Elsevier

Neuropharmacology

Volume 38, Issue 6, 15 June 1999, Pages 735-767
Neuropharmacology

Review
Memantine is a clinically well tolerated N-methyl-d-aspartate (NMDA) receptor antagonist—a review of preclinical data

https://doi.org/10.1016/S0028-3908(99)00019-2Get rights and content

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.

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 d-CPP-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 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, Kornhuber et al., 1991, Parsons et al., 1993, Parsons et al., 1995).

Memantine was first synthesised by researchers at Eli Lilly in order to prepare a N-arylsulfonyl-N′-3,5-dimethyladamantylurea 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, Miltner, 1982b, 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 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).

Section snippets

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

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 μM (Kornhuber et al., 1989, Kornhuber et al., 1991, Kornhuber et al., 1994, Bresink et al., 1995a, Bresink et al., 1995b, 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

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 μM 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

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 with an IC50 of 9.7 mg/kg (Bisaga et al., 1993). Memantine was also potent—ID50

Tolerability in animal models

Early studies indicated that high doses of memantine (20–40 mg/kg i.p.) induce weak components of stereotyped behaviour (Costall et al., 1975, Costall and Naylor, 1975a, Costall and Naylor, 1975b, 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

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, Weller et al., 1993b) 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 μM (Chen et al.,

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

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

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

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, Lipton, 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

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

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

References (346)

  • I. Bresink et al.

    Different binding affinities of NMDA receptor channel blockers in various brain regions—indication of NMDA receptor heterogeneity

    Neuropharmacology

    (1995)
  • M. Bubser et al.

    Differential behavioural and neurochemical effects of competitive and non-competitive NMDA receptor antagonists in rats

    Eur. J. Pharmacol.

    (1992)
  • J.L. Cadet et al.

    Free radical mechanisms in schizophrenia and tardive dyskinesia

    Neurosci. Biobehav. Rev.

    (1994)
  • M. Carlsson et al.

    Interaction between glutamatergic and monoaminergic systems within the basal ganglia—implications for schizophrenia and Parkinson’s disease

    Trends Neurosci.

    (1990)
  • S.M. Carlton et al.

    Treatment with the NMDA antagonist memantine attenuates nociceptive responses to mechanical stimulation in neuropathic rats

    Neurosci. Lett.

    (1995)
  • A.J. Carter

    Antagonists of the NMDA receptor-channel complex and motor co-ordination

    Life Sci.

    (1995)
  • H.S.V. Chen et al.

    Neuroprotective concentrations of the N-methyl-d-aspartate open-channel blocker memantine are effective without cytoplasmic vacuolation following post-ischemic administration and do not block maze learning or long-term potentiation

    Neuroscience

    (1998)
  • E.J. Coan et al.

    Low-frequency activation of the NMDA receptor system can prevent the induction of LTP

    Neurosci. Lett.

    (1989)
  • G.L. Collingridge et al.

    Excitatory amino acid receptors and synaptic plasticity

    Trends Pharmacol. Sci.

    (1990)
  • B. Costall et al.

    Neuroleptic antagonism of dyskinetic phenomena

    Eur. J. Pharmacol.

    (1975)
  • W. Danysz et al.

    Glutamate antagonists have different effects on spontaneous locomotor activity in rats

    Pharmacol. Biochem. Behav.

    (1994)
  • W. Danysz et al.

    Aminoadamantanes as NMDA receptor antagonists and antiparkinsonian agents-preclinical studies

    Neurosci. Biobehav. Rev.

    (1997)
  • E.M. Davidson et al.

    Intraplantar injection of dextrorphan, ketamine or memantine attenuates formalin-induced behaviors

    Brain Res.

    (1998)
  • S.N. Davies et al.

    Differences in results from in vivo and in vitro studies on the use-dependency of N-methylaspartate antagonism by MK-801 and other phencyclidine receptor ligands

    Eur. J. Pharmacol.

    (1988)
  • S.I. Deutsch et al.

    The antiseizure efficacies of MK-801, phencyclidine, ketamine, and memantine are altered selectively by stress

    Pharmacol. Biochem. Behav.

    (1997)
  • A.H. Dickenson

    A cure for wind up: NMDA receptor antagonists as potential analgesics

    Trends Pharmacol. Sci.

    (1990)
  • E. Eisenberg et al.

    The effects of the clinically tested NMDA receptor antagonist memantine on carrageenan-induced thermal hyperalgesia in rats

    Eur. J. Pharmacol.

    (1994)
  • E. Eisenberg et al.

    The clinically tested N-methyl-d-aspartate receptor antagonist memantine blocks and reverses thermal hyperalgesia in a rat model of painful mononeuropathy

    Neurosci. Lett.

    (1995)
  • E. Eisenberg et al.

    The NMDA antagonist memantine blocks pain behaviour in a rat model of formalin-induced facial pain

    Pain

    (1993)
  • S.L. Erdõ et al.

    Memantine is highly potent in protecting cortical cultures against excitotoxic cell death evoked by glutamate and N-methyl-d-aspartate

    Eur. J. Pharmacol.

    (1991)
  • S. Farkas et al.

    Electrophysiologic measurement of the flexor reflex in cats for testing centrally acting muscle relaxant drugs

    Pharmacol. Res. Comm.

    (1988)
  • D. Ferger et al.

    Determination of intracellular Ca2+ concentration can be a useful tool to predict neuronal damage and neuroprotective properties of drugs

    Brain Res.

    (1996)
  • A.V. Ferrer-Montiel et al.

    Structural determinants of the blocker binding site in glutamate and NMDA receptor channels

    Neuropharmacology

    (1998)
  • A. Fisher et al.

    Differential effects of NMDA and non-NMDA antagonists on the activity of aromatic l-amino acid decarboxylase activity in the nigrostriatal dopamine pathway of the rat

    Brain Res.

    (1998)
  • A.S. Fix et al.

    Quantitative analysis of factors influencing neuronal necrosis induced by MK-801 in the rat posterior cingulate/retrosplenial cortex

    Brain Res.

    (1995)
  • H.H. Frey et al.

    Effect of pschotropic agents on a model of absence epilepsy in rats

    Neuropharmacology

    (1991)
  • M.Y.T. Globus et al.

    Excitotoxic index-a biochemical marker of selective vulnerability

    Neurosci. Lett.

    (1991)
  • K.A. Grant et al.

    Dizocilpine-like discriminative stimulus effects of low-affinity uncompetitive NMDA antagonists

    Neuropharmacology

    (1996)
  • A. Grossmann et al.

    The effect of dimethylaminoadamantane on neuronal membranes

    Eur. J. Pharmacol.

    (1976)
  • P.S. Aisen et al.

    Inflammatory mechanisms in Alzheimer’s disease: implications for therapy

    Am. J. Psychiatry

    (1994)
  • P. Andine et al.

    Changes in extracellular amino acids and spontaneous neuronal activity during ischaemia and extended reflow in the CA1 of the rat hippocampus

    J. Neurochem.

    (1991)
  • O.A. Andreassen et al.

    Inhibition by memantine of the development of persistent oral dyskinesias induced by long-term haloperidol treatment of rats

    Br. J. Pharmacol.

    (1996)
  • R.N. Auer et al.

    Postischemic therapy with (+)MK-801 (dizocilpine) in a primate model of transient focal brain ischemia

    Mol. Chem. Neuropathol.

    (1996)
  • C. Backhauss et al.

    A mouse model of focal cerebral ischemia for screening neuroprotective drug effects

    J. Pharmacol. Toxicol. Meth.

    (1992)
  • C. Backhauss et al.

    Extract of Kava (Piper-Methysticum) and its methysticin constituents protect brain tissue against ischemic damage in rodents

    Eur. J. Pharmacol.

    (1992)
  • C.A. Barnes et al.

    Effects of the uncompetitive NMDA receptor antagonist memantine on hippocampal long-term potentiation, short-term exploratory modulation and spatial memory in awake, freely moving rats

    Eur. J. Neurosci.

    (1996)
  • A.S. Basile et al.

    N-methyl-d-aspartate antagonists limit aminoglycoside antibiotic-induced hearing loss

    Nat. Med.

    (1996)
  • Belozertseva, I., Bespalov, A.Y. 1998. Effects of NMDA receptor channel blockers, dizocilpine and memantine, on the...
  • H. Benveniste et al.

    Elevation of the extracellular concentrations of glutamate and aspartate in rat hippocampus during transient cerebral ischemia monitored by intracerebral microdialysis

    J. Neurochem.

    (1984)
  • W. Birkmayer et al.

    The potentiation of the antiakinetic effect after l-DOPA treatment by an inhibitor of MAOB

    deprenyl. J. Neural Transm.

    (1975)
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