a synthetic pathway. Gerzon et al. (1963)
1989 Inhibition of [3H]MK-801 binding by memantine in human postmortem cortical tissue. Kornhuber et al. (1989)
Description of NMDA antagonistic activity of memantine in patch clamp experiments. Bormann (1989)
1991 Description of positive effects of memantine on cognition in demented patients. Ditzler (1991)
1993 Importance of voltage-dependency of memantine for clinical tolerability postulated and Parsons et al. (1993)
similarity to the endogenous NMDA antagonist Mg2þ emphasized. Signal-to-noise concept
as an explanation for symptomatic improvements in AD discussed for the first time.
1993 Review emphasizing importance of affinity for tolerability of memantine and related agents. Rogawski (1993)
1994 Demonstration of behavioural differences between memantine and high affinity NMDA Danysz et al. (1994)
channel blockers.
1994 Demonstration of NMDA antagonism in an in vivo preparation. Herrero et al. (1994)
1994 Study showing free brain memantine levels close to affinity at NMDA receptors. Spanagel et al. (1994)
1995 Data on concentration of memantine in plasma and CSF of patients. Kornhuber and Quack (1995)
1995 Comparison of a series of NMDA channel blockers emphasizing the importance of voltage-dependency Parsons et al. (1995)
and kinetics.
1996 Study showing that memantine may improve neuronal plasticity and learning in old animals. Barnes et al. (1996)
1996 Demonstration that memantine is relatively less potent in blocking neuronal plasticity (LTP) than Frankiewicz et al. (1996)
NMDA receptors as compared to the high affinity NMDA antagonist MK-801.
1996 Demonstration of learning enhancement in rats with learning deficit produced by entorhinal cortex lesion. Zajaczkowski et al. (1996b)
1997 Review describing non-published and published data on the in vitro activities of memantine at numerous Danysz et al. (1997)
receptors and relating pharmacokinetics of memantine to pharmacodynamics.
1997 Importance of partial trapping for tolerability of memantine proposed. Blanpied et al. (1997)
1997 Experimental basis for the concept that overactivation of NMDA receptors impairs neuronal plasticity Zajaczkowski et al. (1997)
(LTP) and learning which are restored by memantine, as suggested through a decrease in synaptic noise.
1998 Efficacy shown in mixed vascular and Alzheimer dementia patients. Winblad and Poritis (1998)
1999 Noise reduction hypothesis of memantine symptomatological action substantiated by experiments showing Frankiewicz and Parsons (1999)
restoration of synaptic plasticity (LTP) under low-magnesium concentrations.
1999 Quantitative analysis of relation between memantine plasma, CSF, ECF and brain homogenates concentration Hesselink et al. (1999a)
using in vivo recovery.
1999 Review describing pharmacology of memantine and hypothesis on the mechanism of action. Parsons et al. (1999b)
2000 Description of the signal-to-noise hypothesis explaining both neuroprotective and symptomatological effects Danysz et al. (2000)
of memantine.
2001 Support for voltage-dependent NMDA channel blockade by memantine in vivo. Jones et al. (2001)
2003 Review on proposed MOA of memantine. Danysz and Parsons (2003)
2003 Study showing cognitive improvement vs. placebo in AD patients treated with memantine. Reisberg et al. (2003)
2003 Review on proposed MOA of memantine. Rogawski and Wenk (2003)
2004 Memantine shown to improve spatial learning in transgenic (PS1/Aß) mice. Minkeviciene et al. (2004)
2004 Memantine showed no change of AchE inhibition by rivastigmine and donepezil in vivo. Enz and Gentsch (2004),
Periclou et al. (2004)
2006 Memantine improves water radial maze learning in rats. Zoladz et al. (2006)

et al., 2002, 2006). It is an open issue whether some of the
effects on cognition may be attributed to a disease-modifying
effect of memantine (slowing of decline). But in Reisberg and
Tariot trials (Reisberg et al., 2003; Tariot et al., 2004) there
was a separation in SIB scores from placebo already after
12 and 8 weeks, respectively, and this is indicative of an early
symptomatic benefit on cognition for memantine treatment vs.
placebo.
Rammsayer and colleagues (Rammsayer, 2001) reported
that memantine impaired object recognition but not face rec-
ognition performance in healthy volunteers. This, at first
glance seems, to contradict the hypothesis discussed below.
However, two factors should be taken into account. First, the
study was performed in healthy volunteers, not AD patients
with presumed glutamatergic hyperactivity. In turn, since there
was no hyperfunction to correct, this is a plausible reason for
the lack of positive effects. Second, in contrast to typical clin-
ical use where the daily dose of 20 mg/day is achieved follow-
ing a 4-week titration, in the study by Rammsayer and
colleagues an acute dose of 30 mg was used. Note that both
in LTP experiments and in in vivo studies in experimental an-
imals memantine showed a bell-shaped doseeresponse curve,
showing even impairment at the higher doses (Frankiewicz
and Parsons, 1999; Zajaczkowski et al., 1997). Thus, it is
likely that given the ‘‘lack of pathological conditions’’, the
higher dose used, and the lack of up-titration, the effects
seen reflect the right end of the bell-shaped doseeresponse
curve with memantine.
In summary, these clinical data provide clear evidence that
memantine is able to improve cognition in demented patients
relative to placebo.
2. PDePK relationship e possible memantine targets
2.1. NMDA receptors
Memantine inhibits NMDA receptors at near resting mem-
brane potentials with an approximate affinity of 1 mM (Parsons
 C.G. Parsons et al. / Neuropharmacology 53 (2007) 699e723
et al., 1999b). The correspondence between pharmacody-
namics (PD, in vitro targets) and pharmacokinetics (PK, extra-
cellular levels in the brain) is a prerequisite to claim any
therapeutic MOA. In other words, active doses both in clinical
studies and in animal models should lead to levels at the locus
of action (here, the central nervous system, CNS), which are
close to the concentrations active at the claimed target (here,
NMDA receptors). This is especially the case for ionotropic
receptors where factors such as receptor reserve seem to be
less pronounced than for other targets such as G-protein cou-
pled receptors (GPCRs).
Microdialysis experiments, with in vivo recovery correc-
tions, are the best method to access free extracellular levels
in the brain. Following administration of behaviourally active
doses in rats, e.g. infusion of 20 mg/kg/d using Alzet osmotic
pumps (for review see e.g. (Danysz et al., 1997; Parsons et al.,
1999b)), free extracellular levels in the brain are similar to free
plasma levels (Hesselink et al., 1999a) and these are close
to plasma concentrations seen in patients, i.e. around 0.5e
1 mM (Quack et al., 1995; Kornhuber and Quack, 1995). In
the case of acute injection the picture is much more compli-
cated since the plasma/brain ratio also depends on the time
of assessment (Hesselink et al., 1999c). Nevertheless, acute
administration of memantine at 10 and 20 mg/kg i.p. in rats
leads to respective peak free brain concentrations of 1.2 and
2.6 mM assessed by microdialysis in the striatum (Quack
et al., 1995). A similar study using in vivo recovery revealed
somewhat higher peak levels, i.e. 4 mM levels after 20 mg/kg
(Hesselink et al., 1999c).
There are two important aspects related to memantine phar-
macokinetics that have, too often, led to confusion:
1. The fact that brain levels assessed in homogenates are very
different from concentrations in the extracellular fluid
should be appreciated, i.e. the difference is over 30-fold
in favour of homogenates (Hesselink et al., 1999a). This
is due to intracellular, and in particular lysosomal accumu-
lation (Honegger et al., 1993) and does not reflect free
concentrations available at CNS plasma membrane recep-
tors in vivo (Wesemann et al., 1980; Wesemann and
Ekenna, 1982; Kornhuber and Quack, 1995; Danysz
et al., 1997). This has sometimes been overlooked by
some researchers (Chen et al., 1998) who stated that ‘‘a
20 mg/kg i.p. memantine administration to the rodent re-
sults in a brain concentration of 1e10 mM within 30e
60 min’’. These authors cited the reference Wesemann
et al. (1982) that presented concentrations in brain homog-
enates and then determined values of over 100 mM after an
i.p. dose of 20 mg/kg (not 1e10 mM) (Fig. 2 of the cited
paper, 1 h time point), but this does not reflect extracellu-
lar levels, which are over 30-fold lower.
2. It is not always recognised that infusion of 20 mg/kg/d is
not comparable with acute i.p. injection of the same dose.
For example, Creeley et al. (2006) wrote ‘‘we chose
20 mg/kg as the initial dose because this is the dose that
others have reported is effective in protecting the adult
rat brain against excitotoxic neurodegeneration (Wenk
703
et al., 1994; Misztal et al., 1996; Danysz et al., 1997;
Chen et al., 1998).’’ The cited papers Wenk et al. (1994)
and Misztal et al. (1996) all used infusion of 20 mg/kg/
d which leads to maximal plasma level which are at least
four times lower than the peak concentration achieved af-
ter a single i.p. administration of the same dose. Readers
are referred to our review (Danysz et al., 1997) which ex-
plicitly states that, if acute administration is used, then
5 mg/kg i.p. is the maximal therapeutically relevant dose
for 30e60 min time point. A similar oversight was made
by Chen et al. (1998).
Thus, a maximal acute dose of 5 mg/kg i.p. in rats can
probably be considered to be of therapeutic relevance for its
use in AD, taking the peak concentration (c.a. 30 min) as
the reference point (Zoladz et al., 2006), although age, strain,
gender, and health status of animals should also be considered
since they can change pharmacokinetics considerably. For ex-
ample older rats and female rats generally show higher free
peak concentrations whereas young adult male rats were
used for most preclinical pharmacodynamic studies to date
(see below).
The estimate of the therapeutically relevant acute dose in
young adult male rats is based on the following rationale:
(a) the difference in drug sensitivity between man and rat is
mainly due to pharmacokinetic rather than pharmacodynamic
aspects; (b) it is very likely that the serum/extracellular brain
ratio is similar for man and rats and the CSF/total serum ratio
is c.a. 0.5 for both rat and man (Kornhuber and Quack, 1995;
Hesselink et al., 1999a).
Bearing in mind these considerations, 5 mg/kg i.p. in the rat
is the acute dose giving rise to serum concentrations at 20e
30 min which correspond to the upper limit of those seen in
the serum of patients and healthy volunteers following treat-
ment with well-tolerated doses of memantine. More relevant
for the clinical use of memantine is repetitive administration.
However, considering the much shorter half-life in rat (3e
5 h) than in humans (up to 100 h) repetitive treatment in rats
would result in substantial fluctuations in brain concentrations.
This would be entirely different from clinical practice where
stable steady-state levels are present in chronically treated pa-
tients. It is known that treatment regimes with fluctuating
levels lead to very different pharmacodynamic changes than
those with stable concentrations (e.g. Hesselink et al.,
1999b). One of the ways to overcome this problem is the
use of Alzet osmotic minipumps for s.c. infusion. Such treat-
ments using memantine (20 mg/kg/d) lead to plasma levels of
c.a. 1 mM (Misztal et al., 1996; Zajaczkowski et al., 1996b;
Nakamura et al., 2006) (see Table 2).
Free cerebrospinal fluid (CSF) levels of memantine after
therapeutic doses in man are within the range of affinity for
NMDA receptors in vitro (Kornhuber and Quack, 1995). Phar-
macokinetic studies together with extensive screening for
many targets imply that, apart from NMDA receptors, four
other candidates could potentially play a role in memantine’s
MOA, i.e. alpha7, alpha4/beta2, alpha9/10 and 5-HT3 recep-
tors. Before the MOA hypotheses related to NMDA receptor
704 C.G. Parsons et al. / Neuropharmacology 53 (2007) 699e723

Table 2
Compilation of studies showing neuroprotective activity of memantine, assessed plasma level and projected brain levels at the neuroprotective dose
Type of insult Parameter assessed Effective dose Plasma concentrations Projected brain/ECF References
(mM) at active dose concentrations (mM)c
Aggregated Aß and Histology (cresyl 10 and 20 mg/kg/da 0.7 and 1.4b 0.6 and 1.1 Nakamura et al. (2006)
ibotenate injection in violet), and Morris
the hippocampus in maze learning
rats
APP23 mice Morris maze learning 14.4 mg/kg/d infusion ed e Van Dam and De Deyn
(2006)
Aggregated Aß Bcl2 immunostaining, 15 mg/kg/d infusion 1.0 0.8 Miguel-Hidalgo et al.
injection in the DNA fragmentation, (2005)
hippocampus in rats caspase 8 activity and
active avoidance
learning
Aggregated Aß DNMTS e operant 20 mg/kg/d infusion 1.2e 1.0 Yamada et al. (2005)
injection in the chamber, histology CA1
hippocampus in rats
NMDA or 3-NP Cortical ChAT activity 20 mg/kg/d infusion 0.9 0.7 Wenk et al. (1996)
infusion in the NBM
in rats
LPS infusion into the ChAT activity in the 20 mg/kg/d infusion 1.2e 1.0 Willard et al. (2000)
NBM in rats frontal cortex
Aß into frontoparietal ChAT staining, 35 mg/kg/d in drinking 1.6f,g 1.3 Nyakas et al. (2006)
cortex in rats microglia activation, water
object recognition test,
passive avoidance,
Morris water maze
APP/PS1/Tau triple Learning in Morris 30 mg/kg/d po for 3 ? ? Luhrs et al. (2006)
transgenic mice at 12 maze and object months in drinking
month recognition water
Negative effects on learning are not seen at plasma levels providing neuroprotection indicating that, in contrast to a claim by Creeley et al. (2006) e it is possible
to achieve neuroprotective effects through NMDA receptor blockade without negative effects on learning. Please note that memantine affinity at NMDA receptors
is approximately 1 mM.
a
Note that in this study the same dosing regime did not impair Morris maze learning when administered to naive rats.
b
Not assessed in this study but taken from Misztal et al. (1996) using the same gender, strain of rats of similar age.
c
Assumed to be 80% of free plasma levels (Hesselink et al., 1999a).
d
In a previous study it has been shown that in the same tg model memantine at 10 mg/kg had no negative effect on cognitive performance (Van Dam et al., 2005).
e
Not assessed in this paper but, based on rats’ gender and weight, predicted to be around the indicated value, in this study memantine treatment after the insult
had no effect on performance of control or Aß treated rats rats in the DNMTP task.
f
No effect of memantine was observed in mice at doses providing neuroprotection against Aß in the object recognition test, passive avoidance and Morris water
maze.
g
This value refers to plasma levels obtained in a pilot study using 40 mg/kg/d. In turn, the dose of 35 mg/kg/d was selected for the main experiments. Expected
plasma level would be then c.a. 1.2 mM.

blockade are discussed in detail, it seems fair that the other
potential targets are first addressed. These possibilities are dis-
cussed and largely dismissed below.
2.2. Alpha7 and alpha4/beta2 nicotinic receptors
The possibility that therapeutically relevant doses of mem-
antine could affect alpha7 and alpha4/beta2 nicotinic receptors
has recently attracted considerable attention from focused
groups (Buisson and Bertrand, 1998; Maskell et al., 2003;
Aracava et al., 2004, 2005).
Memantine has been reported to inhibit human alpha4/
beta2 responses with an IC50 ¼ 6.6 mM (Buisson and Bertrand,
1998), however, this level is probably too high to be of real
therapeutic significance. The reported potency of memantine
at alpha7 receptors varies considerably from 0.33 to 1.68 mM
seen in native/heterologously expressed rat receptors (Aracava
et al., 2004, 2005; Elgoyhen, unpublished data) and 5 mM
observed in heterologously expressed human receptors in
Xenopus oocytes (Maskell et al., 2003), the latter finding mak-
ing it also seem to be less likely to be of real human therapeutic
relevance in AD, although here it should be stressed that poten-
cies can be influenced by the heterologous expression system
used. The effect of memantine on all tested ‘‘neuronal’’ nico-
tinic receptors was only weakly voltage-dependent, as is the
case for 5-HT3 receptors (see below) e which often share a
common pharmacology with neuronal nicotinic receptors e
and implies a site of action which is not deep inside the channel.
Memantine produces discriminative effects indicative of
NMDA antagonism that are shared neither by 5-HT3 blockade
nor by alpha7 antagonism indicating that NMDA antagonism
predominates in rats at relevant doses. In a drug discrimination
paradigm, memantine exhibited generalization to other recep-
tor NMDA antagonists (Grant et al., 1996; Zajaczkowski et al.,
 C.G. Parsons et al. / Neuropharmacology 53 (2007) 699e723
1996a) but produced only modest attenuation (33% decrease)
of a nicotine discriminative cue at 10 mg/kg (this acute dose is
over the therapeutic range) as compared to a 70% decrease
with the non-selective neuronal nicotinic antagonist mecamyl-
amine at 1 mg/kg (Zakharova et al., 2005).
Moreover, acute administration of therapeutically relevant
dose of 5 mg/kg memantine had no effect on dopamine levels
in the striatum, and higher doses produced an increase (Spana-
gel et al., 1994), that would be inconsistent with blockade of
alpha7 receptors which produces a decrease (Alessandri-Haber
et al., 2006). This indicates, at least, that the NMDA receptor
blocking activity predominates.
2.3. Alpha9/alpha10 nicotinic receptors
Although memantine blocks alpha9/alpha10 nicotinic re-
ceptors with similar affinity to NMDA receptors (Oliver
et al., 2001), these receptors show a very discrete, non-CNS,
distribution, i.e. in cochlear hair cells, and this action is there-
fore highly unlikely to be responsible for therapeutic effects of
memantine on symptoms in AD (Elgoyhen et al., 2001; Katz
et al., 2004).
2.4. 5-HT3 receptors
Memantine blocks murine and human 5-HT3 receptors with
similar or somewhat lower affinity to NMDA receptors in vi-
tro, but in a non-use, non-voltage-dependent manner (Rammes
et al., 2001). However, at doses of up to 10 mg/kg, memantine
does not block vomiting evoked by cisplatin in ferrets (Naylor,
internal Merz report), a reaction sensitive to blockade by 5-
HT3 antagonists such as ondansetron. However, as a word of
caution, it should be kept in mind that the pharmacokinetics
of memantine in ferrets is not known.
In conclusion, effects on other neurotransmitter systems
may, to some extent, be involved in the good therapeutic pro-
file of memantine, but the specific mode of NMDA receptor
antagonism is, in our view, the main MOA that is responsible
for both the pharmacodynamic effects and the tolerability of
memantine seen in AD.
2.5. Can neuroprotective effects of memantine be
expected at tolerable doses that block NMDA receptors?
Although a detailed discussion of neuroprotective potential
of memantine is beyond the scope of the present review, one
aspect is discussed here as it is pertinent to our hypothesis un-
derlying the clinically proven symptomatic effects of meman-
tine on cognition. This hypothesis assumes that NMDA
receptor blockade may, under certain conditions, both provide
neuroprotection and improve neuronal plasticity via the same
MOA. In a recent paper, impairment of learning by memantine
was observed at 2.5 mg/kg and much higher doses were
needed to attenuate kainate-induced toxicity (Creeley et al.,
2006). Based on this observation, Creeley et al. (2006) stated
that ‘‘it is impossible to block NMDA receptors sufficiently to
provide neuroprotection without side-effects such as memory
705
impairment’’. Such a generalized statement that blockade of
NMDA receptors must result in very serious CNS-mediated
side-effects is not substantiated by experimental evidence,
even at the most basic level of our understanding of NMDA
receptor physiology and pharmacology. The authors ignored
the fact that magnesium is an NMDA receptor antagonist
and it is present in the brain at concentrations fully blocking
NMDA receptors at resting membrane potentials (Nowak
et al., 1984). Magnesium is neuroprotective since its removal
produces neurodegeneration (Novelli et al., 1988) and at the
same concentrations magnesium does not produce side-effects,
and in particular, it does not impair learning. In complete con-
trast, removal of magnesium actually impairs neuronal plastic-
ity (Coan and Collingridge, 1987).
Moreover, kainate-induced excitotoxicity e which was used
by Creeley et al. (2006) as a model to support this point e is
an acute insult not compatible with AD and chronic neurode-
generation in general. In turn, in their studies, the neuroprotec-
tive potency of memantine was predictably low in contrast to
previous studies (see Table 2 and Wenk et al. (2006)). Addi-
tionally, higher plasma levels of memantine than in most
previous studies may be expected in this study due to the use
of female rats and older animals (6e8 month; see Table 2
and discussion above). This is because memantine metabolism
and/or elimination is slower in female rats and also decreases
with age. The former difference has been shown after infusion
or acute injection of memantine, where serum levels were up to
two times higher in female rats (Zajaczkowski et al., 2000) e it
should however, be noted that differences do not apply to
humans. Regarding the age effects, there are no published
data showing such comparison, however, several unpublished
studies have been performed. For example memantine infusion
at 24 mg/kg/d for 1 week using Alzet 2ML2 pumps implanted
under the back skin produced 4.35  1.64 mM plasma levels in
24 month SD male rats while concentrations of only 1.28 
0.24 mM (Mean  SD, N ¼ 5) were observed in 3 month old
animals. Memantine concentration was assessed using gas
chromatography.
In turn, possibly the acute dose of 2.5 mg/kg used by Cree-
ley et al. (2006) may correspond to higher dose in studies per-
formed in young adult male rats when plasma concentration is
considered. This could explain impairment of learning at ap-
parently moderate doses.
A compilation of studies showing neuroprotective effects of
memantine in relation to plasma levels is shown in Table 2.
Note that free brain levels are approximately 80% (brain mi-
crodialysis) of total plasma levels (Hesselink et al., 1999a).
As can be seen from this table, memantine was neuroprotec-
tive in various insult models (relevant for AD) at doses that
did not produce impairment of learning in control animals (in-
dicated studies in the Table 2) and led to projected concentra-
tions in the brain close to the affinity at NMDA receptors.
3. NMDA receptors and neuronal plasticity
Although, as discussed in detail below, it is widely accepted
that phasic, contingent synaptic NMDA receptor activation is
706 C.G. Parsons et al. / Neuropharmacology 53 (2007) 699e723
necessary for learning-related synaptic plasticity, the glutama-
tergic system requires a finely balanced homeostatic control.
Under certain conditions, overactivation of these receptors
may, in fact, lead to an impairment and their inhibition may
actually lead to enhancement of synaptic plasticity/learning.
Below a compilation of arguments supporting this thesis is
provided with emphasis on data with memantine. It shows
that the assumption that any blockade of NMDA receptors un-
equivocally leads to impairments of neuronal plasticity/learn-
ing (and NMDA receptor activation to the opposite effects) is
a rather drastic over simplification.
3.1. NMDA receptor activation can impair, and blockade
can improve, neuronal plasticity and learning
3.1.1. Long-term potentiation (LTP)
Since some forms of LTP are NMDA receptor-dependent
(see below), complete inhibition of these receptors also in-
hibits the induction of LTP, but factors such as antagonist
type and their concentrations play a crucial role. For example,
in moderately aged rats, memantine actually prolonged the
duration of LTP in vivo (Barnes et al., 1996). Similarly, the
competitive NMDA receptor antagonist CPP (3-((þ)-2-
carboxypiperazin-4-yl)-propyl-1-phosphonic acid) displayed
biphasic effects on LTP in CA1 in vivo e a low dose of
1 mg/kg caused a borderline significance potentiation of LTP
whereas a higher dose of 10 mg/kg reduced LTP (Abraham
and Mason, 1988). In contrast, MK-801((þ) 5 methyl 10,11
dihydro 5H dibenzo[a,d]cyclohepten 5,10 imine, 0.1 to
1 mg/kg) showed only a dose-dependent inhibition of LTP
(Abraham and Mason, 1988).
Removal or reduction of magnesium in hippocampal slices
causes deficits in LTP (Coan and Collingridge, 1987) and this
could be reversed by memantine with a bell-shaped concentra-
tioneresponse curve with near complete reversal of this deficit
by therapeutically relevant concentrations (Frankiewicz and
Parsons, 1999). Similarly, in hippocampal slices, low concen-
trations of NMDA also caused a reduction of LTP in the CA1
region (Izumi et al., 1992; Zajaczkowski et al., 1997). This
deficit was also reversed by memantine at a concentration of
1 mM (Zajaczkowski et al., 1997). Finally, in knockout mice
lacking the glutamate transporter GLT-1, LTP was impaired
in the hippocampal CA1 region in vitro. When tetanic stimu-
lation was applied in the presence of a very low concentration
of the competitive NMDA receptor antagonist AP5 (0.5 mM),
the impairment was reversed (Katagiri et al., 2001).
3.1.2. Learning
As early as in 1989 Jones et al. demonstrated that systemic
administration of NMDA, given before acquisition, dose-
dependently (3e50 mg/kg) impaired passive avoidance learn-
ing retention in rats tested 24 h later. In another study, NMDA
also impaired passive avoidance learning starting at 25 mg/kg
when given before acquisition but not directly after or before
the retention test (Zajaczkowski et al., 1997). This effect was
not due to state-dependency and was not related to toxic
actions. This impairment was reversed by memantine at 2.5
and 5 mg/kg (acute doses indicated above to be close to the
therapeutic range), but not at 10 mg/kg. The bell-shaped
dose-dependency of this effect of memantine was highly rem-
iniscent to that seen with LTP in hippocampal slices (Frankie-
wicz and Parsons, 1999). Similarly, in mice maintained on
a low-magnesium diet and showing other signs of deficiency
of this physiologically very important cation, a deficit of con-
ditioned context freezing was observed that could not be at-
tributed to unspecific effects on activity, exploration, or pain
sensitivity (Bardgett et al., 2005). Unfortunately, the potential
reversal of this effect by an NMDA receptor antagonist was
not tested in this study.
In a lever-pressing instrumental task, NMDA (20e50 mg/
kg) decreased accuracy in both the repeated acquisition and
performance components of a lever-pressing paradigm (Cohn
and Coryslechta, 1994). The disruption of repetitive acquisi-
tion accuracy was related to initial perseverative errors fol-
lowed by errors of skipping forward and backwards in the
three-member response sequence. Again, NMDA receptor an-
tagonists were unfortunately not tested in this study.
NMDA receptor antagonists can, under certain conditions,
paradoxically improve learning. Most studies supporting
such statement have been discussed in a previous review (Da-
nysz et al., 1995) but selected studies, in particular those using
memantine, are discussed below. In a recent study using a low
level of training in the water radial maze followed by a test
trial 24 h later, memantine (at 5 and 7.5 mg/kg but not
3.75 mg/kg) improved the performance when given after the
training (Zoladz et al., 2006). It was suggested by the authors
that the poor performance in this model is related to the effect
of stress on memory storage and involves overactivity of the
glutamatergic system with resulting overactivation of NMDA
receptors. Another study confirmed this hypothesis of the im-
pact of stress and also showed that the glutamate transport in-
hibitor (DL-TBOA) produced a similar impairment of learning
and LTP which may depend on NMDA receptor activation
(Howland et al., 2006). The data also suggest that both effects
may be related to an enhancement of LTD (long-term depres-
sion). In fact, learning impairment (Morris water maze) and
LTD enhancement were prevented by the NR2B antagonist
Ro25-6981. Also in rats with thiamine deficiency, a decrease
of glutamate uptake in the prefrontal cortex was observed
and was accompanied by a deficit in Morris water maze
learning (Carvalho et al., 2006) giving another example of dis-
ruption of learning likely resulting from non-contingent over-
activity in glutamatergic systems.
In rats with learning deficits following an excitotoxic lesion
of the entorhinal cortex, memantine delivered by osmotic
pumps (20 mg/kg/d) after the lesion, improved reference but
not working memory learning in the radial maze (Zajaczkow-
ski et al., 1996b). This effect was unlikely due to neuroprotec-
tive activity per se, but could reflect suppression of ongoing,
residual noise at the remaining, perturbed glutamatergic
synapses.
In F344 9e12 month old rats, memantine produced a strong
trend for improvement in the Morris water maze expressed as
significantly more time spent in the target quadrant during the
 C.G. Parsons et al. / Neuropharmacology 53 (2007) 699e723
probe trial (Barnes et al., 1996). Interestingly, it has been re-
ported that in 24-month-old F344 rats, a high magnesium
diet improved T-maze reversal learning and improved high fre-
quency potentiation in CA1 hippocampal region (Landfield
and Morgan, 1984). This again implies background NMDA re-
ceptor overactivation as a cause for this observed symptomatic
deficit, but the use of magnesium for therapy is questionable
(see below).
In another study, the effects of memantine treatment at
2 mg/kg given for 23 days and starting 1 day after i.c.v. cho-
linergic toxin injection of AF64A (aziridinium ion of ethyl-
choline) were assessed in the Morris maze test. On test days
11 and/or 14 memantine tended to decrease the latency and
significantly improved the ‘‘straightness index’’ (Bachurin
et al., 2001). It is not clear to what extent this effect can be at-
tributed to the functional improvement of memory or to neuro-
protective/restorative activity since it extended over 10 days
beyond the treatment period (Bachurin et al., 2001).
In the Morris water maze, rats withdrawn from chronic al-
cohol treatment also showed a learning deficit that was atten-
uated by memantine but not by MK-801 (Lukoyanov and
Paula-Barbosa, 2001), but in this study the rationale for the
dose-selection design is difficult to follow, i.e. an excessively
high bolus dose was followed by a maintenance dose that was
clearly too low.
There are only few studies in transgenic mice models of
AD addressing the issue of symptomatological improvement
of cognition. In 4-month-old APP23 mice (APP ¼ Amyloid
Precursor Protein) with established cognitive deficits, meman-
tine (10 mg/kg daily) given for 1 week improved performance
in the Morris water maze at the end of the training period (Van
Dam et al., 2005). Similarly, in APP/PS1 (PS1 ¼ preseniline 1)
double transgenic mice, memantine (30 mg/kg p.o. daily for
2e3 weeks) improved acquisition without affecting swimming
speed (Minkeviciene et al., 2004). Most recently, LaFerla and
colleagues (Luhrs et al., 2006) showed that in triple transgenic
mice (APP/PS1/Tau), treatment with memantine in drinking
water (30 mg/kg for 3 months) improved performance both
in the Morris maze (acquisition and probe trial at 1 and
24 h) and object recognition. Interestingly, the same treatment
resulted in a decrease in plaque load but this is outside of the
scope of the present review.
Interestingly, negative effects of NMDA receptor over-
stimulation on learning can be also seen in other species.
For example, even in the honeybee Apis melifera the glutamate
transporter inhibitor, L-trans-2,4-PDC (L-trans-2,4-pyrrolidine
dicarboxylate), impaired long-term (24 h), but not short-term
(1 h), memory (Si et al., 2004). This effect was reversed by
memantine (but it is difficult to refer to the ‘‘doses’’ used)
but not by MK-801 which produced impairment not only fol-
lowing L-trans-2,4-PDC but also on its own.
Similarly, in 1-day-old chicks, stress lead to learning impair-
ment which was suggested by the authors to be due to enhanced
glutamatergic activity. In this model, in non-stressed chicks,
memantine impaired passive avoidance memory at 5 and
15 mg/kg but not 10 mg/kg. However, under isolation-induced
stress conditions memantine did not alter memory when given
707
before stress, but improved learning when administered after
the stress application at 10 mg/kg (Barber et al., 2002).
The studies discussed above indicate that NMDA receptor
antagonists in general may potentially produce a beneficial ef-
fect in AD. However, as discussed above and below, the good
tolerability and specific features of NMDA receptor channel
blockade by memantine seem to render memantine particu-
larly suitable for this indication. It should however, be men-
tioned that although clear superiority of memantine over the
high affinity uncompetitive antagonist MK-801 has been
shown in LTP experiments (Frankiewicz and Parsons, 1999),
in vivo studies provided mixed results (Zajaczkowski et al.,
1997; Lukoyanov and Paula-Barbosa, 2001; Si et al., 2004).
3.2. The NMDA receptor as a co-incidence detector in
Hebbian learning with magnesium block governing the
filter function
Ionotropic glutamate receptors are ligand gated ionic chan-
nels permeable to the monovalent cations Naþ and Kþ and,
depending on the subtype, also to the divalent cation Ca2þ.
AMPA (a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic
acid) receptors show very fast activation and inactivation ki-
netics, are largely postsynaptic, mostly impermeable to Ca2þ
(at least those containing the edited GluR2 subunit) and partic-
ipate in most forms of fast synaptic transmission. In contrast,
NMDA receptors are normally only synaptically activated un-
der certain physiological conditions, i.e. during the induction
of synaptic plasticity. The NMDA receptor has three cardinal
features that permit its function in synaptic plasticity: high
permeability to Ca2þ ions; voltage-dependent block by
Mg2þ ions and relatively slow gating kinetics.
An example of such plastic changes is LTP which can be in-
duced both in vitro and in vivo and is believed to model basic
mechanisms of memory formation in mammals (Collingridge
and Bliss, 1995). There are both presynaptic and postsynaptic
forms of LTP. Postsynaptic NMDA receptor-dependent LTP,
which is most relevant for the proposed MOA of memantine
in AD, can be described by the following, very simplified,
sequence of events (Fig. 3) although it should be stressed that
many mechanisms are involved in this process.
Glutamate binds to both NMDA and AMPA postsynaptic
receptors, however, only the latter are transiently activated
during fast normal synaptic transmission since positively
charged Mg2þ ions block the NMDA receptor channel and
the activation kinetics of NMDA receptors are also much
slower than those of AMPA receptors (Fig. 3A).
When a prolonged, high frequency signal (or convergence
of several signals) arrives at a glutamatergic synapse, this
leads to a stronger/more prolonged glutamate release and
a more pronounced influx of Naþ ions into the postsynaptic
neuron via AMPA receptors (Fig. 3B).
Additionally, slow activation of presynaptic GABAB
receptors on inhibitory interneurones causes dis-inhibition of
GABAergic synapses. Both processes, in turn, lead to a strong,
relatively long lasting (hundreds of milliseconds) decrease
in membrane potential (partial depolarization). This
708 C.G. Parsons et al. / Neuropharmacology 53 (2007) 699e723

A Normal Synaptic Transmission B Tetanic Stimulation AMPA

Glia Glia
NMDA
Na+ Na+
NMDA
Glia Glia
+ + Subtype
- -
GABAA
Cl- Cl-
GABAB
Glia Glia
Secondary
Messagers

C D Mg2+
Tetanic Stimulation Enhanced Synaptic Transmission
Glia Glia
Glutamate
[mM] 1ms
Na+ Na+ GABA
Glia Glia
+ + Glutamate
Ca2+ uptake
Ca 2+ - -
Na+
Cl- Cl-
Ca2+
Glia Glia
Cl-

Fig. 3. Schematic for the processes involved in the induction of NMDA receptor-dependent LTP. Sequence A to D. See text for details.

depolarization removes blockade of the NMDA receptor chan-
nel by Mg2þ since the relative charge of the neuronal mem-
brane is now much less negative for a sufficient time to
allow this divalent cation to leave the channel during the
slower activation of NMDA receptors. At this stage, Ca2þ
ions can freely enter the cell via the NMDA receptor channel
and trigger a cascade of second messenger processes that are
involved in the fixation of increased synaptic strength (neuro-
nal memory formation) (Fig. 3C).
This postsynaptic change is manifested as an enhancement
of AMPA receptor-mediated responses which increases subse-
quent normal synaptic signals (Fig. 3D).
One should emphasize the crucial physiological role of en-
dogenous Mg2þ ions in this process which function as a switch
that keep NMDA receptors blocked under ‘normal’ conditions
but allow Ca2þ ion flux when the pattern of activation has fea-
tures characteristic for those required for learning processes,
i.e. temporal and spatial convergence (co-operativity).
In dementia, one of the consequences of neuronal energy
deficits (Greenamyre, 1991) (see also below) could be a de-
crease in Mg2þ blockade of NMDA receptors (which is
strongly voltage-dependent, i.e. decreases with the degree of
depolarization) and in turn enhanced chronic, low-level activa-
tion of this receptor type (for review see, e.g. Parsons et al.
(1999b)). In this regard, it is important to note that memantine
bears only a single positive charge and is therefore thought to
act as a somewhat more effective surrogate for the divalent
Mg2þ cations which show an even stronger functional
voltage-dependence (Parsons et al., 1999b).
As detailed above, in vitro studies using rat hippocampal
slices provide evidence that reduction in Mg2þ concentration
induces severe functional perturbations, including complete
impairment of LTP, the neuronal model of mammalian
synaptic plasticity and memory formation (Coan and Colling-
ridge, 1987). Memantine completely restored normal synaptic
plasticity functionality following reduction in Mg2þ concen-
tration (Frankiewicz and Parsons, 1999) and this effect was
seen at a therapeutically relevant concentration of 1 mM .
4. Link between glutamate system disturbances and AD
4.1. Why normal function of magnesium could be
disturbed in AD?
In AD several factors are likely to be involved in the aeti-
ology (causal events) and certainly many factors contribute to
the final pathomechanisms. The latter are more relevant for the
current discussion and are systemically, but only briefly listed
below. For more extensive discussion of these factors (which is
not the main aim of this review) the readers should refer to one
of the recent reviews focusing on this aspect (Greenamyre,
1991; Albin and Greenamyre, 1992; Delatorre, 1994; Beal,
1995, 2000). The possible contribution of energy deficit as
a primary deficit in the pathomechanism of AD, although sug-
gested by some findings (see Hoyer, 2000; Blass et al., 2000),
is very controversial. Nevertheless, it can be predicted that at
least a secondary deficit may occur as a reaction to Aß oligo-
mers, oxidative stress, etc.
In AD energy demand may increase because of:
1. Partial depolarization (Blanchard et al., 2002);
2. Impairments of Ca2þ homeostasis (Mattson et al., 1993);
3. Increased neuronal activity due to increase in glutamate
levels (Hoyer and Nitsch, 1989; Harris et al., 1996;
Noda et al., 1999);
 C.G. Parsons et al. / Neuropharmacology 53 (2007) 699e723
4. Increased NMDA receptor sensitivity to glutamate (Wu
et al., 1995);
5. Increased oxidative stress (Mecocci et al., 1994; de la
Torre and Stefano, 2000; Emerit et al., 2004);
6. Decreased activity of Naþ/Kþ ATPase (Hattori et al.,
1998; Kairane et al., 2002; Dickey et al., 2005; Vignini
et al., 2006); and
7. Presence of Aß or Tau (Copani et al., 1991; Bowen et al.,
1992; Mattson et al., 1993; Keller et al., 1997; Brewer and
Wallimann, 2000).
In AD energy supply may decrease because of:
1. Mitochondrial dysfunctions (Blanchard et al., 1993; Me-
cocci et al., 1994; Hutchin and Cortopassi, 1995; Hoyer,
1996; Kwong et al., 2006);
2. Changes in blood flow (it is still a matter of debate
whether this is a primary or secondary effect) (Delatorre,
1994; Franceschi et al., 1995; Crawford, 1996; de la Torre
and Stefano, 2000); and
3. Decrease in glucose metabolism/supply (Hoyer et al.,
1991; Mielke et al., 1992; Goto et al., 1993; Simpson
et al., 1994; Kennedy et al., 1995; Hoyer, 1996; Parpura-
Gill et al., 1997).
It should be kept in mind that these are, to a great extent,
overlapping processes and many are coupled by positive feed-
back mechanisms, as is the energy balance (Henneberry,
1989). Increased energy deficit will result in increased energy
demand.
If we believe that in AD there is an energy deficit, and there
are many reports suggesting that this might be the case
(Greenamyre, 1991), one could expect weaker NMDA recep-
tor blockade by Mg2þ. There are several papers connecting
disturbances of magnesium homeostasis to AD (see for review
Durlach, 1990; Glick, 1990; Ozturk and Cillier, 2006) suggest-
ing decrease in magnesium levels. Additionally, it has even
been reported that in AD patients there is a lower brain level
of Mg2þ in autopsy brains (Andrasi et al., 2000). Independent
of whether or not there are changes in Mg2þ concentrations in
AD, the function of this ion can be disturbed, i.e. weakened by
the above mentioned energy deficits resulting in partial re-
moval of Mg2þ block, by even moderate depolarization.
Bearing in mind the facts discussed above, one could argue
that magnesium could potentially be used to normalize NMDA
receptors dysfunction in AD instead of an NMDA receptor an-
tagonists such as memantine (Ozturk and Cillier, 2006). There
are, however, numerous reasons why such a therapeutic ap-
proach would not work. Firstly, even chronic oral administra-
tion of magnesium does not produce elevated concentrations
either in plasma, red blood cells or in brain, as evidenced
in vivo using 31P-NMR spectroscopy (Wary et al., 1999). In
fact, in order to obtain significant increases in brain magne-
sium concentration, very high, potentially toxic parenteral
doses would be required (Hallak, 1998; see below).
Additionally, multiple side-effects/problems related to
treatment with high parenteral magnesium doses could be
709
anticipated. Severe hypermagnesemia may result in loss of
tendon reflexes and muscle weakness, bradycardia and cardiac
arrest, hypotension (due to peripheral vasodilatation), flushing
of the skin, parasympathetic blockade, fixed and dilated pu-
pils, CNS effects such as drowsiness, confusion, respiratory
depression and coma (Fung et al., 1995). This is of specific im-
portance as impaired renal function, which is quite frequent in
the elderly, as well as gastrointestinal disorders may, in fact,
markedly increase magnesium concentration (Clark and
Brown, 1992).
Specifically, AD could even be regarded as a clear contra-
indication for therapeutic treatment with magnesium. For ex-
ample, it was shown that magnesium triggers pathological
deposition of Tau-paired helical filaments and the formation
of neurofibrillary tangles (Yang and Ksiezak-Reding, 1999)
and may even cause inhibition of acetylcholine release
(Fung et al., 1995) and muscarinic responses (Ladner and
Lee, 1999), both of which would worsen cholinergic deficits.
These arguments indicate that, while it may be useful to
avoid magnesium deficits by careful oral substitution, meman-
tine therapy in AD cannot be simply replaced by high doses of
magnesium.
4.2. Amyloid beta and NMDA receptors
Amyloid beta (Aß) is the principal constituent of senile
plaques in AD and is believed to impair neuronal function and
cognition, even before the appearance of overt toxicity (Lesne
et al., 2006). It seems at present to be accepted that soluble Aß
oligomers rather than their deposits, i.e. plaques are responsible
for impairment of synaptic function and neurodegeneration in
AD (Golde, 2006). Moreover, such oligomers may be central
to AD pathology as they also increase phosphorylation of Tau
which could, then be a secondary effect (De Felice et al., 2007b).
Most of the studies cited below used an undefined species
of Aß, however, it has been recently suggested that oligomers,
in particularly dodecamers (>50 kDa) may be the most reac-
tive species in this regard (Walsh and Selkoe, 2004; Klein
et al., 2004; Barghorn et al., 2005).
There are numerous arguments that Aß may increase gluta-
matergic activity, in particular through NMDA receptors (see
Fig. 4 and reviews by Greenamyre, 1991; Danysz et al.,
2000; Danysz and Parsons, 2003; Walsh and Selkoe, 2004;
Klein et al., 2004).
Inflammatory process may be involved in this enhanced
activity of NMDA receptors through the cascade increase in
Aß-activation of microglia, increase in TNFalpha / microglia
activation, oxidative stress, decrease in glutamate uptake/
increase in glutamate release, increase in NMDA receptor
sensitivity, increased NMDA receptor activation, which ulti-
mately results in neuronal death (Wenk et al., 2006). Addition-
ally, Lesne et al. (2005) have shown that sub-toxic activation of
NMDA receptors increases the proportion of Kunitz pro-
tease inhibitor domain containing APP which favours ß-secre-
tase over a-secretase processing thus enhancing Aß production,
i.e. a vicious circle. This vicious cascade could be blocked by
memantine at low, 1 mM, concentrations (Floden et al., 2005).
710 C.G. Parsons et al. / Neuropharmacology 53 (2007) 699e723
1 diffusible Aß1e42 oligomers (ADDLs) for 45 min prevented
APP
- More recent publications confirm this finding (Walsh et al.,
+ Ca2+
3 ditionally, chronic exposure of hippocampal cultures to solu-
2 4
ß-Amyloid
Glu
5 -
T +
+
Glu
Glia
Fig. 4. Schematic showing how Aß may increase glutamatergic activity and/or
NMDA receptor sensitivity, while soluble APP may have opposite effects. Un-
der normal conditions, APP has functionally antagonistic effects on NMDA re-
ceptors (1) and enhances glutamate transport activity removing glutamate from
the synaptic cleft (2). When APP is falsely processed to ß-amyloid, this has the
opposite effects on NMDA receptors (3) and glutamate uptake (4) thereby in-
creasing glutamate concentrations in the synaptic cleft (5) and may even drive
glutamate transporters in to reversed uptake mode. Numbers refer to selected,
example references: (1) Furukawa and Mattson (1998); (2) Masliah et al.
(1998); (3) Mattson et al. (1993), Wu et al. (1995); (4) Harris et al. (1996);
and (5) Noda et al. (1999).
Detailed discussion of this aspect would require a separate
review, thus, only selected in vitro papers in relation to LTP/
synaptic plasticity are discussed below e for other reviews
please see Rowan et al. (2003, 2004, 2005).
In rat hippocampal slices, a non-toxic concentration of
Aß1e40 (200 nM) caused rapid inhibition of LTP in CA1 whilst
having no long-term effect on normal synaptic transmission or
LTD (Raymond et al., 2003). In this study, Aß1e40 also produced
a small, but significant, inhibition (approx. 25%) of NMDA re-
ceptor-mediated synaptic potentials (Raymond et al., 2003).
The authors claim that NMDA receptors were unlikely to be in-
volved in this effect because MK-801 (0.5 mM) had no effect on
LTP e but this conclusion may be questioned due to the short
incubation (20 min) used e see Frankiewicz et al. (1996). In
the same concentration range effective for inhibiting LTP,
Aß1e42 also reduced the amplitude of NMDA receptor-medi-
ated synaptic currents in dentate granule cells in vitro via a post-
synaptic mechanism (Chen et al., 2002). Moreover, Aß1e42
strongly inhibited the induction of NMDA receptor-dependent
LTP in the dentate gyrus of hippocampal slices, but not
NMDA receptor-independent LTP or long-term depression
(LTD) (Wang et al., 2004a). Furthermore, in one study, pre-
treatment of rat hippocampal slices with Aß1e42 alone only
moderately inhibited LTP but co-treatment with a sub-threshold
concentration of glutamate (30 mM) impaired LTP more
strongly, implicating an interplay between Aß and the glutama-
tergic system (Nakagami and Oda, 2002). There is also evidence
that the Aß1e42-mediated inhibition of LTP induction involves
stimulation of the kinases JNK, Cdk5, and p38 MAPK, the
cytokine tumour necrosis factor (TNFa) and metabotropic
glutamate receptors (mGluR5) (Wang et al., 2004b, 2005).
The most toxic species of Aß seems to be the oligomeric
form. Thus, incubation of rat hippocampal slices with small
LTP in hippocampal slices well before any overt signs of
cell degeneration (Lambert et al., 1998; Wang et al., 2002).
2005; Townsend et al., 2006; Puzzo and Arancio, 2006). Ad-
ble Aß oligomers produced abnormal spine morphology and
a decrease in their density. Subsequent consequences of this
such as synaptic deterioration including loss of the spine cyto-
skeletal protein debrin were completely prevented by meman-
tine at a concentration of 5 mM (Lacor et al., 2007). Similarly,
memantine (5 or 10 mM) prevented oxidative stress and
calcium influx produced by Aß oligomers in hippocampal
neuronal cultures (De Felice et al., 2007a). Interestingly, Aß
co-immunoprecipitate with extracellular domain of NR1 sub-
unit suggesting direct interaction with NMDA receptors.
Moreover, smaller fragments of the Aß peptide have similar
effects. Aß25e35 was also found to impair both posttetanic po-
tentiation (PTP) and LTP in the hippocampal CA1 in vitro and,
in agreement with previous data (Wang et al., 2004b), these ef-
fects were proposed to involve activation of the JNK signalling
pathway (Costello and Herron, 2004). Similarly, 0.1 mM of the
short Aß fragment Aß31e35 suppressed the induction of LTP of
population spikes (PS) in CA1 of rat hippocampal slices in a
similar manner to the longer fragment Aß25e35, whereas neither
treatment changed the amplitude of the baseline population
spikes. These fragments had no effect on NMDA receptor-
mediated multiple PSs when recorded in Mg2þ-free medium,
which could suggest that these Aß fragments suppress the
induction of LTP through an NMDA receptor-independent
pathway (Ye and Qiao, 1999). A similar conclusion was drawn
by Nomura et al. (2005).
Similar effects were also reported for Schaffer-collateral to
CA1 LTP in vivo (Freir et al., 2001). LTP was markedly
reduced by i.c.v. Aß25e35 (10 nmol) and completely blocked
by Aß25e35 (100 nmol). The effects of this Aß fragment on
LTP were probably mediated via a postsynaptic mechanism
because they did not affect paired pulse facilitation (Freir
et al., 2001). The negative effects of i.c.v. Aß1e42 oligomers
on hippocampal LTP in vivo were completely prevented by
co-administration of monoclonal Aß antibodies (Kim et al.,
2001; Walsh et al., 2002). Aß1e42 was also reported to facili-
tate the induction of LTD and depotentiation of LTP in the
CA1 area the rat hippocampus in vivo in an NMDA recep-
tor-dependent manner (Kim et al., 2001). Effects of different
classes/doses of NMDA receptor antagonists in such models
have, unfortunately, not yet been addressed.
The direct involvement of NMDA receptors in mediating
these effects of Aß is still a matter of debate. Application of
Aß1e40 by extracellular perfusion (200 nM) or intracellularly
via the recording pipette (100 nM) resulted in a gradual en-
hancement of NMDA receptor-mediated synaptic currents in
granule cells in the rat dentate gyrus in vitro with no effect
on AMPA receptor-mediated transmission, resting membrane
potential or input resistance (Wu et al., 1995). Similarly, con-
ditioned media from aAPPs/p3- and ßAPPs/Aß-stimulated
cultured human monocyte-derived macrophages directly
 C.G. Parsons et al. / Neuropharmacology 53 (2007) 699e723 711

induced inward currents via NR1a/NR2B receptors expressed
in X. oocytes that were blocked by the NMDA receptor antag-
onist AP5 (2-amino-5-phosphonovalerate, 50 mM) but not by
the AMPA receptor antagonist CNQX (6-cyano-2,3-dihy-
droxy-7-nitroquinoxaline, 20 mM) (Xiong et al., 2004). In con-
trast, others have reported that although Aß25e35 induced
increases in intracellular Ca2þ in cultured hippocampal neuro-
nes that was enhanced by Mg2þ removal and blocked by
NMDA receptor antagonists, this was due to enhanced gluta-
matergic synaptic network activity but not due to direct effects
on NMDA receptors (Brorson et al., 1995). However, more
recently, Ye et al. (2004) showed using primary neocortical
cultures that Aß assemblies in a prefibrilar form produced neu-
ronal activation (patch clamp) that was attenuated by NMDA
receptor antagonist AP5.
Although it is still not clear whether NMDA receptors are
directly or indirectly activated/modulated by Aß, enhanced
NMDA receptor sensitivity might, at first sight, seem contra-
intuitive for the observed deficits in the LTP. However, we
propose similar mechanisms as discussed above for the im-
pairment of learning and synaptic plasticity under conditions
of chronic, non-phasic activation of NMDA receptors as
seen following reduction of Mg2þ concentration or application
of non-toxic concentrations of NMDA receptor agonists (see
above). In line with this assumption, Aß25e35 also was
reported to inhibit L-glutamate uptake in rat hippocampal as-
trocyte cultures (Harris et al., 1996) e this could also lead
to a tonic activation of NMDA receptors and deficits in LTP
similar to that seen in GLT-1 knockout mice (Katagiri et al.,
2001). The decisive experiment would be to test the ability
of memantine to reverse such Aß-induced deficits in LTP
and we are presently performing such studies.
5. Hypothesis of memantine MOA in AD
Several hypotheses have been proposed to explain the
MOA of memantine in AD. Most of them concentrate on ex-
planations as to why memantine has a better therapeutic toler-
ability compared to other NMDA receptor channel blockers
such as (þ)MK-801 and phencyclidine rather than on why
memantine provides a clinical improvement in cognition in
this disease. These theories are discussed below and presented
in a graphic form in several figures.
5.1. Low affinity and kinetics
Most hypotheses are based on the widely documented and
accepted fact that memantine and other well-tolerated open
channel blockers show much faster open channel blocking/un-
blocking kinetics than compounds burdened with psychotropic
side-effects such as (þ)MK-801 or phencyclidine (Rogawski
et al., 1991; Chen et al., 1992; Rogawski, 1993; Parsons
et al., 1993; Black et al., 1996; Parsons et al., 1999b) (see
Fig. 5). Unblocking kinetics are directly related to affinity,
i.e. less potent compounds have faster unblocking kinetics
whereas the on-rate of blockade does not seem to depend on

Low affinity antagonists assure fast association and dissociation

Memantine Glutamate

MK-801 Glutamate

Fig. 5. Schematic illustrating faster blocking kinetics of lower affinity channel blockers in the continuous presence of agonist and without changes in membrane
potential. As lower affinity compounds are required at higher concentrations than higher affinity compounds to provide a similar level of equilibrium block for the
whole receptor population then, by the law of mass action, they block each receptor channel with faster onset kinetics. Similar fast unblocking kinetics of lower
affinity compounds is an inherent feature, directly related to affinity. In the top sequence running left to right, the ephemeral/fast flicking block/unblock in the
continuous presence of memantine is illustrated for one receptor. In the lower sequence, lower concentrations of the more potent compound MK-801 take
much longer to gain access to each receptor channel, but once blocked, also take much longer to unblock. After achieving equilibrium blockade, in the continuous
presence of antagonist, the proportion of receptors in the blocked state at any time is, by definition, the same e here 2 of 6, i.e. 33%.
712 C.G. Parsons et al. / Neuropharmacology 53 (2007) 699e723

affinity, at least when expressed as Kon (Parsons et al., 1995).
However, the onset kinetics are also faster for lower affinity
compounds when the rate of blockade is expressed as ton at
IC50 concentrations (Parsons et al., 1995). The latter is the
therapeutically more relevant parameter and this is a fact
that should be apparent, at least to a biophysicist, due to the
law of mass action, i.e. the higher the concentration of com-
pound needed to block a receptor, the faster the rate of this
block, at least if Kon is not changed.
As to the published data, memantine blocks NMDA chan-
nels activated by high concentrations of agonist at 70 mV
with a Kon of 2e4  105 M1 s1 and Koff of around 0.2 s1
(Parsons et al., 1993, 1995, 1996, 1998; Bresink et al., 1996;
Chen and Lipton, 1997; Blanpied et al., 1997; Sobolevsky
and Koshelev, 1998; Sobolevsky et al., 1998). More detailed
analysis reveals that memantine blocks and unblocks open
NMDA receptor channels with double or even triple exponen-
tial kinetics. The amplitude and speed of the fast component of
block increase with memantine concentration. In contrast, the
speed of fast unblock remains constant but the amplitude de-
creases with memantine concentration (Frankiewicz et al.,
1996; Bresink et al., 1996; Blanpied et al., 1997; Sobolevsky
et al., 1998; Sobolevsky and Koshelev, 1998). These data indi-
cate that memantine binds to at least two sites within the
NMDA receptor channel.
There are divergent opinions as to why such blocking char-
acteristics are advantageous. Both Lipton’s and Rogawski’s
groups assumed that the ability of low affinity open channel
blockers to gain rapid access to the NMDA receptor channel
is important in determining their potential therapeutic safety,
at least in epilepsy for which memantine has not yet been
proven to be clinically useful and which, unfortunately, seems
unlikely on the basis of both preclinical and clinical data (Ro-
gawski et al., 1991; Chen et al., 1992; Rogawski, 1993). How-
ever, this hypothesis alone cannot explain the clinically proven
better tolerability of memantine in AD because, even if recep-
tors were only blocked following pathological activation, they
would then remain mostly blocked in the real therapeutic sit-
uation, i.e. the continuous presence of memantine in AD, and
therefore would still be unavailable for subsequent physiolog-
ical activation.
The partial untrapping hypothesis (Blanpied et al., 1997;
Johnson and Kotermanski, 2006) partially addresses this issue,
at least for potential neuroprotective effects of memantine in,
e.g. AD but cannot alone be used to explain the clinically
proven symptomatic effects of cognition e see below.
5.2. Voltage-dependency and rapid unblocking kinetics
The voltage-dependency of memantine rendered by its pos-
itive charge on the amino group at physiological pH and its
binding at a deep channel site of NMDA channel is reflected
in estimated d values of 0.71e0.83, i.e. memantine seems to
experience 70e80% of the transmembrane field (Parsons
et al., 1993, 1995, 1996, 1998; Bresink et al., 1996; Chen
and Lipton, 1997; Blanpied et al., 1997; Sobolevsky and Kosh-
elev, 1998; Sobolevsky et al., 1998).

High Agonist Concentration Low Agonist Concentration

Equilibrium block is the same

Fig. 6. Schematic illustrating agonist concentration-dependence of channel blocking kinetics for single channel. At high concentrations of agonist, more receptor
channels are open and available for blockade at any one time e left, all three of the three receptors; right, one of the three receptors. The sequence of activation
followed by block is the same for both, i.e. from top to bottom as indicated by the blue arrows. Although the time taken to achieve equilibrium block is different,
the level of this block at the end is the same e in this case three of the three receptors in each case.
 C.G. Parsons et al. / Neuropharmacology 53 (2007) 699e723 713

In addition, when offset kinetics in the continuous presence Memantine Low NMDA
of memantine following depolarization are fit by double expo-
nentials, the predominant effect of depolarization is to increase
dramatically the weight of the faster recovery time-constant of
memantine (Frankiewicz et al., 1996; Bresink et al., 1996; Par- Memantine Moderate NMDA
sons et al., 1998) which provides further support for there be-
ing at least two channel blocking sites for memantine e see
Section 5.1.
Although this d value is very similar to that of Mg2þ, the
functional consequences are different because memantine
bears only one positive charge whereas Mg2þ is a divalent
cation and therefore reacts with even stronger functional
Memantine High NMDA
dependence on changes in membrane potential. As such, in
comparison to Mg2þ, memantine shows somewhat less pro-
nounced functional voltage-dependency, but is still a strongly
voltage-dependent channel blocker when compared to high af-
finity uncompetitive NMDA receptor antagonists.
The kinetics of (þ)MK-801 and phencyclidine are too slow
to allow them to leave the channel upon transient depolariza-
tion plus concomitant NMDA receptor activation and this is
reflected in apparently weaker functional voltage-dependency
reported in almost all studies published to date.
In other words, under physiologically relevant conditions, Memantine Normalized NMDA
the two parameters kinetics and voltage-dependency are
Non-steady state
directly related to antagonist affinity, with lower affinity com- unblock different
pounds showing faster kinetics and apparently stronger func-
tional voltage-dependency (Parsons et al., 1995, 1999a) than
high affinity compounds. These aspects provide the basis for
signal-to-noise hypothesis (Parsons et al., 1999a; Danysz
et al., 2000; Danysz and Parsons, 2003) which is discussed
Non-steady state
in detail below. block different

5.3. Agonist concentration-dependency (use dependency)
NMDA receptor agonist concentration-dependency of
block by memantine has been discussed intensively by some
groups in the literature. The hypothesis is that the higher the
NMDA receptor agonist concentration, the greater the block
by memantine. This has been claimed to have profound ther-
apeutic relevance and is discussed as one of the main reasons
why memantine is different from other NMDA receptor chan-
nel blockers (Lipton and Chen, 2004; Lipton, 2004, 2005,
2006). The fundament of this hypothesis to explain the better
therapeutic utility of memantine is in disaccord with the mM
concentrations of glutamate known to be released during phys-
iological activation of NMDA receptors (Clements et al.,
1992) (see later sections).
In retrospect, any apparent agonist concentration dependent
blocking effects of memantine reported in early experiments
seem to have been observed purely due to technical limita-
tions. When one works with low concentrations of agonist,
the open probability of NMDA receptor channels is reduced
and an open channel blocker therefore needs more time to
gain access to the channel (Figs. 6 and 7). In other words,
an equilibrium block had almost certainly not been achieved
under the experimental conditions used with low agonist con-
centrations at room temperature in both Chen et al. (1992) and
Fig. 7. Schematic illustrating agonist concentration-dependence of channel
blocking kinetics for whole cell patch clamp currents in concentration clamp
experiments. At high concentrations of agonist, more receptor channels are
open and available for blockade at agonist equilibrium and this is reflected
as larger whole cell currents e red low, green moderate and black high con-
centrations of agonist (e.g. NMDA). As a direct consequence, concentration
clamp application/removal of antagonist blocks/unblocks these whole cell cur-
rents with faster kinetics for higher concentrations of agonist. Although this is
reflected in different levels of non-steady state block/unblock by the arrows in
the normalized superimposed traces at the bottom, the degree of block at an-
tagonist equilibrium is the same. When assessing the degree of blockade by
lower, therapeutically relevant concentrations of memantine then, by the law
of mass action, the onset kinetics of blockade would also become much slower.
Finally, it should be clear from the agonist onset kinetics in the normalized fig-
ure, that lower concentrations of agonist take longer to reach steady state re-
ceptor activation. If low concentrations of agonist have not reached equilibrium
levels of activation at the time of antagonist addition then a continued, unobserved
background increase of ‘‘control’’ levels of low concentration agonist activation
might apparently counteract any observed block by uncompetitive antagonist. In
other words, there are three very large technical hurdles that require that such ex-
periments have to be performed with extreme care and that a very long time must
be allowed for the both agonist and antagonist to reach true equilibrium activation/
blockade under such conditions. One needs very good, cultured, neuronal cells
without significant run down to be able to address this issue.
Parsons et al. (1993). It should also be noted that kinetics are
much slower at room temperature used in most in vitro exper-
iments than in vivo, i.e. 37  C (Davies et al., 1988). One needs
very good, primary, neuronal cells without significant run
714 C.G. Parsons et al. / Neuropharmacology 53 (2007) 699e723

down to be able to address this issue. On another note Chen
et al. (1992) used retinal ganglion cells, which are not really
so relevant for the CNS, and never described or subsequently
discussed the possible technical problems discussed above,
nor the additional potential problems of receptor run down.
Our recent experiments (Gilling et al., 2007) attempt to take
these problems into account, and indicate, that there is NO true
agonist concentration-dependency of equilibrium NMDA re-
ceptor channel blockade by memantine (Fig. 7). Any further dis-
cussion on the possible relevance of such an effect seems to be
beyond the scope of this review, because this previously pub-
lished and very much discussed ‘‘observation’’ was most likely
an experimental artefact (Gilling et al., 2007).
5.4. Partial untrapping
Partial untrapping has been claimed to explain the better
therapeutic utility of memantine as a proportion of channels e
around 15e20% e would always unblock upon cessation of
agonist activation and would thereby be available for subse-
quent physiological activation (Blanpied et al., 1997)
(Fig. 8). The phenomenon also occurs in the continuous pres-
ence of memantine, which is the case in the therapeutic use of
memantine (Parsons et al., 1999b). The newest data from
Johnson’s group are consistent with a model in which there
are two binding sites for memantine (see above), a deep site
inside the external gate that allows full trapping, and a shallow
site outside the gate that does not (Kotermanski and Johnson,
2004). Ketamine only binds to the deep site and this might ac-
count for the fact that ketamine and (þ)MK-801 do not share
this property with memantine (Lanthorn et al., 2000). How-
ever, attractive this hypothesis might be for the tolerability
of memantine, such a MOA alone cannot explain the symp-
tomatic therapeutic effects of memantine on learning and syn-
aptic plasticity observed in animal models and proven in the
clinical situation.
Other important differences between ketamine and meman-
tine are more likely to be responsible for the differences
observed in the clinical tolerability of these two fast, volt-
age-dependent open channel NMDA receptor antagonists e
namely PK and route of administration. In strong contrast to
memantine, ketamine has an extremely short half-life in
both rodents and man and was normally administered i.v. in
most clinical studies addressing, e.g. effects on chronic pain.
It is therefore probably, that excessive peak plasma/CSF levels
were needed in such studies and that this was the cause for
poor tolerability.
5.5. NMDA receptor subtype selectivity
Memantine blocked NR2A, NR2B, NR2C and NR2D re-
ceptors expressed in X. oocytes with IC50s of 0.89, 0.40,
0.32 and 0.28 mM, respectively (Parsons et al., 1999a).
NR2B selective antagonists also seem to have a better thera-
peutic profile in many animal models (Parsons et al., 1998).
There are several hypotheses why this could be the case that
are outside the scope of the present review but the most prev-
alent are related to the selective expression of NR2B in fore-
brain regions (Monyer et al., 1994); a use- and agonist
concentration state-dependent block by NR2B selective antag-
onists (Kew et al., 1998) and their extrasynaptic localisation
(Li et al., 1998). Memantine and other well-tolerated NMDA
receptor antagonists such as dextromethorphan and dextrorphan
were considerably more potent against [14C]acetylcholine than
[3H]spermidine release from rat striatal slices in vitro whereas
(þ)MK-801 and phencyclidine were equipotent e for review
see Nankai et al. (1998). This similarity was also proposed to
be due to NR2B selective effects of memantine, an assumption
partially supported by the finding that memantine was three
times more potent against NMDA-induced Ca2þ influx in hu-
man NR1a/NR2B receptors than in human NR1a/NR2A

MK-801 Glutamate Complete trapping

Memantine Glutamate Partial untrapping

Fig. 8. Very simplified schematic illustrating partial untrapping by memantine. Top, MK-801 takes longer to block open NMDA receptor channels due to slower
onset kinetics at the lower concentrations needed. Once inside the channel, block is maintained for a long time and agonist can dissociate and trap MK-801 in the
closed, inactive channel. Bottom, memantine gains quicker access to the open NMDA receptor channel but a proportion (around 20%) of the receptor channels
release memantine before closure and release of agonist. See Fig. 5 for a more temporal schematic of differences between memantine and MK-801.
 C.G. Parsons et al. / Neuropharmacology 53 (2007) 699e723
receptors permanently expressed in L(tk-) cells (Grimwood
et al., 1996).
However, the relevance of this moderate two- to three-fold
greater potency at NR2B over NR2A receptors is unclear and
is not supported by other studies. Thus, memantine was equi-
potent against glutamate-induced currents in NR2A and NR2B
receptors expressed in HEK-293 cells (IC50 0.93 and 0.82 mM,
respectively, at 70 mV) but again somewhat more potent
against NR2D receptors (IC50 ¼ 0.47 mM) (Bresink et al.,
1996). Memantine was also previously reported to be almost
equipotent against NR2A and NR2B receptors expressed in
X. oocytes (IC50 of 0.29 and 0.23 mM, respectively) although
the absolute potencies reported in this study (Avenet et al.,
1997) where considerably higher than those reported by sev-
eral different groups. Even if memantine were to show
a greater potency at NR2B receptors than NR2A, there is no
published reason that would support the notion that meman-
tine shares the same reported mechanisms for state-dependent
effects as classical NR2B antagonists (Kew et al., 1998).
Binding studies indicate that the better therapeutic profile
of memantine and other drugs known to be well tolerated in
humans may be related to relatively higher affinity in the cer-
ebellum than in forebrain regions (Bresink et al., 1995; Porter
and Greenamyre, 1995). This increased potency in the
cerebellum could be related to the enhanced expression of
NR2C receptors in this region (Monyer et al., 1994) and
memantine has indeed been reported to be three-fold more po-
tent against NR2C receptors than NR2A receptors (Parsons
et al., 1999a). In this regard, a clinical study showing that
memantine can block classical eyeblink conditioning at doses
having no effect on verbal or visuospatial memory is of par-
ticular interest (Schugens et al., 1997) as classical eyeblink
conditioning is critically dependent upon intact cerebral cir-
cuitry. It is not clear why memantine should block synaptic
plasticity mediated via NR2C but not NR2A/B receptors but
it is likely that the three-fold greater potency at these recep-
tors is associated with slower blocking kinetics and therefore
less ability to leave these receptor channels upon transient
physiological activation. However, it is again unclear how
such a moderate preference of memantine for NR2C/2D re-
ceptors can explain its improved therapeutic profile in AD,
in particular, improvement of cognition. In fact, NR2C block-
ade might rather be expected to cause more pronounced cer-
ebellar motor deficits.
5.6. Signal-to-noise hypothesis
Physiologically, NMDA receptors are transiently activated
by mM concentrations of glutamate in the synapse (Clements
et al., 1992) following strong depolarization of the postsynap-
tic membrane which rapidly relieves their voltage-dependent
blockade by Mg2þ (Nowak et al., 1984) whereas during path-
ological activation, NMDA receptors are activated by lower
concentrations of glutamate but for much longer periods of
time (Benveniste et al., 1984; Andine et al., 1991; Globus
et al., 1991a,b; Mitani et al., 1992; Buisson et al., 1992). How-
ever, the functional voltage-dependency of the divalent cation
715
Mg2þ is so pronounced that it also leaves the NMDA channel
upon moderate depolarization under pathological conditions.
Although uncompetitive antagonists also block the NMDA re-
ceptor channel, high affinity compounds such as (þ)MK-801
have much slower unblocking kinetics than Mg2þ and appar-
ently far less pronounced functional voltage-dependency (see
above) and are therefore unable to leave the channel within
the time course of a normal NMDA receptor-mediated excit-
atory postsynaptic potential. As a result, (þ)MK-801 blocks
both the pathological and physiological activation of NMDA
receptors.
We were the first to suggest that the combination of fast off-
set kinetics and relatively strong functional voltage-depen-
dency allow memantine to rapidly leave the NMDA channel
upon transient physiological activation by mM concentrations
of synaptic glutamate but block the sustained activation by mM
concentrations of glutamate under moderate pathological
conditions (Parsons et al., 1993, 1995, 1996) (Fig. 9). This
Pathology Physiology
Rest
Mg2+ Ca2+ Ca2+
- 70 mV - 50 mV - 20 mV
Ca2+
Memantine
- 70 mV - 50 mV - 20 mV
MK-801
- 70 mV - 50 mV - 20 mV
Fig. 9. Schematic illustrating the hypothesis explaining how the fast unblock-
ing kinetics of memantine allow this voltage-dependent compound to differen-
tiate between the physiological and pathological activation of NMDA
receptors. Under resting therapeutic conditions, i.e. in their continuing pres-
ence at 70 mV (left), Mg2þ (top), memantine (middle) and MK-801 (bottom)
all occupy the NMDA receptor channel. Both Mg2þ and memantine are able to
leave the NMDA receptor channel upon strong synaptic depolarization
(20 mV, right) due to their pronounced voltage-dependency and rapid un-
blocking kinetics whereas the slow blocker MK-801 remains trapped. How-
ever, memantine e in contrast to Mg2þ e does not leave the channel so
easily upon moderate prolonged depolarization during chronic excitotoxic in-
sults (50 mV, centre). Transient strong and prolonged moderate Ca2þ influx
illustrated by the full and dashed red arrows, respectively. Modified after Korn-
huber and Weller (1997) and Parsons et al. (1999b).
716 C.G. Parsons et al. / Neuropharmacology 53 (2007) 699e723

1 2

noise noise

NMDA receptor NMDA receptor

magnesium magnesium
glutamate glutamate
-70mV -70mV

3 4
signal
noise noise

NMDA receptor NMDA receptor

magnesium magnesium
glutamate glutamate

-20mV -70mV

Fig. 10. Under normal conditions, synaptic plasticity/learning depends on the detection of a relevant (sufficiently strong) signal over background activity (here
referring to transient strong vs. prolonged moderate intracellular Ca2þ levels), i.e. sufficient signal-to-noise ratio. Intracellular Ca2þ levels at any one time-point
represented by different sizes of the Ca2þ containing circles. Electrodes/potentiometers illustrate the postsynaptic membrane potential: 70 mV, resting; 50 mV,
mild prolonged pathology; 20 mV, transient strong synaptic activation. Jagged red arrow indicates arrival of a presynaptic signal. Mg2þ and glutamate are illus-
trated by blue circles and red triangles, respectively.

hypothesis is further supported by the fact that, although the
predominant component of offset kinetics upon rapid removal
of memantine at room temperature in vitro at near resting
membrane potentials is still too slow to allow synaptic activa-
tion e i.e. around 5 s, the relief of blockade in the continuous
presence of memantine upon depolarization is much faster due
to an increase in the weight of the faster recovery time-
constant (see above). The unblocking rate of memantine from
cultured hippocampal neurones and NR1a/NR2A receptors
expressed in X. oocytes following voltage-steps is very rapid
and well within the time course of an NMDA receptor-mediated
EPSP (Parsons et al., submitted for publication). This finding
adds further support to our hypothesis that rapid, voltage-depen-
dent relief of blockade following synaptic activation of NMDA
receptors underlies the clinical utility of memantine.
These kinetics are likely to be even faster in vivo due to
higher temperatures (Davies et al., 1988). Furthermore, the
rate of recovery from memantine blockade is dependent on

Aß, Tau, Energy deficit Aß, Tau, Energy deficit

1 2 noise 3 noise

noise

NMDA receptor NMDA receptor NMDA receptor

magnesium magnesium magnesium
glutamate glutamate glutamate
-70 mV -50 mV -50mV

Aß , Tau, Energy deficit Aß, Tau, Energy deficit

4 signal noise 5

NMDA receptor NMDA receptor

magnesium magnesium
glutamate glutamate
-20mV 0 mV

Fig. 11. The signal-to-noise ratio hypothesis assumes that in AD, due to a tonically overactive glutamatergic system, Mg2þ is not effective enough to play its
‘filtering’ function. In turn, synaptic noise rises, impairing detection of the relevant signal such as in learning. One bound glutamate to NMDA receptor represents
continuous, low-level NMDA receptor activation (even though two molecules in fact have to be bound to activate the receptor). Potentiometer at 0 mM indicates
cell death. Aß, Tau and energy deficit are shown as factors favouring, either directly or indirectly, conditions for overactivation of NMDA receptors. Other aspects
are as in Fig. 10.
 C.G. Parsons et al. / Neuropharmacology 53 (2007) 699e723
Aß, Tau, Energy deficit
1 noise 2
NMDA receptor
magnesium
glutamate
M Memantine -50 mV
Aß, Tau, Energy deficit
3 4
M noise
NMDA receptor
magnesium
glutamate
-70 mV
Fig. 12. Schematic explaining the MOA of memantine in AD based on the signal-to-noise hypothesis. Memantine is able to serve as a filter blocking ‘synaptic
noise’ and thereby allowing detection of the relevant signal, i.e. synaptic plasticity is restored. Memantine illustrated as a large, ‘‘M&M like’’ blue circle; for other
aspects, see legends to Figs. 10 and 11.
the open probability of NMDA channels (Chen and Lipton,
1997), i.e. would be faster in the presence of higher, synaptic
concentrations of glutamate (Clements et al., 1992).
In summary, we feel that the biophysical properties of
memantine would allow this compound to clearly differentiate
between chronic low-level pathological activation of NMDA
receptors in AD (‘‘noise’’) and physiological synaptic
NMDA receptor activation (‘‘signal’’) (Danysz et al., 2000;
Danysz and Parsons, 2003). It is our belief that memantine,
at therapeutically relevant concentrations, is able to suppress
the pathological background ‘‘noise’’ but preserve or even
enhance the desired physiological synaptic NMDA receptor-
mediated plasticity ‘‘signal’’. In our opinion, memantine pro-
vides both neuroprotection and symptomatic improvement by
the same MOA, i.e. moderate-affinity NMDA receptor channel
blockade (Figs. 10, 11 and 12).
6. Conclusions
As discussed above, various hypotheses attempt to explain
why memantine, in contrast to some other NMDA receptor an-
tagonists, may provide both the clinically proven symptomatic
improvement in AD plus the potential for neuroprotective ac-
tivity with few side-effects. However, in our opinion, only the
signal-to-noise hypothesis e which considers both voltage-
dependence and fast offset kinetics in the continuous presence
of memantine e can adequately explain both the rapid symp-
tomatological, cognitive effects of memantine seen already
after a few weeks of treatment in clinical trials e and the pre-
dicted long-term neuroprotective effects of this compound.
To sum up our working hypothesis, the effects of meman-
tine can be likened to a slightly more potent Mg2þ block.
717
Aß, Tau, Energy deficit
M noise
NMDA receptor
magnesium
glutamate
-70 mV
Aß, Tau, Energy deficit
signal
M
noise
NMDA receptor
magnesium
glutamate
-20 mV
Under resting conditions, and in their continuing presence,
both Mg2þ and memantine occupy the NMDA receptor
channel. Likewise, both are able to leave the NMDA receptor
channel upon strong synaptic depolarization due to their pro-
nounced voltage-dependency and rapid unblocking kinetics.
However, memantine e in contrasts to Mg2þ e does not leave
the channel so easily upon moderately prolonged depolariza-
tion during chronic excitotoxic insults (Parsons et al., 1993,
1995). This property of memantine could indeed provide
both neuroprotection and symptomatic improvement by the
same MOA, i.e. fast, moderate affinity, voltage-dependent
NMDA receptor channel blockade.
Acknowledgements
The authors would like to thank Andrzej Dekundy for the
compilation of information of magnesium effects in man;
Claudia Jatzke, Kate Gilling (Merz Pharmaceuticals), Jan
Egebjerg, and Julie Lotharius (Lundbeck) for valuable com-
ments to the manuscript.
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