Download Memantine is a clinically well tolerated N-methyl-D

Neuropharmacology 38 (1999) 735 – 767
Review
Memantine is a clinically well tolerated N-methyl-D-aspartate
(NMDA) receptor antagonist—a review of preclinical data
C.G. Parsons *, W. Danysz, G. Quack
Department of Pharmacological Research, Merz and Co., Eckenheimer Landstrasse 100 -104, D-60318 Frankfurt am Main, Germany
Accepted 19 January 1999
Abstract
N-methyl-D-aspartate (NMDA) receptor antagonists have therapeutic potential in numerous CNS disorders ranging from acute
neurodegeneration (e.g. stroke and trauma), chronic neurodegeneration (e.g. Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, ALS) to symptomatic treatment (e.g. epilepsy, Parkinson’s disease, drug dependence, depression, anxiety and
chronic pain). However, many NMDA receptor antagonists also produce highly undesirable side effects at doses within their
putative therapeutic range. This has unfortunately led to the conclusion that NMDA receptor antagonism is not a valid
therapeutic approach. However, memantine is clearly an uncompetitive NMDA receptor antagonist at therapeutic concentrations
achieved in the treatment of dementia and is essentially devoid of such side effects at doses within the therapeutic range. This has
been attributed to memantine’s moderate potency and associated rapid, strongly voltage-dependent blocking kinetics. The aim of
this review is to summarise preclinical data on memantine supporting its mechanism of action and promising profile in animal
models of chronic neurodegenerative diseases. The ultimate purpose is to provide evidence that it is indeed possible to develop
clinically well tolerated NMDA receptor antagonists, a fact reflected in the recent interest of several pharmaceutical companies
in developing compounds with similar properties to memantine. © 1999 Elsevier Science Ltd. All rights reserved.
Keywords: Memantine; NMDA receptor antagonist uncompetitive; Kinetics; Voltage-dependence; Learning; Neuroprotection; Dementia
Contents
1.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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2.
Clinical tolerability of memantine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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3.
Memantine is a NMDA receptor antagonist
3.1. Receptor binding . . . . . . . . . . . .
3.2. Electrophysiology . . . . . . . . . . . .
3.3. Other effects of memantine in vitro. .
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4.
Pharmacokinetics—are brain concentrations sufficient to block NMDA receptors? . . .
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5.
In vivo evidence for NMDA blockade at therapeutic doses. . . . . . . . . . . . . . . . .
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6.
Tolerability in animal models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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7.
Neuroprotection in vitro . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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* Corresponding author. Tel.: +49-69-1503-368; fax: +49-69-596-21-50.
E-mail address: [email protected] (C.G. Parsons)
0028-3908/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S 0 0 2 8 - 3 9 0 8 ( 9 9 ) 0 0 0 1 9 - 2
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C.G. Parsons et al. / Neuropharmacology 38 (1999) 735–767
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8.
Neuroprotection in vivo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.1.
Acute ischæmia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.2.
Models of excitotoxicity relevant for chronic neurodegenerative diseases . . . .
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Positive symptomatological effects on learning . . . . . . . . . . . . . . . . . . . . . . . .
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10.
Why is memantine well tolerated clinically? . . . . . . . . . . . . . . . . . . . . . . . . . .
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Further
11.1.
11.2.
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11.14.
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Neurotoxicity in the cortex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Bibliography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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possible therapeutic applications of memantine
AIDS . . . . . . . . . . . . . . . . . . . . . . . .
Glaucoma . . . . . . . . . . . . . . . . . . . . .
Hepatic encephalopathy . . . . . . . . . . . . .
Multiple sclerosis . . . . . . . . . . . . . . . . .
Tinnitus . . . . . . . . . . . . . . . . . . . . . .
Parkinson’s disease . . . . . . . . . . . . . . . .
Tardive dyskinesia . . . . . . . . . . . . . . . .
Chronic pain . . . . . . . . . . . . . . . . . . .
Tolerance, sensitisation and drug addiction . .
Epilepsy . . . . . . . . . . . . . . . . . . . . . .
Spasticity. . . . . . . . . . . . . . . . . . . . . .
Depression and anxiety . . . . . . . . . . . . .
Other possible indications . . . . . . . . . . . .
Chronic and subchronic treatment . . . . . . .
1. Introduction
When a new therapeutic concept is proposed, this is
usually followed by intensive screening in in vitro and
in vivo studies, testing of selected agents in appropriate
animal models and finally therapeutic verification with
a few agents in clinical trials. This process may well
take more than a decade to accomplish, and then
discouraging clinical results with non-optimally selected
agents might finally ‘kill’ the concept (see Muir and
Lees, 1995). This is probably particularly true for
NMDA receptor antagonists as clinical trials with
newly developed agents failed to support good therapeutic utility due to numerous side effects (e.g. Dizocilpine
((+)MK-801);
Cerestat
(CNS-1102);
Licostinel (ACEA 1021); Selfotel (CGS-19755) and DCPP-ene) raising doubts about the possibility of developing NMDA receptor antagonists with a satisfactory
side effect to benefit ratio (Leppik et al., 1988; Sveinbjornsdottir et al., 1993; SCRIP 2229/30, 1997, p. 21;
Yenari et al., 1998).
NMDA receptor antagonists potentially have a wide
range of therapeutic applications ranging from acute
neurodegeneration (e.g. stroke and trauma), chronic
neurodegeneration
(e.g.
Parkinson’s
disease,
Alzheimer’s disease, Huntington’s disease, ALS) to
symptomatic treatment (e.g. epilepsy, Parkinson’s disease, drug dependence, depression, anxiety, chronic
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pain etc.—for reviews see: Meldrum, 1992; Danysz et
al., 1995a; Müller et al., 1995; Parsons et al., 1998c).
Functional modulation of NMDA receptors can be
achieved through actions at different recognition sites
such as: the primary transmitter site (competitive), the
phencyclidine site located inside the cation channel
(uncompetitive), the polyamine modulatory site and the
strychnine-insensitive,
coagonistic
glycine
site
(glycineB). However, NMDA receptors also play a crucial physiological role in various forms of synaptic
plasticity such as those involved in learning and memory (see Collingridge and Singer, 1990; Danysz et al.,
1995b). Neuroprotective agents which completely block
NMDA receptors also impair normal synaptic transmission and thereby cause numerous side effects—a
double sided sword. The challenge has therefore been
to develop antagonists that prevent the pathological
activation of NMDA receptors but allow their physiological activity. However, the potential for good clinical
tolerability of NMDA receptor antagonism was in fact
verified years before the concept was formulated.
Memantine (1-amino-3,5-dimethyl-adamantane, Fig. 1)
was already registered in Germany for a variety of
CNS-indications in 1978 but its most likely therapeutic
mechanism of action—uncompetitive NMDA receptor
antagonism—was only discovered 10 years later (Bormann, 1989; Kornhuber et al., 1989, 1991; Parsons et
al., 1993, 1995).
C.G. Parsons et al. / Neuropharmacology 38 (1999) 735–767
Fig. 1. Chemical structure of memantine.
Memantine was first synthesised by researchers at Eli
Lilly in order to prepare a N-arylsulfonyl-N%-3,5dimethyladamantylurea derivative as an agent to lower
elevated blood sugar levels (Gerzon et al., 1963) but it
was completely devoid of such activity. In 1972 Merz
and Co. applied for a German patent demonstrating that
this compound (code D 145) has central nervous system
(CNS) activity indicating potential for the treatment of
Parkinson’s disease, spasticity and cerebral disorders like
coma, cerebrovascular and geronto-psychiatric disturbances (see Grossmann and Schutz, 1982; Miltner,
1982a,b; Schneider et al., 1984; Mundinger and Milios,
1985). In 1975 and 1978, patents were granted in Germany and the USA, respectively. At that time, three
major groups were engaged in the biochemical, pharmacological and pharmacokinetic evaluation of D 145
which had been given the INN memantine. In 1983,
these groups published a joint synopsis on memantine in
an attempt to summarise experimental evidence to explain clinical observations (Wesemann et al., 1983). They
postulated direct and indirect dopaminomimetic activity
as well as effects on serotonergic and noradrenergic
Fig. 2. Graphic presentation of in vitro effects of memantine in
relation to its serum levels. The scale for brain levels is also shown on
the basis of CSF sampling in man and brain microdialysis experiments in rats. NB: logarithmic scales.
737
systems. However, most in vitro data were obtained at
concentrations 100 fold higher than those achieved
therapeutically, a fact that was not recognised at the
time. Since then, extensive preclinical research has revealed the most likely therapeutic mechanism of action
of memantine to be via antagonism of NMDA receptors
(Bormann, 1989; Kornhuber et al., 1989; Chen and
Lipton, 1991; Kornhuber et al., 1991; Parsons and
Pantev, 1991; Chen et al., 1992; Parsons et al., 1993).
Based on these results, Merz filed an international
application in 1989 claiming the treatment of cerebral
ischæmia and Alzheimer’s dementia. Since then, clinical
research has focused on the treatment of dementia
(Ditzler, 1991; Görtelmeyer et al., 1993; Pantev et al.,
1993; Schulz et al., 1996a).
The present review discusses the mechanism of action
of memantine as a clinically used and well tolerated
NMDA receptor antagonist. It is an attempt to summarise the prerequisite features of memantine that determine its clinical safety in the treatment of dementia and
possible utility in other CNS disorders. The aim is to
demonstrate that NMDA receptor antagonism is indeed
a valid therapeutic approach and that it is possible to
develop compounds that show the desired separation
between pathological and physiological activation of
NMDA receptors. For other reviews on memantine
which came to the same conclusion the reader is referred
to the following (Rogawski, 1993; Müller et al., 1995;
Kornhuber and Weller, 1997).
2. Clinical tolerability of memantine
As indicated above memantine has been applied clinically for over 15 years showing good tolerability and the
number of treated patients exceeds 200 000. Although
memantine has been reported to produce psychotomimetic effects in man (Riederer et al., 1991), as shown
before for several other uncompetitive NMDA receptor
antagonists, such reports should be put into context.
Psychotomimetic effects only appear if the recommended titration of dosing from 5 to 20 mg over 3–4
weeks is skipped or when memantine is combined with
dopaminomimetic therapies. In this respect it is noteworthy that in spite of the 15 year clinical history, side effects
are sporadic and memantine is widely accepted as a very
well tolerated medication (Grossmann and Schutz, 1982;
Miltner, 1982a,b; Schneider et al., 1984; Mundinger and
Milios, 1985; Ditzler, 1991; Görtelmeyer et al., 1993;
Pantev et al., 1993; Schulz et al., 1996a).
The clinical observations indeed indicate the therapeutic utility of memantine. But to defend the concept of the
validity of NMDA receptor antagonism it must first be
proven that memantine is a NMDA receptor antagonist
with sufficient affinity to block CNS NMDA receptors
at therapeutic doses.
738
C.G. Parsons et al. / Neuropharmacology 38 (1999) 735–767
3. Memantine is a NMDA receptor antagonist
3.1. Receptor binding
Memantine displaces the binding of [3H]( +)MK-801
in human cortex, rat cortex and the CA1 region of
hippocampus with Kis of around 1 mM (Kornhuber et
al., 1989, 1991, 1994; Bresink et al., 1995a,b; Porter and
Greenamyre, 1995). Due to the uncompetitive nature of
such binding, inhibition could theoretically be indirect via
antagonism at other sites of the NMDA receptor complex. This is unlikely, as our own previously unpublished
binding date indicate no antagonistic interactions with
the glutamate, glycine and sigma sites at therapeuticallyrelevant concentrations: memantine (10 – 100 mM) doesn’t
displace the binding of [3H]aspartate, [3H]glutamate,
[3H]glycine or [3H]MDL-105,519 and high concentrations
are required to displace [3H]( +)pentazocine binding
from sigma-1 sites (Ki 20 mM, Kornhuber et al., 1993).
Despite its relatively moderate affinity, memantine seems
to be selective for the ( + )MK-801 site and doesn’t
influence the binding of ligands for numerous other CNS
receptors at 10–100 mM (e.g. Wesemann et al., 1979,
1981, 1983; Wesemann and Von Pusch, 1979, 1981;
Osborne et al., 1982; Wesemann and Ekenna, 1982;
Reiser et al., 1988; Verspohl et al., 1988; Reiser and Koch,
1989; Kornhuber et al., 1993; see Danysz et al., 1997 for
review of previously unpublished data; see also Fig. 2).
A radiolabelled memantine derivative (1-amino-3[18F]fluoro-methyl-5-methyl-adamantane) has been developed recently and should provide further insights into
the nature and distribution of binding sites for memantine
in the CNS (Samnick et al., 1997, 1998). The distribution
of binding sites for 1-amino-3-[18F]fluoro-methyl-5methyl-adamantane in the murine CNS was similar to
that of [3H](+)MK-801 except for higher levels in the
cerebellum, as expected for compounds binding with
higher affinity to NR2C receptors (Bresink et al., 1995a,b;
Porter and Greenamyre, 1995).
3.2. Electrophysiology
Whole cell patch clamp data from cultured and
freshly dissociated neurones, retinal ganglion cells and
NMDA receptors expressed in HEK-293 or CHO cells
provide more conclusive evidence for open channel
blockade of NMDA receptors by memantine, i.e. uncompetitive antagonism (Bormann, 1989; Chen et al.,
1992; Parsons et al., 1993, 1995, 1996; Bresink et al.,
1996; Frankiewicz et al., 1996; Blanpied et al., 1997;
Chen and Lipton, 1997; Sobolevsky and Koshelev,
1998; Sobolevsky et al., 1998). In all studies, memantine
antagonised NMDA receptor-mediated inward currents
in a use and strongly voltage-dependent manner with
IC50s of 1–3 mM at −100 to −70 mV. For example,
memantine blocked NMDA-induced currents in freshly
dissociated hippocampal neurones with an IC50 of 1.04
mM at − 100 mV (Parsons et al., 1996).
The antagonistic effects of memantine at −70 mV
were not influenced by increasing concentrations of
glycine (Parsons et al., 1993). Thus, antagonism via
interactions at the glycineB site is unlikely. However, it
is possible that memantine increases the affinity of
glycine at NMDA receptors as reflected in a potentiation of NMDA currents at positive potentials by low
concentrations of memantine (Wang et al., 1994; Wang
and MacDonald, 1995; Parsons et al., 1998a). Although
Berger et al. (1996) have proposed that part of the
inhibition by memantine is due to interactions with the
polyamine site, our own patch clamp data with cultured
neurones indicate that the potency of memantine is
identical in the absence and presence of spermine (with
spermine 100 mM at − 70 mV IC50 of 2.1 9 0.1 mM,
without spermine IC50 of 2.39 0.3 mM; Parsons et al.
unpublished). It seems more likely that any changes in
the displacement of [3H](+ )MK-801 binding in the
presence of polyamine antagonists or agonists is secondary to effects on the apparent affinity of [3H](+)
MK-801 itself. Much higher concentrations of memantine also gain access to the channel in the absence of
agonist but the 100 fold lower affinity negates the
therapeutic significance of such interactions (Blanpied
et al., 1997; Sobolevsky et al., 1998).
Memantine and Mg2 + seem to block at the same or
similar channel site as they are mutually exclusive—as
evidenced by the kinetics of unblock in the presence of
both (Chen et al., 1992; Sobolevsky et al., 1998).
Memantine blocked human NR1/NR2A receptors expressed in Xenopus oocytes in a strongly voltage-dependent manner (IC50 at −80 mV= 0.3 mM, d=0.77;
Ferrer-Montiel et al., 1998). The potency of memantine
was reduced 20 fold by mutations at the N-site of the
M2 membrane inserted segment in NR1 subunits
(N598Q) and 30–100 fold by double mutations
(W593L/N598Q) within the channel forming domain.
Double mutations at the equivalent L- (L577W) and
Q/R-sites (Q582T) in GluR1 receptors permitted open
channel blockade of AMPA receptors by memantine
(IC50 at − 70 mV = 1.3 mM, d= 0.75) (Ferrer-Montiel
et al., 1998).
Memantine is two to three times more potent against
NMDA receptors expressed in Xenopus oocytes than
against NMDA-induced currents in cultured hippocampal neurones at the same membrane potential, i.e. −70
mV. The difference between these two electrophysiological assays is probably related to the following factors.
Firstly, the NR1 splice variants expressed in cultured
hippocampal neurones are not known but are very
likely to influence the potencies of NMDA receptor
channel blockers at heteromeric receptor complexes
containing NR2A or NR2B subunits (Sakurada et al.,
1993; Rodriguez Paz et al., 1995). Secondly, in order to
C.G. Parsons et al. / Neuropharmacology 38 (1999) 735–767
minimise artefacts mediated via voltage-activated K +
channels at positive potentials, Cs + ions are often used
as the major intracellular cation in most patch clamp
experiments. Cs + ions have recently been reported to
lower the affinity of memantine as a NMDA receptor
antagonist in cultured retinal ganglion cells by increasing
voltage-dependency (see Chen and Lipton, 1997). The
fact that the influence of ‘ionic pressure gradients’ on
Mg2 + block are different for various cations (Ruppersberg et al., 1994) prompted us to test the potency of
memantine with intracellular K + . We observed a 2.6
fold increase in the potency of memantine when K + was
used as the major intracellular cation (IC50 =1.1 mM at
− 70 mV, Parsons et al., 1999). Finally, memantine is
also more potent at NMDA receptor subtypes expressed
in HEK-293 and CHO cells (Bresink et al., 1996;
Blanpied et al., 1997) and native NMDA receptors in
freshly dissociated hippocampal neurones (Parsons et
al., 1996; Sobolevsky and Koshelev, 1998; Sobolevsky et
al., 1998) all of which lack the large dendritic arborization of cultured hippocampal pyramidal neurones. As
such, the strong voltage-dependency of memantine
might weaken its antagonistic effects at NMDA receptors on inadequately clamped distal dendrites in large
cultured hippocampal pyramidal neurones.
The potency of memantine and other uncompetitive
NMDA receptor antagonists is often apparently much
lower in in vitro slice preparations used for electrophysiological recordings (Parsons et al., 1993; Rohrbacher et
al., 1994; Apland and Cann, 1995) than against NMDAinduced currents in isolated neurones or finely chopped
tissue used for biochemical experiments (e.g. Lupp et al.,
1992; Nankai et al., 1995a,b, 1996, 1998). This is likely
to reflect slow penetration of lipophyllic substances into
relatively thick slices and the use-dependent nature of
the blockade (Frankiewicz et al., 1996). Such factors
should always be considered when comparing potencies
in different preparations. For example, the fact that
memantine (6 mM) was claimed to be completely without
effects on the induction of LTP in hippocampal slices
(Stieg et al., 1993; Chen et al., 1998) has to be regarded
with some degree of caution. In our hands high concentrations of memantine were able to block the induction
of LTP with an IC50 of 11.6 mM in the same preparation
when slices were pre-incubated for several hours with
memantine (Frankiewicz et al., 1996) although full inhibition was not observed with the highest concentration
tested (30 mM). In the same study we saw no effect on
the induction of LTP following short 30 min incubations
of memantine at 100 mM. The technical problems of this
approach are further highlighted by the fact that Chen
et al. (1998) required huge concentrations of (+)MK801 (6–10 mM) to block LTP in the same preparation
(Chen et al., 1998) whereas long pre-incubations with
( + )MK-801 are in fact able to block the induction of
LTP with an IC50 of 0.13 mM (Frankiewicz et al., 1996).
739
3.3. Other effects of memantine in 6itro
Antagonism of neuronal nicotinic receptor channels is
probably of therapeutic relevance for the in vivo effects
of amantadine (Parsons et al., 1995, 1996; Blanpied et
al., 1997; Matsubayashi et al., 1997; Buisson and
Bertrand, 1998; Parsons et al., unpublished: IC50 of 3–6
mM compared to IC50s against NMDA of 20–70 mM).
Memantine also blocks neuronal nicotinic receptor
channels but its relative potency in this regard is probably too weak to be of therapeutic significance (IC50 at
− 70 mV= 12.3 mM; Parsons et al., 1998b; see also
Grossmann et al., 1976; Masuo et al., 1986; Tsai et al.,
1989). Similarly, the fact that high concentrations of
memantine (100 mM) block repetitive action potential
firing in cultures by decreasing the activation of voltageactivated Na + channels (Grossmann et al., 1976; Grossmann and Jurna, 1977; Klee, 1982; Netzer et al., 1986;
McLean, 1987; Netzer and Bigalke, 1990) is unlikely to
be of therapeutic relevance. Recent patch clamp data
indicate that memantine only blocks TTX-sensitive and
TTX-resistant voltage-activated Na + channels in freshly
dissociated dorsal root ganglion neurones with IC50s\
100 mM (Krishtal, unpublished).
Memantine was also much less potent as an L-type
Ca2 + channel antagonist with an IC50 of 62 mM against
Ca2 + influx in response to 30 mM KCl assessed with
FURA2 measurements in cultured cerebellar granule
cells (Müller et al., unpublished). In patch clamp experiments, memantine only blocks L- and N-type voltageactivated Ca2 + channels in freshly dissociated
hippocampal neurones and P-type voltage-activated
Ca2 + channel in freshly dissociated cerebellar Purkinje
neurones with IC50s\ 180 mM (Krishtal, unpublished).
Although memantine (10–100 mM) had no effect on
whole cell inward currents to GABA, AMPA, kainate or
quisqualate (Chen et al., 1992; Parsons et al., 1993, 1996)
we have observed a moderate potentiation (10–20%) of
AMPA-induced currents by high concentrations of
memantine (30 mM) using perforated patch recordings
from cultured superior colliculus neurones (Parsons et
al., 1994). This acute effect was somewhat more pronounced (20–30%) following subchronic pre-treatment
of cultures for 2 weeks with memantine (10 mM). These
effects were similar to those observed on AMPA responses in the cortical wedge preparation (Parsons et al.,
1993). However, the relevance of these observations is
unclear. Firstly, the concentrations of memantine were
high and the effects were only moderate. Secondly, we
have not observed similar effects on AMPA receptormediated fEPSPs in hippocampal slices (Frankiewicz et
al., 1996). Thirdly, the potentiation seen with perforated
patch recordings often developed slowly and was not
reversible. This indicates that it may have been an
artefact due to changes in cell access resistance, a
common problem with this difficult recording technique.
740
C.G. Parsons et al. / Neuropharmacology 38 (1999) 735–767
Memantine has also been reported to increase phosphoinositide turnover with an EC50 of 4.1 mM (Osborne
and Quack, 1992) but this effect is probably related to
an increase in the rate of inositol incorporation into the
phosphoinositide pool (Mistry et al., 1995) and not due
to interactions with metabotropic glutamate receptors
(Osborne and Quack, 1992; Pilc et al., unpublished;
Wroblewski et al., unpublished). Memantine was also
claimed to potentiate classical inhibitory glycine receptors in spinal cord cultures at concentrations of 1–5
mM (Lampe and Bigalke, 1991) but we were not able to
confirm this observation with patch clamp experiments
in our own laboratory and memantine does not displace [3H]strychnine or [3H]glycine binding (Danysz et
al., 1997).
4. Pharmacokinetics — are brain concentrations sufficient
to block NMDA receptors?
Under therapeutic conditions in man the serum levels
of memantine with daily maintenance doses of 20 mg
range from 0.5 to 1.0 mM whereas free CSF (man) and
brain microdialysate (rat) levels (based on in vitro
recovery) are 20–50% lower due to albumin binding in
serum (Kornhuber and Quack, 1995; Quack et al.,
1995; Quack, unpublished). Although the content of
brain homogenates from rodents and man is much
higher for both amantadine and memantine (10 – 30× ),
this is probably due to lysosomal accumulation and
doesn’t reflect free concentrations available at CNS
receptors in vivo (Wesemann et al., 1980, 1982; Honegger et al., 1993; Kornhuber and Quack, 1995; Danysz et
al., 1997).
In rats, acute i.p. administration of memantine 5–10
mg/kg leads to plasma levels of 1.0 – 3.2 mM (see
Danysz et al., 1997). Acute administration of memantine 10 and 20 mg/kg i.p. in rats leads to peak free CNS
concentrations of 1.2 and 2.6 mM respectively as assessed by microdialysis with in vitro recovery in the
striatum (Quack et al., 1995). A similar study using in
vivo recovery revealed somewhat lower levels (Hesselink et al., 1997, 1999b) but still within the range of
affinity, at NMDA receptors. Thus, a maximal acute
dose of 5 mg/kg i.p. in rats can probably be considered
to be therapeutically-relevant for its use in dementia,
although age, strain, gender and health status of animals should be considered since they can change pharmacokinetics considerably. This estimate of the
therapeutically relevant acute dose is based on the
following rational: (a) the difference in drug sensitivity
between man and rat is mainly due to pharmacokinetic
rather than pharmacodynamic features; (b) there are
reasons to believe that the serum/brain ratio is similar
for man and rats; and (c) 5 mg/kg is the dose where
peak serum concentrations at 20 – 30 min are at the
upper limit of those seen in the serum of patients and
healthy volunteers following treatment 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 (3–5 h) than in humans
(up to 100 h) repetitive treatment in rats would produce
substantial fluctuations in brain concentrations. This
would be entirely different from clinical practice where
steady-state levels are present in chronically treated
patients. It is known that treatment regimes leading to
constant or fluctuating levels lead to different pharmacodynamic changes. Thus, we found that the best technique to mimic the pharmacokinetics seen in patients is
to use s.c. infusion by Alzet minipumps (see Danysz et
al., 1997, for review). Such memantine treatment (20
mg/kg per day) leads to plasma levels of ca. 1 mM and
has no effect on spatial learning in normal rats (Misztal
et al., 1996; Wenk et al., 1996; Zajaczkowski et al.,
1996b). This treatment leads to 0.4–0.7 mM levels in the
CNS-as assessed by brain microdialysis (Hesselink et
al., 1999b).
Although the therapeutic free CSF levels of memantine are up to four fold lower than the IC50s for
NMDA receptor in vitro (Kornhuber and Quack, 1995)
it should be borne in mind that in vivo concentrations
would not necessarily have to reach these subjective
50% blocking levels to be of significance. Furthermore,
technical aspects such as the presence of intracellular
Cs + may have served to artificially decrease the apparent potency of memantine in most patch clamp studies
detailed above. On the other hand, extracellular CNS
levels in animal models should not greatly exceed the
IC50s for NMDA receptors in vitro.
In summary, in male rats (200–300 g) acute doses of
up to 5 mg/kg i.p. or subchronic infusion of 20 mg/kg
per day (s.c.) can be considered to be of therapeutic
relevance as this produces plasma levels similar to those
mediating clinical effects in the treatment of demented
patients. Such treatment also leads to brain levels sufficient to affect NMDA receptors. Higher doses are also
likely to be selective at NMDA receptors but side
effects can be expected at acute doses ] 20 mg/kg i.p.
5. In vivo evidence for NMDA blockade at therapeutic
doses
Memantine selectively reduced responses of single
spinal neurones to microiontophoretic application of
NMDA with a 50% inhibitory dose (ID50) of around 2
mg/kg i.v. in anaesthetised rats (Neugebauer et al.,
1993) and inhibited NMDA-induced convulsions in
mice with an ID50 of 4.6 mg/kg i.p (Bisaga et al., 1993;
Parsons et al., 1995). In rats, convulsions produced by
i.c.v. injection of NMDA were inhibited by memantine
C.G. Parsons et al. / Neuropharmacology 38 (1999) 735–767
with an IC50 of 9.7 mg/kg (Bisaga et al., 1993). Memantine
was also potent—ID50 of 2.7 mg/kg — against NMDAinduced damage of cholinergic neurones in the NBM
(Wenk et al., 1995).
In another study in Headley’s laboratories, much
higher doses of memantine were required to block
responses of spinal neurones to microiontophoretic
NMDA (ID50 of 26 mg/kg i.v.) (Herrero et al., 1994).
More recent data from the same group (McClean et al.,
1996; Jones et al., submitted), show memantine to be
much more potent when the control NMDA responses
were of low intensity. Memantine (10 mg/kg), ketamine
(2 mg/kg) and ( + )MK-801 (0.1 mg/kg i.v.) reduced
responses to similar levels (15 – 25% of control). Memantine was much less effective against stronger intensity
responses of the same neurones. The efficacy of ( +)MK801 was relatively independent of control firing rate and
ketamine was somewhat less effective against stronger
responses. This difference likely reflects the stronger
voltage-dependency of memantine and probably underlies the differences observed in the potencies of memantine in different laboratories (see Neugebauer et al., 1993;
Herrero et al., 1994). Further evidence for NMDA
receptor antagonism in vivo was provided by the study
of Dimpfel et al. (1987) where low acute doses of 1–6
mg/kg i.p. caused changes in the EEG of conscious rats
similar to those seen following treatment with low doses
of phencyclidine (PCP) and (+)MK-801. Higher doses
of PCP and (+)MK-801 produced different effects
similar to dopaminergic drugs (Spüler et al., 1986) which
weren’t seen with higher doses of memantine.
Taken together with data presented previously (Kornhuber et al., 1994; Danysz et al., 1997) it seems clear that
NMDA receptor antagonism is the primary (if not only)
mechanism of action of therapeutic relevance for memantine —at least at our present stage of knowledge. Additional support for NMDA receptor antagonism in vivo
at therapeutically-relevant doses is provided by its strong
neuroprotective activity in animal models discussed later.
741
(20–40 mg/kg i.p.) induce weak components of stereotyped behaviour (Costall et al., 1975; Costall and Naylor,
1975a,b; Randrup and Mogilnicka, 1976; Mogilnicka et
al., 1977). However, such findings should be put into
context. The doses used in these studies were high, and
more careful analysis reveals that memantine shows very
clear differences to (+ )MK-801, PCP and ketamine.
Thus, memantine (20–60 mg/kg) enhanced horizontal
activity in the automated open field at later observation
periods only and did not produce statistically significant
stereotypy (head waving) in contrast to (+ )MK-801,
PCP and ketamine (Danysz et al., 1994a).
Although memantine does produce a number of sideeffects in animals characteristic for NMDA receptor
antagonists (ataxia, myorelaxation, amnesia), they appear at acute doses (20–30 mg/kg) clearly higher than
those considered to be therapeutically relevant. Thus, the
difference between memantine and many other NMDA
receptor antagonists is not qualitative, but rather quantitative. However, this difference is clearly sufficient. For
example, in mice the therapeutic index (TI) measured as
ED50 for impairment of rotarod performance divided by
ED50 for anticonvulsive action (maximal electroshock,
MES model) is approximately 2.5–3, whilst for (+)MK801 it is ca. 1 (Parsons et al., 1995). Moreover a similar
comparison of memantine’s neuroprotective and learning
impairing potency in vivo (Table 1) leads to a TI of 7.1
as compared to 1.3 for (+ )MK-801 (see Misztal and
Danysz, 1995; Wenk et al., 1995).
One of the possible serious side-effects of NMDA
receptor antagonists is their abuse potential. This concern
has mainly been raised in the USA due to the wide abuse
of PCP (‘Angel dust’) which was a major problem in the
1970s (Fauman and Fauman, 1981). Although memantine caused a dose-dependent substitution for PCP or
(+ )MK-801 in rats and monkeys in standard two lever
drug discrimination paradigms, full substitution only
occurred at relatively high doses causing a reduction in
response rate (Sanger, 1992; Sanger et al., 1992; Grant
et al., 1996; Zajaczkowski et al., 1996a; Nicholson et al.,
1998). Similarly, although intravenous memantine and
amantadine also served as positive reinforces in rhesus
monkeys trained to self-administer PCP, both were
considerably less potent than would be predicted from
6. Tolerability in animal models
Early studies indicated that high doses of memantine
Table 1
Comparison of the neuroprotective and synaptic plasticity impairing potency of Memantine and (+)MK-801 in vitro and in vivo
Agent
In vitro
LTP IC50 (mM)
In vivo
Hypoxia IC50
(mM)
Memantine
11.60
14.80
(+)MK-801
0.13
0.53
TI ratio Memantine vs (+)MK-801
a
MID, minimal effective dose.
In vitro TI
Learning impairment
MIDa (mg/kg)
Neuroprotection in the NBM ED50
(mg/kg)
TI
0.78
0.28
3.12
20.0
0.1
2.81
0.077
7.1
1.3
5.4
742
C.G. Parsons et al. / Neuropharmacology 38 (1999) 735–767
studies in rodents (Nicholson et al., 1998). Recent
experiments from Bespalov’s group indicate that
memantine is clearly not self administered (i.v.) in naive
mice (Semenova et al., submitted). Memantine had no
effect in rats trained to discriminate cocaine (Sanger et
al., 1992). Also, memantine failed to potentiate lateral
hypothalamic self stimulation in rats — in contrast to
( + )MK-801 (Tzschentke et al., 1998). Although (+
)MK-801, cocaine and morphine caused clear dose-dependent decreases in the threshold frequency for
electrical self-stimulation reinforcement, memantine
was without effect on threshold frequency and motor
performance at a therapeutically-relevant dose (5 mg/
kg) (Tzschentke et al., 1998). Finally, in the place
preference paradigm no effect of memantine was observed up to a dose of 7.5 mg/kg indicating the absence
of motivational effects (either positive or negative)
(Popik and Danysz, 1997).
Thus, memantine seems to have little abuse potential,
which is also supported by many years of clinical
practice, recent clinical studies and no report of abuse
in humans (see below).
7. Neuroprotection in vitro
Several studies indicated that memantine protects
against the toxic effects of NMDA receptor agonists in
cultured cortical neurones and chick retina in vitro
(Erdõ and Schäfer, 1991; Osborne and Quack, 1992;
Weller et al., 1993a,b) but they did not address the
concentration-dependency of this effect. Lipton’s group
were the first to publish that memantine protected
against NMDA-induced toxicity in cultured retinal
ganglion cells with an IC50 of around 2 – 3 mM (Chen et
al., 1992). Similarly, memantine blocked glutamate-induced toxicity in differentiated SHSY5Y cells with an
IC50 of 2.1 mM (Kyba et al., unpublished) and in
cultured hippocampal neurones with an IC50 of 1.1 mM
(Krieglstein et al., 1996, 1997). Our own recent data
showed that memantine protected cultured cortical neurones from the toxic effects of glutamate (100 mM for
20 h) with an IC50 of 1.4 mM (Parsons et al., 1999).
Memantine also ameliorated NMDA receptor-mediated
retinal ganglion cell death if given up to 4 h post insult
in vitro (Pellegrini and Lipton, 1993) and reduced the
percentage of chick telencephalic neurones showing elevated [Ca2 + ](i) and neurotoxicity following exposure to
NaCN 1 mM for 2 h (Ferger and Krieglstein, 1996).
Memantine (10 mM) provided complete protection, similar to that seen with (+)MK-801 (1 mM).
As predicted, higher concentrations are required to
block the induction of LTP in vitro (IC50 =11.6 mM)
and even then, full inhibition was not observed with the
highest concentration tested (30 mM) (Frankiewicz et
al., 1996). This is in strong contrast to substances such
as ( + )MK-801, which also block physiological processes such as LTP (Frankiewicz et al., 1996). We
recently systematically addressed the issue whether
memantine is able to differentiate better between the
physiological and pathological activation of NMDA
receptors in hippocampal slices (Frankiewicz and Parsons, 1998). We compared the effects of different concentrations of memantine and (+ )MK-801 with those
of 5,7-DCKA and CGP 37849 (glycineB and competitive antagonists respectively) on the induction of LTP
and 7 min of profound hypoxia/hypoglycæmia-induced
damage in CA1 of hippocampal slices in vitro. Memantine, (+ )MK-801, 5,7-DCKA and CGP 37849 blocked
the induction of LTP with IC50s of 11.6, 0.13, 2.53 and
0.37 mM respectively. The same drugs were able to
block hypoxia/hypoglycæmia-induced depression of
fEPSP amplitude with IC50s of 14.8, 0.53, 3.30 and 4.3
mM respectively. The relative in vitro side effect/benefit
ratios—hereafter termed ‘in vitro TI’ where as follows:
memantine and (+)MK-801, 0.78 and 0.28 respectively; 5,7-DCKA and CGP 37849, 0.77 and 0.09 respectively. These results show that memantine and a
glycineB antagonist exhibit a better therapeutic profile
than ( +)MK-801 and a competitive NMDA receptor
antagonist, even when tested in a severe model of
hypoxia/ischæmia (see Table 1). On the basis of the
clear neuroprotective effects observed with lower concentrations of memantine in cell cultures detailed
above, it may be assumed that in milder forms of
pathology, the observed differences in the ‘in vitro TIs’
will remain the same or increase but that the absolute
values can be expected to be higher.
8. Neuroprotection in vivo
8.1. Acute ischæmia
It is widely accepted that NMDA receptor antagonists have neuroprotective activity in a variety of models. In acute ischæmia they are generally more active in
models of focal, than global ischæmia when confounding factors such as changes in body temperature are
taken into account (Buchan, 1990; Meldrum, 1992;
Scatton, 1994). However, neuroprotective doses are
usually much higher than those producing other behavioural effects regarded as either positive (anticataleptic, antinociceptive) or as side effects (amnesia,
ataxia, stereotypy) (Koek et al., 1988; Buchan, 1990;
Meldrum, 1992; Scatton, 1994; Carter, 1995). It should
be noted that acute ischæmia models are generally of a
severe nature and the doses of NMDA receptor antagonist required are therefore high. It is likely that lower
doses provide neuroprotection inhibiting the progression of chronic neurodegenerative disorders such as
Alzheimer’s disease (see later). Nonetheless, prior treat-
C.G. Parsons et al. / Neuropharmacology 38 (1999) 735–767
ment with relatively high doses of memantine (10–20
mg/kg i.p.) reduced acute excitotoxic damage in models
of global and forebrain ischæmia in vivo (Seif El Nasr
et al., 1990; Backhauss et al., 1992; Backhauss and
Krieglstein, 1992; Chen et al., 1992; Stieg et al., 1993;
Block and Schwarz, 1996; Krieglstein et al., 1997; Chen
et al., 1998). Memantine (20 mg/kg i.p. 30 min post
infarct followed by 1 mg/kg b.i.d. for 48 h) also reduced
infarct volumes (37 mm3 c.f. 81 mm3 for controls) in a
photothrombotic model of ischæmia/stroke (Stieg et al.,
1993). A similar treatment was also effective against 2 h
of MCA occlusion in spontaneously hypertensive rats
when initiated at the time of reperfusion (Wang et al.,
1995; Chen et al., 1998). The same group reported that
memantine (20 mg/kg bolus followed by 1 mg/kg i.p.
every 12 h) had no negative effective on learning in the
Morris maze whereas (+)MK-801 (1 mg/kg i.p. every
24 h) produced clear learning deficits (Chen et al.,
1998). However, it should be noted that testing was first
started 72 h after the memantine bolus. As such, rats
receiving memantine were essentially only on the
maintenance dose and it is therefore hardly surprising
that they showed no learning deficits. Also the fact that
( +)MK-801 at 1 mg/kg every 24 h produced deficits in
the Morris maze is predictable — this dose is in fact
within the toxicological range for this compound and
irrelevant for behavioural studies.
Importantly, the neuroprotective effects of memantine in global ischæmia were also reflected in prevention
of learning deficits in the Morris water maze (Heim and
Sontag, 1995; Block and Schwarz, 1996). Memantine (5
mg/kg i.p.) also caused a trend towards improvement of
neurological deficits in a rat model of intracerebral
hæmatomas (Kleiser et al., 1995). Combination of
memantine with flunarizine caused a significantly
greater improvement in neurological outcome. In contrast, memantine failed to affect either the neurological
or morphological outcome of ischæmic (laser-induced
photothrombosis) or traumatic (clip compression)
spinal cord injury (Von Euler et al., 1997). This difference was attributed to a two fold lower affinity of
memantine at spinal cord NMDA receptors determined
with displacement of [3H]( +)MK-801 binding.
8.2. Models of excitotoxicity rele6ant for chronic
neurodegenerati6e diseases
Chronic dietary intake of memantine (31 mg/kg per
day) for 14 days prevented death, convulsions and
hippocampal damage induced by i.c.v. quinolinic acid
(Keilhoff and Wolf, 1992). Memantine also significantly
attenuated malonate-induced striatal lesions implicating
utility in chronic neurodegenerative diseases associated
with deficits in mitochondrial function (Schulz et al.,
1996b).
743
Of particular relevance to the clinical use of memantine are preclinical studies on the neurotoxic effects of
glutamate in structures known to be affected in
Alzheimer’s disease. One such structure is the cholinergic nucleus of Meynert (NBM, nucleus basalis of
Meynert in rats) which may provide a link between the
cholinergic
and
glutamatergic
hypotheses
of
Alzheimer’s dementia.
Wenk et al. (1994, 1995, 1996, 1997) studied the
effects of lesions of cholinergic neurones in the NBM in
rats by directly injecting NMDA or the mitochondrial
toxin 3 nitropropionic acid (3-NP) into this brain region. These treatments cause a considerable decrease in
levels of the acetylcholine synthesising enzyme, choline
acetyltransferase in target cortical areas resembling post
mortem findings in the brains of Alzheimer patients.
Memantine given i.p. before NMDA microinjection
produced clear cut, dose-dependent protection with an
ED50 of 2.8 mg/kg (Wenk et al., 1995). This dose results
in plasma levels similar to those observed in the plasma
of demented patients treated with therapeutic doses,
and is several times lower than that producing side-effects typical for NMDA receptor antagonists. In contrast, the therapeutic index for (+ )MK-801 in this
model was close to unity (Table 1). Similar higher doses
were also protective against the toxic effects of 3-NP
(Wenk et al., 1996). It could be demonstrated that the
protective effect of memantine was also expressed in
functional terms relevant for ACh function and associated symptoms in Alzheimer’s dementia, i.e. spatial
learning (Wenk et al., 1994). In a ‘T’-maze alternation
task memantine pre-treatment completely antagonised
the learning deficits induced by microinjection of
NMDA into the NBM.
Although the experiments described above demonstrates the neuroprotective potential of memantine, two
important features of the therapy of Alzheimer’s dementia with memantine were not accounted for in this
model. Firstly, the insult was of an acute nature and
not progressive; secondly memantine was given as a
bolus injection which does not mimic the steady-state
levels seen in the plasma of patients. In an attempt to
get closer to the clinical situation, the NMDA agonist
quinolinic acid was infused chronically directly to the
brain via an Alzet osmotic minipump while a second
pump delivered either saline or memantine s.c. both for
2 weeks (Misztal et al., 1996). The memantine concentration was adjusted to assure that steady-state plasma
levels were similar to those seen in Alzheimer’s patients
(around 1 mM). Under these conditions, animals infused with quinolinic acid alone showed clear learning
deficits in the T-maze whilst those infused in parallel
s.c. with memantine were able to acquire the task
normally. Similarly, a decrease in choline uptake sites
(an indicator of the density of ACh terminals) was seen
in the cortex of animals treated with quinolinic acid but
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C.G. Parsons et al. / Neuropharmacology 38 (1999) 735–767
Fig. 3. Scheme of the hypothesis explaining why memantine could improve cognition (plasticity) under conditions of increased tonic activation
(noise) of NMDA receptors.
not in those receiving additional treatment with
memantine. In this context it is important that infusion
of this same dose of memantine in normal rats had no
effect on T-maze learning or LTP in hippocampal slices
ex vivo (Misztal et al., 1996). Furthermore, chronic
treatment with therapeutically-relevant doses of
memantine had no negative effects on LTP in the rat
dentate gyrus in vivo (Barnes et al., 1996).
Recently, Miguel-Hidalgo et al. (1998) found that
memantine (15 mg/kg per day) infused s.c. by Alzet
minipumps prevented pathological changes in the
hippocampus produced by direct injection of b-amyloid. This included attenuation of damage, GFAP
staining, ED1 labelled bAP deposits, and the number of
picnotic/fragmented nuclei in the hippocampus (ibid.).
There is increasing evidence that inflammatory processes contribute to cell loss in Alzheimer’s dementia
(Aisen and Davis, 1994). Bearing this in mind Wenk et
al. (1998) developed a model of chronic brain inflammation where lipopolysaccharide (LPS, a component of
Gramm negative bacteria cell walls) was infused for 37
days in the area of NBM with an Alzet minipump. This
treatment lead to a massive inflammatory reaction followed by cell loss in the NBM. Memantine (20 mg/kg
per day) infused s.c. in parallel to LPS provided significant protection of NBM neurones but, as expected, did
not change the inflammatory reaction measured as microglial activation (using OX-6 antibody). The above
studies indicate that therapeutically-relevant doses of
memantine are potentially able to reach neuroprotective
levels in demented patients. Hence, if the contribution
of NMDA receptors in the neuropathology of
Alzheimer’s disease is accepted (Greenamyre et al.,
1988; Palmer and Gershon, 1990) then memantine
could possibly slow down the progression of this disorder. Unfortunately, proof of such effects in the clinic
would require long term, placebo-controlled studies
with large numbers of patients. Clinical studies with
memantine have therefore not addressed this question
directly but rather have concentrated on characterising
symptomatological improvement. However, in one
study in demented patients the symptomatological im-
provement seen with memantine did not deteriorate
over a 12 month, non-placebo controlled follow up
period (Görtelmeyer et al., 1993).
9. Positive symptomatological effects on learning
Although these preclinical data clearly indicate that
memantine might be able to slow down the progression
of chronic neurodegenerative diseases, the main effect
of memantine assessed in clinical studies so far has been
symptomatological improvement (Ditzler, 1991;
Görtelmeyer and Erbler, 1992; Pantev et al., 1993;
Schulz et al., 1996a). It should be noted that the acute
facilitatory effect of memantine on hippocampal synaptic transmission per se reported by Dimpfel (1995) was
not observed in the studies of others (Stieg et al., 1993;
Barnes et al., 1996; Frankiewicz et al., 1996; Chen et
al., 1998). Moreover, although its is easy to reconcile
neuroprotective activity with NMDA receptor antagonism, the symptomatological effects on cognition is not.
This is because the activation of NMDA receptors
seems to be necessary for various forms of plasticity
including learning (Collingridge and Singer, 1990;
Danysz et al., 1995b). This has been demonstrated in
various learning paradigms and LTP experiments.
However, some experimental data apparently contrast to these findings. A few years ago Mondadori’s
group showed that low doses of NMDA receptor antagonists may in fact enhance learning under certain
conditions, i.e. in animals with inherently poor levels of
performance in learning tasks (Mondadori et al., 1989).
Interestingly, in the study of Barnes et al. (1996) in
moderately-aged rats, memantine prolonged the duration of LTP in vivo and also showed a trend to improve
memory retention in the Morris maze. We previously
suggested that such findings may be related to the fact
that under certain conditions, direct tonic activation of
NMDA receptors —in contrast to learning—may lead
to an increase in synaptic ‘noise’ and in turn to a loss of
association detection (Parsons et al., 1993; Danysz et
al., 1995b; see Fig. 3).
C.G. Parsons et al. / Neuropharmacology 38 (1999) 735–767
This issue was addressed by Zajaczkowski et al.
(1997) using a two choice passive avoidance task and
LTP in vitro. Dark avoidance learning was impaired by
systemic administration of NMDA (starting at 25 mg/
kg) that was neither related to toxic effects nor state-dependent learning. NMDA-induced amnesia was
antagonised by memantine at low doses of 2.5 and 5
mg/kg, but not higher. This issue was pursued further
in the LTP model in hippocampal slices. NMDA depressed synaptic transmission in CA1 and also caused a
moderate reduction of LTP induction/expression —similar results were obtained previously (Izumi et al.,
1992). This later effect was also antagonised by low
concentrations of memantine (1 mM), (Zajaczkowski et
al., 1997). Thus, under conditions of tonic activation of
NMDA receptors, memantine can reverse deficits in
synaptic plasticity, both at the neuronal (LTP) and
behavioural (learning) level.
These results are reminiscent of early data from
Collingridge’s group (Coan et al., 1989) showing that in
the same in vitro model, removal of magnesium impairs
LTP induction and that this can also be restored by
treatment with low concentrations of 2-amino-5-phosphonovaleric acid (APV, a low affinity competitive
NMDA receptor antagonist). Very recent data from
our laboratories have confirmed such effects with
memantine. Decreasing Mg2 + from 1 mM to 10 mM
for 60 min enhanced baseline fEPSP slopes and impaired LTP ( −4.1%). Long pre-incubations with
memantine (1 mM) partially restored the induction of
LTP (43.4%) and memantine (10 mM) fully restored the
induction of LTP (61.595.3%). In contrast, (+ )MK801 (0.01, 0.1 and 1 mM) was not able to restore the
induction of LTP at any concentration tested
(Frankiewicz and Parsons, submitted).
It therefore seemed pertinent to test if a similar
positive effect of memantine could be seen in animals
showing learning deficits as a result of brain lesions.
The entorhinal cortex lesion model was selected as this
is the most affected structure in early stages of
Alzheimer’s disease (Braak et al., 1993). A few days
after lesioning, minipumps containing either (+ )MK801 (0.312 mg/kg per day) memantine (20 mg/kg per
day) or saline were implanted subcutaneously and then
rats were tested in a typical spatial learning task-the
radial maze. Initially all lesioned groups showed a clear
learning impairment, however after 9 days of testing
(and parallel infusion) memantine-treated animals
started to learn better reaching levels identical to non
lesioned animals whereas ( +)MK-801 enhanced the
lesion-induced deficit in reference memory (Zajaczkowski et al., 1996b). Hence, these data indicate
that memantine at the same doses/concentrations that
show neuroprotective activity also produces positive
effects on learning, supporting its use in neurodegenerative dementia.
745
The positive symptomatological effects of memantine
on learning in the absence of NMDA seem to be
dependent on subchronic administration of memantine:
30 mg/kg per day for \ 8 weeks in the study of Barnes
et al. (1996) and 20 mg/kg per day for 2 weeks in the
study of Zajaczkowski et al. (1996b). In both studies,
therapeutically-relevant serum concentrations of
memantine (around 1 mM; Kornhuber and Quack,
1995; Quack et al., 1995) were achieved for prolonged
periods of time and the results correlate well with
clinical reports of improved cognition in demented
patients within a few weeks of treatment (Ditzler,
1991).
10. Why is memantine well tolerated clinically?
The reason for the better therapeutic safety of
memantine compared to other channel blockers such as
(+ )MK-801 and phencyclidine is still a matter of
debate. There are several theories and it seems likely
that many factors are involved. Most hypotheses are
based on the widely documented fact that memantine
and other well tolerated open channel blockers such as
amantadine, dextromethorphan, ARL 15896AR and
ADCI show much faster open channel blocking/unblocking kinetics than compounds burdened with negative psychotropic effects such as (+ )MK-801 or
phencyclidine (Rogawski et al., 1991; Chen et al., 1992;
Parsons et al., 1993; Rogawski, 1993; Black et al., 1996;
Mealing et al., 1997; see Figs. 4 and 5 for previously
unpublished data from our laboratories). Moreover, the
kinetics of (+ )MK-801 and phencyclidine are too slow
to allow them to leave the channel upon depolarisation
and this is reflected in apparently weaker voltage-dependency (Figs. 4 and 5, NB: different time scales).
These two parameters are directly related to affinity,
with lower affinity compounds showing faster kinetics
and apparently stronger voltage-dependency (Parsons
et al., 1995, 1999). Memantine blocks NMDA channels
activated by high concentrations of agonist at -70 mV
with a Kon of 1–4× 105 M − 1s − 1 and Koff of 0.20–0.44
s − 1 (Parsons et al., 1993, 1995, 1996, 1998a; Bresink et
al., 1996; Blanpied et al., 1997; Chen and Lipton, 1997;
Sobolevsky and Koshelev, 1998; Sobolevsky et al.,
1998). The strong voltage-dependency is reflected in
estimated d values of 0.71–0.83, i.e. memantine experiences 70–80% of the transmembrane field when blocking the NMDA receptor channel (ibid).
More detailed analysis reveals that memantine blocks
and unblocks open NMDA receptor channels with
double exponential kinetics. The amplitude and speed
of the fast component of block increases with memantine concentration. In contrast, the speed of fast unblock remains constant but the amplitude decreases
with memantine concentration (Bresink et al., 1996;
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C.G. Parsons et al. / Neuropharmacology 38 (1999) 735–767
Frankiewicz et al., 1996; Blanpied et al., 1997;
Sobolevsky and Koshelev, 1998; Sobolevsky et al.,
1998). Moreover, the predominant effect of depolarisation is to increase dramatically the weight of the faster
recovery time-constant (Bresink et al., 1996;
Frankiewicz et al., 1996; Parsons et al., 1998b). These
data indicate that memantine binds to two sites within
the channel.
The interpretation as to why such blocking characteristics could be advantageous is divergent. 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 therapeutic safety in ischæmia and epilepsy
(Rogawski et al., 1991; Chen et al., 1992; Rogawski,
1993). However, this hypothesis alone cannot explain
the better therapeutic profile of memantine as, even if
receptors are only blocked following pathological activation, they would then remain blocked in the continuous presence of memantine, and therefore be
unavailable for subsequent physiological activation.
Physiologically, NMDA receptors are transiently activated by mM concentrations of glutamate (Clements
et al., 1992) following strong depolarisation of the
postsynaptic membrane which rapidly relieves their
voltage-dependent blockade by Mg2 + (Nowak et al.,
1984) whereas during pathological 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;
Buisson et al., 1992; Mitani et al., 1992). Unfortunately,
the voltage-dependency of the divalent cation Mg2 + is
so pronounced that it also leaves the NMDA channel
upon moderate depolarisation under pathological conditions. Although uncompetitive antagonists also block
the NMDA receptor channel, high affinity compounds
such as (+ )MK-801 have much slower unblocking
kinetics than Mg2 + and less pronounced voltage-dependency and are therefore unable to leave the channel
within the time course of a normal NMDA receptormediated excitatory post synaptic potential. As a result,
(+ )MK-801 blocks both the pathological and physiological activation of NMDA receptors.
We were the first to suggest that the combination of
fast offset kinetics and strong voltage-dependency allow
memantine to rapidly leave the NMDA channel upon
transient physiological activation by mM concentrations of synaptic glutamate but block the sustained
Fig. 4. Fractional block by memantine (10 mM) at various holding potentials in hippocampal neurones. (A) Original patch clamp data for a single
cultured hippocampal neurone. NMDA (200 mM) was applied for 41 s every 60 s at different holding potentials from − 90 to +60 mV in 10
mV increments. Memantine (10 mM) was applied for 11 s as indicated by the bar. Fifteen seconds following removal of memantine, neurones were
clamped to + 70 mV for 5 s in the continuing presence NMDA to facilitate complete recovery from antagonism. The traces are averages from
75 recordings, 5 at each holding potential. Kinetics at − 90 mV were best fit by double exponentials (n = 9), but this effect was more pronounced
for onset (tonfast 171 931 ms weight 48%, tonslow 1950 9 183 ms) than for offset (tofffast 619 942 ms weight 18%, toffslow 3794 9 432 ms).
Depolarisation had little effect on onset kinetics but caused an increase in the weight of the fast offset kinetics (60% at +40 mV). (B) Pooled data
from 9 neurones were well fit by the following equation (Subramaniam et al., 1994):Fractional current =(1-b)[1+ [memantine]/IC50(0 mV)
exp(− zdFV/RT)] − 1. The fraction of voltage-independent sites (b) was 0.06, i.e. 6%, the fraction of the electric field sensed by the
voltage-dependent site (d) was 0.80 and the IC50 (0 mV) was 15.9 mM. Other parameters have their normal meaning.
C.G. Parsons et al. / Neuropharmacology 38 (1999) 735–767
747
Fig. 5. Fractional block by ( +)MK-801 (1 mM) at various holding potentials in hippocampal neurones. (A) Original patch clamp data for a single
cultured hippocampal neurone. NMDA (200 mM) was applied for 140 s every 190 s at different holding potentials from −90 to + 70 mV in 20
mV increments. ( +)MK-801 (1 mM) was applied for 30 s as indicated by the bar. 60 s following removal of ( +)MK-801, neurones were clamped
to + 70 mV for 40 s in the continuing presence NMDA to facilitate complete recovery from antagonism (note the accelerated, but still slow
recovery from block during this voltage-step, 13.4 9 1.4 s). The traces are averages from 27 recordings, three at each holding potential. NB:
different time scale to Fig. 4. Single exponential fits described the data adequately. Onset kinetics at − 90 mV were 3.71 90.61 s (n =3). Offset
kinetics at −90 mV could not be fit but it is clear that responses had recovered by less than 15% following removal of (+)-MK-801 for 60 s.
Onset kinetics at + 70 mV (8.80 93.47 s) were somewhat slower than those at negative potentials. Offset kinetics were faster at depolarised
potentials (21.19 2.5 s at + 70 mV). (B) Pooled data from three neurones were fit by the following equation (Subramaniam et al., 1994):
Fractional current =(1-b)[1+[MK-801]/IC50(0 mV) exp( −zdFV/RT)] − 1. The fraction of voltage-independent sites (b) was 0.47, i.e. 47%, the
fraction of the electric field sensed by the voltage-dependent site (d) was 0.46 and the IC50 (0 mV) was 0.38 mM. When b was fixed to 0%, d was
0.37 and the IC50 (0 mV) was 0.16 mM. Other parameters have their normal meaning.
activation by mM concentrations of glutamate under
moderate pathological conditions (Parsons et al., 1993,
1995, 1996). This hypothesis is further supported by the
fact that although the predominant component of offset
kinetics at near resting membrane potentials is still too
slow to allow synaptic activation — i.e. around 5 s—the
relief of blockade in the continuous presence of memantine upon depolarisation is much faster due to an
increase in the weight of the faster recovery time-constant (Bresink et al., 1996; Frankiewicz et al., 1996;
Sobolevsky and Koshelev, 1998; Parsons et al., 1998b).
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 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). Moreover, we have also observed a moderate potentiation of NMDA-induced outward currents by memantine at positive potentials in
hippocampal neurones (Parsons et al., 1998a). This
could be related to the finding that Mg2 + and ketamine
increased NMDA receptor-mediated currents in cul-
tured mouse hippocampal neurones and HEK-293 cells
expressing NMDA j1/o2 receptors by increasing the
affinity of the glycineB site (Wang et al., 1994; Wang
and MacDonald, 1995). Such a facilitation would be
predicted to be more pronounced with lower concentrations of glycine. This could have important functional
implications as the differentiation between block of
NMDA receptors at near resting membrane potentials
and less block following strong synaptic depolarisation
to around − 20 mV would be enhanced by such a
mechanism and would facilitate the ability of memantine to differentiate between pathological and physiological activation of NMDA receptors.
To sum up, our working hypothesis is that memantine can be likened to a potent Mg2 + ion. Under
resting conditions, and in their continuing presence,
both Mg2 + and memantine occupy the NMDA receptor channel. Likewise, both are able to leave the
NMDA receptor channel upon strong synaptic depolarisation due to their pronounced voltage-dependency
and rapid unblocking kinetics (Fig. 6). However,
memantine contrasts to Mg2 + in that it does not leave
the channel so easily upon moderate prolonged depo-
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C.G. Parsons et al. / Neuropharmacology 38 (1999) 735–767
larisation during chronic excitotoxic insults (Parsons et
al., 1993, 1995).
A third theory was proposed recently in an excellent
paper by Blanpied et al. (1997) and supported by data
from Sobolevsky et al. (1998). Their data indicate that
memantine and amantadine appear to have a lesser
tendency to be trapped in NMDA receptor channels than
do phencyclidine or (+)MK-801. This difference was
attributed to the ability of some channel blockers to
increase the affinity of NMDA receptors for agonist but
the faster kinetics of aminoadamantanes. Receptors
blocked by memantine retain agonist and thereby open
and release memantine following removal of both agonist
and memantine from the extracellular solution (see also
Chen and Lipton, 1997). This partial trapping is less
pronounced for higher affinity compounds such as PCP
as their slower unblocking kinetics does not allow them
to leave the channel quickly enough following agonist
removal. The relief of block in the absence of agonist was
greater in the experiments of Sobolevsky et al. (1998).
However, this may have been due to the use of higher
concentrations of aspartate which would have increased
the proportion of liganded receptors at the time of
agonist/antagonist removal. Blanpied et al. (1997) proposed that partial trapping may underlie the better
therapeutic profile of memantine as a proportion of
channels—around 15–20%—would always unblock in
the absence of agonist and thereby be available for
subsequent physiological activation. In other words, the
antagonism by memantine is like that of a low intrinsic
activity partial agonist in that it doesn’t cause 100%
blockade of NMDA receptors. Although this theory is
attractive, it is only relevant for the therapeutic situation
if partial trapping also occurs in the continuous presence
of memantine. This point has not been addressed previously. This prompted us to perform experiments on partial
trapping in the continuing presence of memantine and the
results of these studies were very similar to those reported
by Blanpied et al. (1997), i.e. around 15% of channels
released memantine following agonist removal (Fig. 7).
Fig. 6. Scheme of the hypothesis explaining how the fast unblocking kinetics of memantine allow this strongly voltage-dependent compound to
differentiate between the physiological and pathological activation of NMDA receptors. Modified after Kornhuber and Weller (1997).
C.G. Parsons et al. / Neuropharmacology 38 (1999) 735–767
749
Fig. 7. Partial trapping of memantine in the NMDA receptor channel. In each series (left to right) NMDA (200 mM) was first applied for 10 s
in the absence of memantine followed by a 15 s interval. Memantine (10 mM) was then pre-incubated for 20 s (open bar) followed by the
coapplication of NMDA in the continuing presence of memantine (10 mM, black bar) for 10 s. Memantine (10 mM) showed clear open channel
block of responses to 13.5 9 1.2% of control plateau currents. Thereafter, partial trapping of memantine in the channel in the absence of agonist
was demonstrated by introducing a delay of 35 s in the continuing presence of memantine (10 mM) alone (top) or memantine plus L-APV (200mM,
bottom). Both were washed off for 2 s before the third 10 s application of NMDA alone. This third response to NMDA showed clear, double
exponential onset kinetics (ton1= 659 6 ms, ton2= 2.5390.26 s for memantine; ton1 =66 99 ms, ton2 =3.38 90.97 s for memantine+ L-APV).
The amplitude of this fast component was used to estimate the fraction of channels that released memantine in the absence of NMDA (15.5%
for memantine alone; 14.8% for memantine + L-APV-both compared to control peak responses). A fourth 10 s application of NMDA was then
made ensure full recovery from antagonism. Similar results were obtained on 10 cells tested with memantine alone and six cells tested with
memantine+ L-APV.
A fourth theory to explain the better therapeutic
profile of memantine is NMDA receptor subtype selectivity. It is now clear that ifenprodil and eliprodil are
NR2B selective antagonists and also seem to have a
better therapeutic profile in many animal models (see
Danysz et al., 1995a; Parsons et al., 1998c). There are
several explanations as to why this could be the case
which are outside of the scope of this review. However,
the conceptually most obvious is related to that fact
many cortical and hippocampal neurones express
NR2A and NR2B receptor to similar levels. Selective
blockade of NR2B receptors by ifenprodil in these
neurones thereby causes a maximal reduction of responses to around 50% of control, i.e. NR2B selective
antagonists also inhibit with a similar profile as would
be expected for a non-selective partial agonists with
50% intrinsic activity.
NMDA-induced release of [14C]acetylcholine from
rat striatal slices in vitro is blocked by NR2B selective
agents such as ifenprodil and eliprodil whereas
[3H]spermidine release is not (Nankai et al., 1995a,b,
1996, 1998). Likewise, memantine and other well toler-
ated NMDA receptor antagonists such as dextromethorphan and dextrorphan were considerably
more potent against [14C]acetylcholine release whereas
(+ )MK-801 and phencyclidine were equipotent (see
also Lupp et al., 1992). This similarity was 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 Ca2 + influx in human NR1a/NR2B
receptors than in human NR1a/NR2A receptors permanently expressed in L(tk-) cells (Grimwood et al.,
1996). Similarly, memantine blocked NR2A, 2B, 2C
and 2D receptors expressed in Xenopus oocytes with
IC50s of 0.89, 0.40, 0.32 and 0.28 mM respectively
(Parsons et al., 1999; Spielmanns et al., 1998).
However, the relevance of this moderate two to three
fold greater potency at NR2B over NR2A receptors is
unclear and isn’t supported by other studies. Thus,
memantine was equipotent 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 somewhat more potent against NR2D
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C.G. Parsons et al. / Neuropharmacology 38 (1999) 735–767
receptors (IC50 = 0.47 mM, Bresink et al., 1996). Similarly, in the study of Blanpied et al. (1997) memantine
(20 mM) blocked NR2A and NR2B receptors expressed
in CHO cells to a similar degree and, as in native
receptors, memantine was released from one-sixth of
blocked channels rather than being trapped in all of
them. Memantine was also previously reported to be
almost equipotent against NR2A and NR2B receptors
expressed in Xenopus oocytes (IC50 of 0.29 and 0.23 mM
respectively, Avenet et al., 1997).
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 cerebellum than in forebrain regions
(Bresink et al., 1995a; Porter and Greenamyre, 1995). In
this regard a recent study showing that memantine can
block classical eyeblink conditioning in humans at doses
having no effect on verbal or visuospatial memory is of
particular interest (Schügens et al., 1997) as classical
eyeblink conditioning is critically dependent upon intact
cerebellar circuitry.
This increased potency in the cerebellum could be
related to the enhanced expression of NR2C receptors in
this region (Monyer et al., 1992, 1994; Wenzel et al.,
1995). A less inconsistent finding in studies on NMDA
receptor subtypes, is the fact that memantine is three fold
more potent against NR2C receptors than NR2A receptors (Prado de Carvalho et al., 1993; Avenet et al., 1997;
Parsons et al., 1999). This relatively weak subtype
selectivity of memantine was increased (to five fold)
under more ‘physiological’ conditions, i.e. at −30 mV
in the presence of 1 mM Mg2 + : IC50s of 10.3, 2.0 and
1.9 mM at NR2A, NR2C and NR2D respectively (Spielmanns et al., 1998). Memantine was similarly voltage-dependent against NR2C and NR2D receptors expressed
in Xenopus oocytes (d =0.74 and 0.8, Spielmanns et al.,
1998) as previously reported for NR2A and NR2B
receptors in HEK 293 cells (d =0.75, Bresink et al.,
1996). ( +)MK-801 showed a very different profile and
preferentially blocked NMDA-induced currents in
NR2A and NR2B receptors compared to NR2D in
HEK-293 cells and was apparently far less voltage-dependent (Bresink et al., 1996).
Memantine was also found to be relatively potent in
antagonising NMDA-induced Ca2 + influx in cultured
cerebellar neurones (IC50 =0.23 mM, Müller et al., unpublished). Our own data indicate no difference in the
potency of memantine against cultured hippocampal,
cortical, superior colliculus, striatal or spinal cord neurones under otherwise identical conditions (IC50s at − 70
mV of 2.3–2.9 mM, Parsons et al., 1998a). We haven’t
tested the effects of memantine on cultured cerebellar
neurones but one general caveat to this approach is the
fact that cultured neurones may not express the same
receptors as those expressed in vivo. It is already clear
that NMDA receptor subtype expression is dependent
on ontogeny (e.g. Zhong et al., 1995). Moreover, although we saw no clear difference in the potencies of
memantine or amantadine between cultured hippocampal and striatal neurones (Parsons et al., 1998a) we
found clear differences in their relative potencies on
freshly dissociated hippocampal and striatal neurones
(Parsons et al., 1996).
Again, it is unclear whether a three to five fold greater
potency of memantine on NR2C receptors is alone
enough to explain it’s improved therapeutic profile. As
such, if there is a relationship between receptor subtype
selectivity of uncompetitive NMDA receptor antagonists and their therapeutic indices in vivo, it may be due
to the fact that poorly tolerated compounds such as
(+ )MK-801 have been reported to show at least a ten
fold greater potency at NR2A/NR2B than NR2C receptors (Yamakura et al., 1993; Laurie and Seeburg, 1994;
Bresink et al., 1996; but see Monaghan and Larsen,
1997). Obviously, a thorough comparative study of the
selectivity of memantine and (+ )MK-801/phencyclidine
on all four NR2 receptor subtypes and isoforms of NR1
receptors is necessary to finally clarify whether subtypeselective effects of memantine could contribute to its
better therapeutic tolerability.
11. Further possible therapeutic applications of
memantine
11.1. AIDS
Although neurones themselves are not infected by the
HIV-1 virus at least part of the neuronal injury observed
in the brain of AIDS patients is related to NMDA
receptor activation (see Lipton, 1994, 1997). There is
growing support for the existence of HIV- or immune-related toxins that lead indirectly to the injury or death of
neurones via complex interactions between macrophages
(or microglia), astrocytes, and neurones.
Exposure of primary neuronal cultures to the HIV
envelope glycoprotein gp120 leads to activation of PLA2
followed by arachidonic acid release which then inhibits
astrocyte glutamate uptake and/or up-regulates NMDA
receptors enhancing vulnerability to neurotoxicity
(Dreyer and Lipton, 1995; Ushijima et al., 1995; Müller
et al., 1996). Recently, gp120 was also reported to
potentiate NMDA-evoked [3H]noradrenaline release in
human synaptosomes and this effect was prevented
(+ )MK-801, 7-chlorokynurenic acid, as well as by
memantine (Pittaluga and Raiteri, 1994; Pittaluga et al.,
1996). Low mM concentrations of memantine completely
prevented the neuronal degeneration produced by gp120
in neuronal cultures (Bormann et al., 1992; Lipton, 1992;
Müller et al., 1992; Ushijima et al., 1993; Müller et al.,
1996). Platelet-activating factor (PAF) is produced during HIV-1-infected monocyte-astroglia interactions and
C.G. Parsons et al. / Neuropharmacology 38 (1999) 735–767
is detected in high levels in the CSF of HIV-1 infected
patients. PAF was reported to be neurotoxic in primary
neuronal cultures and memantine (6 mM) partially
blocked these neurotoxic effects (Gelbard et al., 1994).
Memantine (2 mM) was also found to display a significant anti-HIV effect on enriched cultures of GFAP
positive cells infected with human immunodeficiency
virus type 1 (HIV-1) in vitro (Rytik et al.,
1991).Recently, neuroprotective effects were also obtained with memantine (20 mg/kg per day) in transgenic
mice expressing gp120 protein (Toggas et al., 1996).
These animals show an increase in HPA axis activity
(increase in ACTH and corticosterone levels) that is
dependent on NMDA receptor stimulation and might
result in immuno-suppression, neuronal damage and
enhanced HIV-1 replication seen in AIDS patients
(Raber et al., 1996). Memantine is currently under
clinical trials for inhibition of neurological deficits associated with HIV infection.
11.2. Glaucoma
Mild chronic intravitreal elevation in glutamate concentration (up to 34 mM) by serial intravitreal glutamate
injections over 3 months in rats resulted in 42% death of
retinal ganglion cells after 5 months. Concurrent daily
injections of memantine 1 mg/kg per day completely
prevented this cell death (Vorwerk et al., 1996). Retinal
ischæmia induced in rats by elevating intraocular pressure also caused an elevation in the mean vitreous
concentration of glutamate and glycine (Lagreze et al.,
1998) and caused pronounced loss of retinal ganglion
cells (Lagreze et al., 1998). Memantine 10 mg/kg was
protective even when given up to 4.5 h post ischæmia
and 20 mg/kg per day administered by osmotic
minipumps starting 2 days before ischæmia also increased retinal ganglion cell survival (Lagreze et al.,
1998). Memantine also reduced the depression of the
b-wave of the electroretinogram (ERG) in in vivo models of retinal ischæmia and accelerated the recovery of
the b-wave during reperfusion (Block and Schwarz,
1998).
11.3. Hepatic encephalopathy
NMDA-receptor activation has also been proposed to
be involved in the pathogenesis of hyperammonemia-induced encephalopathy and of acute hepatic encephalopathy caused by complete liver ischæmia. Thus, chronic
hyperammonemia and experimental acute liver failure
cause pathological changes in perineural astrocytes,
which may lead to a reduced uptake of released glutamate and a decreased detoxification of ammonia by the
brain (Michalak et al., 1996, for review see Butterworth,
1996). Studies on thioacetamide-induced acute liver failure also suggest that reuptake of glutamate into presy-
751
naptic nerve terminals may be impaired (Oppong et al.,
1995) and there is a decrease of glutamate transporters
(GLT-1) in the frontal cortex of rats with acute liver
failure (Knecht et al., 1996; Michalak and Butterworth,
1997; Michalak et al., 1997). Taken together, such
changes might be expected to trigger excitotoxicity by
chronically increasing basal levels of glutamate. This
idea is supported by the recent finding that acute and
subacute encephalopathy-induced increases in CSF glutamate/aspartate concentrations, intracranial pressure
and brain water content were reduced by memantine
(10–20 mg/kg i.p) (Vogels et al., 1997).
11.4. Multiple sclerosis
In a mouse model of allergic encephalomyelitis there
is a deficit of astroglial enzymes (glutamate dehydrogenase and glutamine synthase) responsible for degradation of glutamate taken up from the extracellular space
(Hardin Pouzet et al., 1997). This may lead to an
increase in extracellular glutamate and neurotoxicity
seen in this disease. Memantine (10–20 mg/kg) dose-dependently ameliorated neurological deficits in experimental autoimmune encephalomyelitis (EAE) in Lewis
rats. This therapeutic effect was not via interactions
with the immune system per se and implies that effector
mechanisms responsible for neurological deficits in EAE
may involve NMDA receptors (Wallstrom et al., 1996).
11.5. Tinnitus
NMDA receptor-mediated excitotoxicity has been
implicated in some cochlea pathologies characterised by
acute or progressive hearing loss and tinnitus (Ehrenberger and Felix, 1995; Puel, 1995; Puel et al., 1997). A
recent study claimed that aminoglycoside antibiotic induced hearing loss in guinea pigs is inhibited by treatment with ( + )MK-801 or ifenprodil and that
aminoglycosides express a positive modulatory effect on
NMDA receptors resembling that of polyamines (Basile
et al., 1996). Microelectrophoretic application of
memantine depressed spontaneous activity of mammalian inner hair cells at doses that selectively reduced
responses to NMDA but not to AMPA (Oestreicher et
al., 1998). However, it should be noted that although
some studies have reported the presence of most known
glutamate receptors in the mature cochlea (Niedzielski
et al., 1997) other studies indicate that cochlea NMDA
receptors are only transiently expressed at early stages
of postnatal development and that AMPA receptor
subtypes seem to be dominant in the adult (Knipper et
al., 1997). Verification of efficacy following systemic
administration of therapeutically-relevant doses of
memantine is necessary before any conclusions on the
use if memantine in tinnitus can be drawn.
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C.G. Parsons et al. / Neuropharmacology 38 (1999) 735–767
11.6. Parkinson’s disease
It is now widely accepted that NMDA receptor antagonists might manifest their anti-Parkinsonian effects by
attenuating and imbalance between dopaminergic and
glutamatergic pathways within the basal ganglia network (Schmidt and Kretschmer, 1997). In fact, NMDA
receptor antagonists show activity in a number of animal
models of Parkinson’s disease. Many uncompetitive
NMDA receptor antagonists increase locomotion in
naive animals while competitive antagonist are ineffective, at least at moderate doses (see Danysz et al., 1997;
Schmidt and Kretschmer, 1997). In this respect memantine differs somewhat to other uncompetitive NMDA
receptor antagonists in that it only enhances locomotion
at later recording periods and amantadine shows no
locomotor stimulation and even some inhibition during
initial recording periods (Svensson, 1973; MoniuszkoJakoniuk and Wisniewski, 1977; Menon and Clark,
1978, 1979; Menon et al., 1984; Ljungberg, 1986; Youssif
and Ammon, 1986; Messiha, 1988; Danysz et al., 1994a,
1997; Starr, 1995).
Both uncompetitive and competitive NMDA receptor
antagonists antagonise catalepsy induced by dopamine
receptor antagonists. Amantadine shows clear dose-dependent anticataleptic effects against haloperidol-induced catalepsy starting at 25 mg/kg. In contrast,
although a similar effect is also observed after memantine, it is modest and shows a bell shaped dose – response
relationship. The ineffectiveness of memantine at higher
doses (20 mg/kg) does not indicate that anticataleptic activity is lost but rather that myorelaxant
effects dominate and mask the expression of the antiakinetic action. Similarly, although amantadine dose-dependently ameliorated haloperidol-induced movement
initiation and execution deficits in a food reinforced
runway test (Schmidt et al., 1991; Danysz et al., 1997)
memantine was less effective, again possibly due to
stronger myorelaxant effects. The weaker D1 receptormediated catalepsy seen with SCH 23390 at 1 mg/kg was
only weakly inhibited by memantine (10 mg/kg) whereas
the synergistic effects of haloperidol 0.5 mg/kg and SCH
23390 0.1 mg/kg were more effectively antagonised
(Schmidt et al., 1991; Danysz et al., 1997).
A pronounced hypokinesia is observed in rodents
depleted of monoamines (using a-MT or reserpine or
both). This hypokinesia is attenuated by a number of
NMDA receptor antagonists (see Schmidt and
Kretschmer, 1997). Similar anti-hypokinetic effects have
been observed for memantine (Svensson, 1973; Henkel et
al., 1982) and amantadine by some authors (see Danysz
et al., 1997 for review) but it should be stressed that
effect of amantadine is normally very modest and sometimes even absent. Such contradictory results are likely
to be due to methodological differences such as the
species or the type of monoamine depletion used, which
determines the basal levels of activity. In monoamine-depleted rodents memantine and amantadine were found
to enhance the effect of L-DOPA in a clearly synergistic
manner (Skuza et al., 1994). Moreover, a similar synergism between L-DOPA and amantadine, memantine or
L-deprenyl has also been observed in Parkinson’s patients (Feilling, 1973; Birkmayer et al., 1975; Rabey et
al., 1992).
It has been reported that the combination of NMDA
receptor antagonists with D-2 agonists (bromocriptine,
RU 24213, quinpirol) actually leads to an opposing
rather than to an over-additive effect (Svensson et al.,
1992; Starr and Starr, 1995). In our hands slight potentiation (but not synergism) by (+)MK-801, amantadine
and memantine was obtained if the dose of bromocriptine was low (Skuza et al., 1994).
In rodents with unilateral lesions of the substantia
nigra pars compacta (SNc), systemic administration of
NMDA receptor antagonists produce ipsilateral rotations—an action implying an indirect presynaptic locus
of action (see Danysz et al., 1997). Memantine and
amantadine produced similar effects although the absolute magnitude of rotations was moderate in the case of
memantine and minor in amantadine-treated animals
(Costall and Naylor, 1975a; Danysz et al., 1994b).
Memantine (10–50 mg/kg) also dose-dependently reversed contralateral turning to ipsilateral turning in rats
following unilateral inactivation of the striatum with
KCl. This effect was similar to that of apomorphine
(Laschka et al., 1976).
When given together, amantadine and memantine are
actually counteractive in some models, i.e. amantadine
decreases the locomotor stimulation produced by
memantine (Menon et al., 1984). Interestingly, amantadine also inhibits PCP-induced activation (46 mg/kg
i.p. versus 10 mg/kg i.p. respectively, not published).
NMDA receptor antagonists in general and
aminoadamantanes in particular have been suggested as
potential neuroprotective therapies in Parkinson’s disease (Kornhuber et al., 1994; Mizuno et al., 1994). In
fact, it has recently been reported that amantadine
increases life expectancy in Parkinson’s patients—an
effect attributed to neuroprotective activity of this agent
(Uitti et al., 1996). In turn, on the basis of the above
listed arguments and assuming relevance of NMDA
receptor-mediated excitotoxicity as a factor underlying
neurodegeneration in Parkinson’s disease, neuroprotective effects of both amantadine and memantine might be
predicted. However, it should be noted that glutamate
toxicity of dopaminergic neurones in mesencephalic
cultures was only mildly attenuated by memantine (50–
100 mM) in contrast to much clearer effects with lower
concentrations in cultured cerebellar and cortical neurones (Weller et al., 1993a).
Memantine was about three fold less potent against
NMDA-induced currents in freshly dissociated striatal
C.G. Parsons et al. / Neuropharmacology 38 (1999) 735–767
neurones than in hippocampal neurones whereas amantadine was more potent on striatal neurones (Parsons et
al., 1996). As a result, amantadine was about 18 times
less potent than memantine in the hippocampus but only
four times less potent in the striatum. This difference in
the relative potencies of amantadine and memantine in
freshly dissociated striatal neurones agrees well with the
effects of these two compounds in blocking NMDA-induced acetylcholine release and NMDA receptor-mediated EPSPs in striatal slices (Lupp et al., 1992; Stoof et
al., 1992; Rohrbacher et al., 1994). Taken together, these
data suggest that therapeutically-relevant concentrations
of amantadine may be somewhat more active in the
striatum whereas memantine is likely to be more active
in non-striatal structures (Danysz et al., 1994b; Spanagel
et al., 1994). This could offer an explanation for the
better clinical profile of amantadine than memantine in
Parkinson’s disease. Thus, the expression of NMDA
receptors is increased in the striatum of Parkinson’s
patients (Weihmuller et al., 1992; Ulas et al., 1994) and
NMDA antagonists have been proposed to mediate their
positive effects in Parkinson’s disease within the striatum
as well as in other basal ganglion structures (Carlsson
and Carlsson, 1990; Greenamyre and O’Brien, 1992;
Schmidt et al., 1992; Klockgether and Turski, 1993). As
a result, the relatively higher doses of memantine required in animal models of Parkinson’s disease might be
expected to cause more side effects associated with their
higher activity in non-striatal structures (Danysz et al.,
1994b).
It is still not clear as to why low affinity open channel
blockers such as amantadine and memantine are able to
reduce NMDA receptor-mediated synaptic transmission
in the striatum as high concentrations of memantine are
required to block NMDA receptor-dependent long term
potentiation in the hippocampus (Frankiewicz et al.,
1996). The somewhat reduced voltage-dependency of
memantine on NMDA responses of striatal neurones
reported by (Parsons et al., 1996) may indicate that a
subclass of NMDA receptors showing altered relative
voltage-dependency of channel blockade is expressed in
the striatum (see also Jiang and North, 1991;
Rohrbacher et al., 1994).
The fact that enhancement of dopamine release or
inhibition of dopamine uptake by memantine and amantadine is only seen at concentrations of 100 – 300 mM
(Osborne et al., 1982; Jackisch et al., 1992; Lupp et al.,
1992; Stoof et al., 1992; Kornhuber et al., 1994; Clement
et al., 1995) excludes this as the primary mechanism of
action of these aminoadamantanes in Parkinson’s disease (see Danysz et al., 1997). Although memantine (10
mM) has also been reported to cause very moderate
increases in cAMP levels in striatal slices (Janiec et al.
1977, 1978) others saw no effect at up to 100 mM on
dopamine sensitive adenylate cyclase in rat striatal homogenates (Karobath, 1974). Memantine 10 – 40 mg/kg
753
has also been reported to cause small (5 50%) but highly
variable changes in the levels of 5-HT, dopamine and/or
their metabolites in the striatum (Maj et al., 1974, 1977;
Maj, 1975, 1977, 1982; Wesemann et al., 1983) prefrontal
cortex and nucleus accumbens (Svensson, 1973;
Grabowska, 1975, 1976; Randrup and Mogilnicka,
1976; Smialowska, 1976; Haacke and Wesemann, 1977;
Haacke et al., 1977; Sontag et al., 1982; Dunn et al.,
1986; Bubser et al., 1992). In microdialysis experiments
memantine (20 mg/kg) only produced a very moderate
increase in dopamine overflow in the striatum not
paralleled by HVA or DOPAC (Spanagel et al., 1994;
Quack et al., 1995). This increase was probably indirect,
i.e. via NMDA receptor blockade and also probably not
relevant for anti-Parkinsonian activity. In summary, the
small magnitude of these changes and highly inconsistent results for dopamine in the striatum indicate that
such effects are not relevant for memantine’s therapeutic
effects.
However, recently (+ )MK-801 (0.01–1 mg/kg),
amantadine, memantine and dextromethorphan (all 40
mg/kg i.p.) were reported to cause a pronounced increase in L-amino acid decarboxylase (AADC) activity,
more especially in the substantia nigra pars reticulata
than in the striatum (Fisher et al., 1997, 1998). The
results suggest that glutamate tonically suppresses the
activity AADC, and hence the biosynthesis of dopamine.
Restoration of dopamine synthesis might contribute to
the L-DOPA-facilitating actions of amantadine, but this
effect is unlikely to be of therapeutic relevance for
memantine due to the high dose required.
To sum up, memantine is actually more active than
amantadine in some animal models of Parkinson’s disease (monoamine-depletion and lesions of the substantia
nigra) but it is less effective in neuroleptic induced
catalepsy, probably due to myorelaxation observed at
the higher doses required. Although there are clinical
reports of positive effects of memantine in Parkinson’s
disease (Rabey et al., 1992) most physicians agree that
memantine is less effective than amantadine. However,
the antiparkinsonian activity of both agents has never
been compared in one clinical study. Combination therapy of either aminoadamantane with L-DOPA seems to
be the most promising approach due to clear synergistic
interactions and likely inhibition of the development of
dyskinesias (Danysz et al., 1997).
11.7. Tardi6e dyskinesia
According to current concepts, tardive dyskinesia seen
after long-term treatment with some neuroleptics involves progressive neuronal damage resulting from excitotoxicity and free radical production (Dekeyser, 1991;
Cadet and Kahler, 1994). At the level of the striatum
chronic blockade of D2 inhibitory dopaminergic receptors localised on glutamatergic terminals from the cortex
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may lead to a persistent, enhanced release of glutamate
that eventually damages output neurones (Dekeyser,
1991; Gunne and Andren, 1993). In monkeys treated
chronically with neuroleptics there are indications for
excitotoxic damage to glutamatergic projection areas
(Gunne and Andren, 1993). Similarly, in rats treated for
6 months with haloperidol there is progressive development of oral vacuous movement analogous to chorea
symptoms which persists for 12 weeks after cessation of
treatment (Andreassen et al., 1996). Although cotreatment with memantine (20 or 40 mg/kg per day) increased
oral vacuous movement during the treatment period, it
prevented the chronicity of this alteration with rat
behaviour returning to normal within 1 week of treatment cessation indicating neuroprotective effects (Andreassen et al., 1996).
11.8. Chronic pain
There is considerable preclinical evidence that hyperalgesia following peripheral tissue injury is not only due
to an increase in the sensitivity of primary afferent
nociceptors at the site of injury but also depends on
NMDA receptor-mediated central changes in synaptic
excitability (Dickenson, 1990; Coderre, 1993). However,
the therapeutic relevance of effects seen with memantine
are still far from clear.
Memantine only has weak effects in electrophysiological models of acute somatic pain, as expected for
NMDA receptor antagonists (e.g. Malec and Langwinski, 1981). Thus memantine at 32 mg/kg and ( + )MK801 at 1.3 mg/kg i.v. reduced acute nociceptive single
motor unit reflexes (SMUR) recorded in spinally-intact,
a-chloralose-anaesthetized rats to noxious pinch to similar levels (8–12% of control) when the control responses
were of low intensity (1.5 N) (McClean et al., 1996; Jones
et al., submitted). Memantine was much less effective
against stronger intensity responses (2.2 N) only reducing responses to (75% of control) whereas this difference
was less pronounced for ( +)MK-801 (40% of control).
This probably reflects the stronger voltage-dependency
of memantine and may explain the differences observed
in the potencies of memantine in different laboratories
(see Neugebauer et al., 1993; Herrero et al., 1994).
Memantine (20 mg/kg), ketamine (2 mg/kg) and (+ )
MK-801 (0.2 mg/kg i.v.) reduced wind up of SMUR to
50, 51 and 46% of control respectively (McClean et al.,
1996; Jones et al., submitted). In the same animals,
memantine was far less effective against acute nociceptive pinch reflexes (80% of control) whereas ketamine
and (+ )MK-801 were equieffective. In animals with
carrageenan-induced inflammation the absolute potency
of memantine on wind-up was increased approximately
two fold with 13 mg/kg i.v. reducing responses to 48%
of control whereas its potency against pinch was not
(90% of control). In contrast, the absolute potency of
ketamine on both responses was unchanged. Therapeutically-relevant doses of memantine (2.5–10 mg/kg) selectively blocked formalin-induced tonic nociceptive
responses in rats (Eisenberg et al., 1993). Memantine
also provided a very good separation between the acute
and prolonged phases in a rat formalin model following
intrathecal administration (Chaplan et al., 1997). In
contrast, memantine reduced both phases of the licking
response to vibrisal formalin in mice with an ED50 of
around 2.5 mg/kg. This same dose also produced ataxia
implying that this species is very different to the rat
(Millan and Seguin, 1994). However, this finding contrasts with our experience. Memantine is used as one of
our standard agents for screening assays and only
produces ataxia and myorelaxation in NMR female mice
at 10 fold higher doses (around 20 mg/kg i.p., e.g.
Parsons et al., 1995). Memantine was also recently
shown to block capsaicin-induced licking behaviour with
an ID50 of 14.5 mg/kg s.c. which was four fold lower
than doses producing ataxia in the same strain of
animals (Taniguchi et al., 1997).
Memantine had both therapeutic and prophylactic
antinociceptive effects (10 and 15 mg/kg) against carrageenan-induced hyperalgesia (Neugebauer et al., 1993;
Eisenberg et al., 1994). Memantine also blocked and
reversed thermal hyperalgesia and mechanical allodynia
in rat models of painful mononeuropathy without obvious effects on motor reflexes following systemic (10–20
mg/kg; Carlton and Hargett, 1995; Eisenberg et al.,
1995) and local spinal administration (Chaplan et al.,
1997). Interestingly, in the study of Chaplan et al. (1997)
memantine provided the best separation between antinociceptive and ataxic activity of all agents tested (96%
maximal possible effect at non-ataxic doses) and was
superior to dextrorphan (64%)= dextromethorphan
(65%)\ (+)MK-801 (34%)\ ketamine (18%).
Very large doses of memantine 25–75 mg/kg given
acutely i.m. or orally to Macaques (1.5–2.5 kg) were
reported to selectively reduce mechanical allodynia induced by ligation of the seventh spinal nerve. Intrathecal
administration (10 mM at 5ml/min) also decreased mechanical allodynia in neuropathic animals and was antinociceptive against mechanical and thermal nociceptive
responses of STT cells in normal and neuropathic animals (Carlton et al., 1994). It should be noted that this
high intrathecal dose is the equivalent of 8 mg/kg per day
following systemic administration. It has been reported
that intrathecal administration of some lipophilic drugs
actually mediates effects due to systemic redistribution
(Parsons et al., 1989). As such, the locus of action of
memantine following intrathecal administration is unclear.
High doses of memantine inhibited acute visceral
nociceptive responses with an ID50 of 14.5 mg/kg i.v. (c.f.
2.4 mg/kg i.v. for ketamine) assessed via increases in
blood pressure evoked by graded destinations of the
C.G. Parsons et al. / Neuropharmacology 38 (1999) 735–767
ureter in anaesthetised rats. In contrast, acute somatic
nociceptive reflexes to mechanical pinch were not affected by ketamine 10 mg/kg i.v. (Olivar et al., 1997).
Intraplantar pre-treatment with memantine significantly attenuated formalin-induced lifting and licking
behaviours, however flinching behaviour was not effected. Control experiments indicated that the effects of
memantine were not via systemic redistribution and
suggest that peripheral NMDA receptors on unmyelinated sensory axons in the skin contribute to nociceptor activation and can be manipulated to reduce pain of
peripheral origin (Davidson and Carlton, 1998).
In summary, although there are some positive data
on the effects of memantine in animal models of
chronic and neuropathic pain, the doses required are
normally quite high and might be predicted to produce
some undesirable side effects. If the involvement of
peripheral NMDA receptors in inflammatory pain finds
verification by other groups, then this could offer a very
attractive target for NMDA receptor antagonists that
don’t penetrate the blood brain barrier as they would
be predicted to produce antinociceptive effects at doses
essentially devoid of CNS mediated side effects. However, the very good penetration of memantine to the
brain would not allow such a separation following
systemic administration of high doses.
11.9. Tolerance, sensitisation and drug addiction
It is believed that phenomena such as sensitisation,
tolerance and drug-dependence might also involve
synaptic plasticity. In fact, numerous studies indicate
that NMDA receptor antagonists block sensitisation to
amphetamine and cocaine as well as tolerance to ethanol
and opioids in animal models (for reviews see Danysz et
al., 1995a; Parsons et al., 1998c). Moreover, NMDA
receptor antagonists inhibit withdrawal symptoms seen
after termination of chronic treatment with opioids and
ethanol (for review see Toru et al., 1994; ibid). Recent
studies indicate that memantine (10 – 20 mg/kg i.p.)
prevents the expression of withdrawal symptoms in mice
and causes a long term reversal of morphine dependence
after it has been established (Popik and Skolnick, 1996).
This is of particular relevance to the clinical situation
where such negative symptoms should not only be
temporally suppressed, but permanently reversed. Preliminary experiments also indicate that a high dose of
memantine (30 mg/kg) inhibits tolerance to the analgesic
effects of morphine in mice (Belozertseva and Bespalov,
1998). Taken together with the above mentioned effects
of memantine in models of chronic pain, these data
indicate the utility of the combined use of memantine
with morphine in the treatment of chronic pain. The
antinociceptive effects of memantine and morphine
would be predicted to be synergistic and the presence of
memantine should block both the development of
755
chronic pain states and inhibit the development of
tolerance to the analgesic effects of morphine. However,
it should be noted that the doses required were high.
With regard to drug abuse, memantine (7.5 mg/kg i.p.)
has been shown to inhibit the acquisition and expression
of the reinforcing effects of morphine and motivational
aspects of naloxone precipitated opioid withdrawal assessed with a place preference paradigm (Popik and
Danysz, 1997). Recent experiments on morphine self-administration in mice (nose poking) indicate that memantine already at a very low doses of 1 mg/kg inhibited self
administration of this opioid, indicating anti-abuse potential (Semenova et al., submitted). This seems to find
confirmation in preliminary results of clinical studies
which show that memantine might in fact decrease
morphine intake in addicts (Kleber’s group, Columbia
University, Department of Psychiatry), data presented at
the ACNP meeting in December 1998. Interestingly, they
dosed memantine up to 60 mg/subject without serious
side effects or indications of abuse potential.
Finally, memantine infused at 20 mg/kg per day s.c.
has also been shown to have anti-craving like properties
in alcohol-dependent rats (Hölter et al., 1996; Spanagel
and Zieglgänsberger, 1997). As both ethanol and
memantine block NMDA receptors, the anti-craving
effects of memantine could partially be related to substitution. Thus memantine and other NMDA receptor
antagonists dose-dependently generalised for ethanol in
rats trained to discriminate ethanol from saline (Bienkowski et al., 1998; Hundt et al., 1998). However,
memantine (2.25 and 4.5 mg/kg) failed to change the
ethanol dose-response relationship in a drug discrimination paradigm indicating that the ‘recognition’ of the
ethanol cue is not affected by memantine (Koros et al.,
1999). Moreover, memantine potentiated ethanol-induced behavioural sleep but had virtually no effect on
hypothermia induced by ethanol (Beleslin et al., 1997).
It is still unclear how memantine could block synaptic
plasticity associated with chronic pain and the development of some aspects of drug tolerance and dependence
at doses having no negative effects on learning and
memory. It is tempting to speculate that different subtypes of NMDA receptor are involved in these processes
(see above) or that the levels/patterns of synaptic activity
are different.
11.10. Epilepsy
Memantine and (+)MK-801 both suppress epileptiform activity in hippocampal slices in Mg2 + -free aCSF
but ( + )MK-801 is 10–100-fold more potent (Apland
and Cann, 1995; Frankiewicz et al., 1996; Frankiewicz
and Parsons, submitted).
Memantine blocks MES-induced seizures with an
ED50 of around 5–10 mg/kg (Chojnacka-Wojcik et al.,
1983; Urbanska et al., 1992; Kleinrok et al., 1995;
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C.G. Parsons et al. / Neuropharmacology 38 (1999) 735–767
Parsons et al., 1995; Czuczwar et al., 1996; Deutsch et
al., 1997). These effects have been reported to be potentiated in the presence of other anticonvulsants (Chojnacka-Wojcik et al., 1983; Kleinrok et al., 1995;
Czuczwar et al., 1996). Memantine had an ED50 of
7 – 12 mg/kg against tonic seizures in mice induced by
pentylenetetrazol, bicuculline, picrotoxin, 3-mercaptopropionic acid and NMDA (Meldrum et al., 1986;
Parsons et al., 1995). But had no effect on clonic
seizures in mice induced by the same agents and was
also inactive in photosensitive baboons (Meldrum et al.,
1986). Memantine (5 – 10 mg/kg) also depressed spontaneous absence-like paroxysms in the cortical EEG of
rats (Frey and Voits, 1991). Although memantine (5–10
mg/kg) was virtually ineffective against amygdala kindling in rats when given alone, coadministration with
NBQX (2.5–10 mg/kg) synergistically potentiated the
effects of NBQX alone at doses of both drugs which
did not induce behavioural adverse effects (Löscher and
Hönack, 1982, 1994).
Although memantine is effective in animal models of
generalised seizures, therapeutically-relevant doses are
ineffective in animal models of partial complex seizures
and higher doses (20 mg/kg) actually enhance seizures
in amygdala-kindled rats. This form of epilepsy represents the desired therapeutic target as effective therapies
for generalised seizures are already available. However,
the fact that memantine was clearly synergistic with
NBQX in kindled rats indicates that combination therapy might represent a promising therapeutic approach.
11.11. Spasticity
As expected for NMDA receptor antagonists,
memantine (10–20 mg/kg) selectively reduced polysynaptic spinal reflexes in rats (Svensson, 1973; Schwarz
et al., 1992, 1995) and blocked polysynaptic reflexes in
a-chloralose-anaesthetised cats with an ID50 of 6.8 mg/
kg i.v. (Farkas and Karpati, 1988). Others have reported that memantine (10 mg/kg) administered i.v.
also decreased the fusimotor reflex in cats i.e. decreased
the activity of the g-reflex whilst having no effect on the
basal 1a discharge rate (Mühlberg and Sontag, 1973;
Sontag and Wand, 1973; Sontag et al., 1974; Wand et
al., 1977). The fact that higher doses of memantine
have myorelaxant effects (Danysz et al., 1994a; Carter,
1995) could be put to therapeutic use in the treatment
of spasticity (Fünfgeld, 1985; Noth, 1991). Moreover,
memantine (5–20 mg/kg i.p.) dose-dependently delayed
the progression of dystonic attacks in a model of
paroxysmal dystonia in Syrian golden hamsters but did
not reduce the severity of the dystonic movements
(Richter et al., 1991). These antidystonic effects were
seen at doses which did not cause marked ataxia or
sedation.
11.12. Depression and anxiety
Amantadine but not memantine was effective against
reserpine-induced hypothermia (Moryl et al., 1993). In
the forced swim test both aminoadamantanes produced
antidepressive-like activity (decreased immobility time).
This effect was specific, i.e. it was apparently not the
result of an increase in general activity as evidenced by
control experiments in the open field (5 min observation
period, Moryl et al., 1993). Prolonged treatment with a
very low dose of memantine (2.5 mg/kg per day) also
counteracted chronic stress-induced deficits of aggression assessed with electric footshock-induced fighting
behaviour (Ossowska et al., 1997). These preclinical
findings are supported by observations connected with
the clinical use of memantine and amantadine indicating improved motivation/drive (Vale et al., 1971; Ditzler, 1991). In contrast, memantine and amantadine
showed no anxiolytic activity in the Vogel conflict test
or the elevated plus-maze (Karcz-Kubicha et al., 1997).
11.13. Other possible indications
Infectious scrapie prion protein was reported to
cause DNA fragmentation, apoptosis and cell death in
cultured rat cortical cells which was completely prevented by memantine (10 mM) and other uncompetitive
NMDA receptor antagonists (Müller et al., 1993, 1997).
Memantine has been shown to counteract behavioural
signs of acute toxicity following sublethal doses of
organophosphorus cholinesterase inhibitors such as the
nerve agents, soman, sarin, tabun or carbofuran (e.g.
Gupta and Kadel, 1989, 1990, 1991; Gupta and Dettbarn, 1992; McLean et al., 1992; Gupta et al., 1993;
Deshpande et al., 1995). However, memantine (18 mg/
kg i.p.) or memantine plus atropine (10 mg/kg i.p.) did
not terminate electrographic seizure activity or prevent
seizure-related brain damage (Shih et al., 1996; Koplovitz et al., 1997). These results indicate that somaninduced CNS seizure activity is not ameliorated by
memantine and that the presence or absence of somaninduced CNS seizure activity cannot be verified reliably
through overt behavioural observations alone.
Memantine may afford protection against cisplatininduced emesis but the specificity of this effect is uncertain since it may relate to general CNS depression
(Lehmann and Karrberg, 1996).
Electrical stimulation of the paraventricular nucleus
of the hypothalamus in the anaesthetised rabbit induced an increase in indexes of myocardial oxygen
demand which was antagonised by memantine indicating cardioprotective activity (Monassier et al., 1996).
Eleven patients with fixational pendular nystagmus
who were given memantine (15–60 mg/day for 1 week)
experienced complete cessation of the nystagmus. In
contrast, scopolamine caused no or only a minor reduc-
C.G. Parsons et al. / Neuropharmacology 38 (1999) 735–767
tion of the nystagmus. It was concluded that memantine is a safe treatment option for acquired pendular
nystagmus (Starck et al., 1997).
11.14. Chronic and subchronic treatment
Chronic treatment of rats for 20 months with
memantine in the diet (30 mg/kg per day starting at 3
months of age) had no adverse effects on behaviour or
spatial leaning but significantly increased the number of
cortical [3H](+)MK-801 binding sites and the affinity
of [3H]glycine (Bresink et al., 1994, 1995b, unpublished). Glycine-dependent functional [3H]( +)MK-801
binding in dissociated membranes and thin slices revealed that a decreased ability of glycine to stimulate
channel opening in aged rats was partially attenuated
by the long-term memantine treatment (Bresink et al.,
1994, 1995b, unpublished). As such, chronic treatment
with memantine in aged animals especially increased
the sensitivity of the glycine coagonistic site of the
NMDA receptor complex. This finding may be related
to the putative increase in glycine affinity inferred from
the potentiation of NMDA-induced currents by low
concentrations of memantine at depolarised potentials
(Wang et al., 1994; Wang and MacDonald, 1995; Parsons et al., 1998a). This could have important functional implications for the cognitive improvement seen
with memantine in the treatment of dementia as functional deficits in glycine-stimulation of [3H]( +)MK-801
binding have reported in the brains of Alzheimer’s
patients (Procter et al., 1989a,b, 1991). Chronic treatment with memantine also increased the ability of
spermidine to enhance [3H]( +)MK-801 binding
(Bresink et al., 1995b). This effect could also be related
to interactions between the glycineB and polyamine
recognition sites (see Danysz et al., 1995a and Parsons
et al., 1998c for reviews).
Our recent studies indicate that subchronic infusion
of memantine for 2 weeks leads to tolerance to some
effects (e.g. amnesia in the passive avoidance test or
ataxia) but no change in other effects such as locomotor activation (Hesselink et al., 1999a). This is not
paralleled by adaptation in NMDA receptors ([3H]MK801 autoradiography) as this was unaffected by such
treatments. Interestingly, substantially different effects
were obtained when memantine was administered as
once daily i.p. injections since sensitisation to the locomotor stimulatory action was observed (ibid).
These changes in the effects of memantine following
chronic or subchronic treatment are also relevant to the
clinical situation where memantine doses are titrated
from 5 to 20 or 30 mg/kg per day over 4 – 6 weeks to
minimise the occurrence of side effects such as
restlessness.
757
12. Neurotoxicity in the cortex
Neuronal alterations (vacuolisation, HSP 70 and
dead neurones) in the cingulate/retrosplenial cortex are
seen in rodents after application of high doses of some
types of NMDA receptor antagonist. Some of the
neurones containing vacuoles may eventually die by
necrosis and possibly also via programmed cell death.
This feature is seen with most tested uncompetitive and
competitive antagonists but has not been reported for
antagonists acting at the glycineB site or the NR2B
selective antagonist eliprodil (see Parsons et al., 1998c).
With regard to memantine, single bolus doses of
memantine (25, 50, 75 mg/kg i.p.) induced HSP 70 in
the posterior cingulate, retrosplenial cortex and dentate
gyrus of rat brain. (Tomitaka et al., 1996, 1997). On the
other hand, vacuolisation and dead neurones were not
found after repeated oral treatment with fairly large
doses of memantine (50 mg/kg) over a prolonged period (Drommer, unpublished observations). This may
have been due to adaptation seen following semichronic treatment (see Hesselink et al., 1999a). However, Lipton’s group reported that vacuoles were not
seen in the cell bodies of retrosplenial or cingulate
cortex neurones of female Sprague–Dawley rats 4 h
after memantine 20 mg/kg i.p. whereas ( + )MK-801 1
mg/kg i.p. produced moderate to prominent vacuolisation (Chen et al., 1998)
Moreover, it seems probable that this phenomenon
might be specific for rodents since it has never been
reproduced in primates. In fact, a study with memantine in baboons revealed no neuronal toxicity at high
doses causing obvious behavioural signs of intoxication
(Schwaier et al. not published). Similarly Auer et al.
(1996) failed to detect any changes in the cingulate/retrosplenial cortex of squirrel monkeys after a high dose
of ( + )MK-801 (1 mg/kg) and the competitive NMDA
receptor antagonist CGS 19755 (cis-4-(phosphonomethyl)-2-piperidine carboxylic acid) produced no
changes in monkeys up to 20 mg/kg (Huber et al.,
1997). However, although in a recent study in guinea
pigs vacuoles were seen only occasionally in the cingulate/retrosplenial cortex even after a very high dose of
(+ )MK-801 (12 mg/kg), neocortical areas were affected (Raboisson et al., 1997).
It should also be born in mind that such experiments
are normally performed on female rats because this
gender shows a much higher susceptibility whereas
most pharmacological profiling studies in animal models are normally performed in males. Existing data
indicate clear pharmacokinetic and pharmacodynamic
differences between genders, especially for uncompetitive NMDA receptor antagonists. In turn, if vacuolisation studies were performed in male rats, even
(+)MK-801 would in this regard have a TI index ten
times higher than that assessed comparing therapeutic
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C.G. Parsons et al. / Neuropharmacology 38 (1999) 735–767
and neurotoxic potencies in different genders (Fix et al.,
1995). In the opinion of the authors, to assure proper
scientific conclusions on safety, T-max or AUC in
plasma should be used as reference factors and the
same sex of animals should always be used. This raises
considerable doubts as to the relevance of using female
rats to assess the possible neuronal toxicity of NMDA
receptor antagonists in humans.
13. Conclusions
1. Memantine is a clinically well tolerated uncompetitive NMDA receptor antagonist with strong
voltage-dependency and rapid blocking/unblocking
kinetics.
2. Mild excitotoxicity in vitro and in vivo is blocked by
memantine at concentrations seven to ten fold lower
than those impairing synaptic plasticity.
3. Neuroprotective activity of memantine in models of
chronic neurodegenerative diseases is seen at doses
producing plasma levels within the therapeutic
range and lacking negative effects typically observed
with several different NMDA receptor antagonists.
4. Disruption of neuronal plasticity produced by tonic
over stimulation of NMDA receptors is attenuated
by memantine. This symptomatological improvement possibly results from a decrease of noise i.e. an
increase of the signal to noise ratio and supports the
clinical use of memantine in dementia.
5. Preclinical studies indicate that memantine may also
have utility in the treatment of drug tolerance and
opiate/alcohol dependence.
6. Relatively high doses of memantine selectively block
thermal hyperalgesia and mechanical allodynia in
some models of chronic and neuropathic pain without obvious effects on motor reflexes. Possible complementary interactions between memantine and
opioids might be useful in the treatment of chronic
pain.
7. Although memantine is presently used in the treatment of dementia, this moderate affinity uncompetitive NMDA receptor antagonist could also be useful
in the treatment of other CNS disorders associated
with disturbances in glutamatergic transmission.
For Parkinson’s disease and spasticity there is already clinical evidence for the efficacy of memantine. For others, such as AIDS dementia, epilepsy,
glaucoma, hepatic encephalopathy, multiple sclerosis, stroke and tardive dyskinesia the evidence is
based on preclinical studies. However, high doses
were sometimes required which might be expected to
produce some undesirable side effects.
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