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