Moretti et al.indd Drug Target Insights 2008:3 77–85 77 REVIEW Correspondence: Rita Moretti, M.D., Department of Neurology, University of Trieste, Cattinara Hospital 34149 Trieste, Italy. Tel: +39-40-3994321; Fax: +39-40-910861; Email: moretti@univ.trieste.it Copyright in this article, its metadata, and any supplementary data is held by its author or authors. It is published under the Creative Commons Attribution By licence. For further information go to: http://creativecommons.org/licenses/by/3.0/. Memantine: Reality and Potentiality Rita Moretti, Paola Torre, Cristina Vilotti, Davide Manganaro, Luca Zanet and Rodolfo M. Antonello Department of Medicine and Neurology, University of Trieste, Trieste, Italy. Abstract: Memantine protects cultured neurons from excitotoxin-induced cell-death; it attenuated loss of cholinergic neurons in the CNS induced by injection of NMDA into the basal forebrain of rats. It has been shown that memantine induced pro- duction of brain-derived neurotrophic factor (BDNF), a substance shown to promote survival and differentiation of CNS neuron. Due to the preclinical effects of memantine owing to its anti-ischemic and anti-excitotoxic properties, recent clini- cal effi cacy has been demonstrated in patients with advanced dementia of vascular origins. Therefore, it has been employed in different trials, in vascular dementia, showing a potential benefi t and no unbearable side effects. Different studies under- line the possible role of memantine in Parkinson Disease. Keywords: memantine, NMDA, glutamate, degeneration Glutamate is the principal excitatory neurotransmitter in the brain and is active in about one-third of all the synapses in the central nervous system. Although glutamate is a crucial mediator of physiologi- cal communication between neuronal cells, under certain conditions activation of glutamate receptors kills neurones—a term called “excitotoxicity” (Rothman et al. 1987). It has been implied that excito- toxicity is involved in many types of acute and chronic CNS neurodegenerative disorders and is con- nected with Ca2+ overload (Choi et al. 1995). Disturbance of glutamate homeostasis probably plays a pivotal role in neuropathology triggered by other factors such as: energy defi cits, free radicals forma- tion, etc. that facilitate the neurotoxic potential of endogenous glutamate (Danysz et al. 2000). Glutamate activates three major types of ionotropic receptors, namely a-amino-3- hydroxy-5-methyl- 4-isoxazolepropionic acid (AMPA), kainate and N-methyl-D-aspartate (NMDA) and several types of metabotropic receptors. AMPA receptors are probably involved in all forms of fast glutamatergic neu- rotransmission (Danysz et al. 2000). There are four known subunits GluR1 to GluR4 which form functional receptors as tetrameric subunit assemblies. All AMPA receptors are permeable to Na+ and K+ while complexes lacking GluR2 subunits are also permeable to Ca2+. NMDA-sensitive ionotropic glutamate receptors are coupled to high conductance cationic channels permeable to Na+, K+, and Ca2+ (Danysz et al. 2000). The NMDA channel is blocked in a use- and voltage dependent manner by Mg2+ and many exogenous agents. NMDA receptors are only activated following depolarisation of the postsynaptic membrane which physiologically follows AMPA receptor stimulation which relieves blockade by Mg2+. This unique feature and the high Ca2+ permeability renders NMDA receptors inherently suitable as mediators of synaptic plasticity (e.g. learning and memory). Similar to Mg2+, uncompetitive NMDA receptor antagonists such as ketamine, dextromethorphan, memantine, phencyclidine and (+)-5-methyl-10,1l-dihydro-5H- dibenzocyclohepten-5,10-imine meleate (+)MK-801 block the NMDA channel in the open state, although the blocking kinetics and voltage dependence of this effect vary considerably (Danysz et al. 2000). Glutamate and NMDA receptors are involved in long-term potentiation (LTP), a fundamental process for memory consolidation, whereby brief high-frequency stimulation leads to an increased response after subsequent activation. NMDA receptors are involved in mediating the postsynaptic components of LTP in the hippocampus e.g. in the Schaffer collateral projection from CA3 to CA1 (Danysz et al. 1995; Parsons et al. 1998; Fischer et al. 1977). Under normal physiological resting conditions, the ion channels of the NMDA receptors are blocked by magnesium ions in a voltage-dependent manner. The small amounts of glutamate that are released http://creativecommons.org/licenses/by/3.0/. http://creativecommons.org/licenses/by/3.0/. 78 Moretti et al Drug Target Insights 2008:3 are not suffi cient to displace the magnesium ions and remove the blockade of the NMDA receptor channels; there is a so-called “low background noise”. During normal synaptic activity, larger concentrations of glutamate are released, the post- synaptic membrane is depolarised, the magnesium blockade is transiently inactivated, calcium ions enter the cell and a signal is generated. Under conditions of impaired metabolism, there is a sus- tained release of glutamate, and excessive gluta- mate activity is associated with excitotoxicity. The magnesium ions are lost from the NMDA recep- tors—allowing a continuous infl ux of calcium ions into the cell-creating a high level of background noise and impairing the recognition of signals, resulting from physiological activation of the receptor. High intracellular concentrations of cal- cium eventually lead to neuronal degeneration and cell death. Memantine blocks NMDA receptor channels in cultured neurons in a voltage-dependent manner as measured by patch clamp technique (Chen et al. 1997; Blanpied et al. 1997; Borman et al. 1989). The effects of memantine were not reversed by exposure to glycine �100 micromol/L (Borman et al. 1989). Memantine induces open-channel blockade of NMDA receptors (Ambrozi et al. 1988) and is ‘par- tially trapped’ in NMDA receptor channels (Chen et al. 1999; Frankiewicz et al. 1999). Memantine could be washed from approximately one-sixth of channels during in vitro experiments (Frankiewicz et al. 1999). Memantine protects cultured neurons from excitotoxin-induced cell death (Parsons et al. 1993; Krieglstein et al. 1996; Erdo et al. 1991; Weller et al. 1993; Pellegrini et al. 1993). Memantine exerts neuroprotective effects in several models of brain injury. The drug attenuated loss of cholinergic neurons in the CNS induced by injection of NMDA into the basal forebrain of rats (Wenk et al. 1997). Memantine also attenuated neuronal injury in various rat models including traumatic brain injury (Rao et al. 2001), ischaemic stroke induced by occlusion of cerebral (Gorgiilii et al. 2000; Dogan et al. 1999) or carotid arteries (Seif eJ NasI’ et al. 1990; Heim et al. 1995), a photo-induced throm- botic model of cerebral focal ischaemia (Stieg et al. 1999) and quinolinic acid-induced hippocampal damage (Keilhoff et al. 1992). At a dosage of 5–50 mg/kg in rats, memantine induced production of brain-derived neurotrophic factor (BDNF), a substance shown to promote survival and differentiation of CNS neurons, and trkB, a tyrosine kinase receptor for BDNF (Keilhoff et al. 1992). mRNA for BDNF and trkB was detected in limbic cortex slices by in situ hybridi- sation (Lundbeck AIS, 2002). Clinical Therapy Due to its preclinical effects, above described, memantine, late in 2003, was approved by the FDA as a drug for AD treatment. Memantine is indicated for the treatment of moderate to severe Alzheimer’s disease, refl ecting a license extension granted by the European Commission in October 2005 to include the moderate AD patient population. Post-mortem orepidemiological studies suggest a strong association between glutamate dysfunc- tion and Alzheimer ’s disease. Some authors observed co-localisation of glutamatergic neu- rones and pathological alterations (neurofi brillary tangles and senile plaques) in post-mortem analy- sis of the brains of Alzheimer’s patients (Braak et al. 1993; Francis et al. 1993). In Alzheimer's disease there is an increase of glutamate, caused by a decrease of uptake and/or increase of release. There is a decrease in astroglial glutamate carrier EAA2 in the frontal cortex of post-mortem sam- ples from brains of Alzheimer’s patients (Li et al. 1997). In vitro constituents of senile plaques stimulate microglia to produce an unknown neu- rotoxin having agonistic properties at NMDA receptors (Giulian et al. 1995; Klegeris et al. 1997). Beta-amyloid peptide either activates NMDA receptors or enhances their sensitivity (Goodwin et al. 1995); in fact, beta-amyloid (1–40) stimulates nitric oxid (NO) production by microglia (Goodwin et al. 1995)—NO is known to enhance glutamate release and to inhibit uptake (Brorson et al. 1995). Beta-amyloid peptide enhances the toxicity of glutamate in in vitro test (Mattson et al. 1992; Wu et al. 1995) and augments NMDA receptor mediated transmission (Cullen et al. 1996). In vivo injection of beta-amyloid produces long lasting depression of EPSPs in the hippocampus, which is an expression of ongoing mild excitotoxicity. It is prevented by the NMDA receptor antagonist 3-(2-carboxypiperazin- 4-yl)propyl-1-phosphonic acid (CPP) (Cullen et al. 1996). In multi centre placebo-controlled trials, memantine has demonstrated effi cacy and safety 79 Memantine: reality and potentiality Drug Target Insights 2008:3 in AD patients. The N-methyl-D-aspartate (NMDA) antagonist memantine has been shown to be effective in moderately-severe to severe AD. 252 patients were enrolled, with equal numbers (n = 126) receiving either memantine 20 mg/day or placebo for 28 weeks. Effi cacy was assessed using the clinician’s interview-based impression of change (NYU CIBICplus), the modified Alzheimer’s Disease Cooperative Study activities of daily living (ADCS-ADLsev) inventory, the severe impairment battery (SIB), and functional assessment staging (FAST) (Reisberg et al. 2003; Reisberg et al. 2000). In Study Two, 166 patients were enrolled to the study and randomised to receive either memantine 10 mg/day or placebo for 12 weeks. The primary effi cacy endpoints were measured using the Clinical Global Impression of Change (CGI-C) and the Behavioural Rating Scale for Geriatric Patients (BGP). The modifi ed D-scale (Arnold/Ferm) was used to assess basic activities of daily living as a secondary endpoint. Both stud- ies demonstrated that patients treated with meman- tine show improvements in the three main AD domains: function, cognition and global response. Memantine was well tolerated in both studies, being the incidence of adverse events (AEs) and serious AEs was similar in both groups (Winblad et al. 1999). In conclusion, memantine treatment offered functional improvements and reduced care dependence for patients with moderately-severe to severe AD. Another well designed study, involving patients with moderate-to-severe Alzheimer’s disease, who were randomly assigned to receive placebo or 20 mg of memantine daily for 28 weeks has been conducted (Bleich et al. 2003). 252 patients were enrolled. Of these, 181 (72%) completed the study and were evaluated at week 28. 71 patients discon- tinued treatment prematurely (42 taking placebo and 29 taking memantine). Patients receiving memantine had a better outcome than those receiv- ing placebo, according to the results of the clinical global impression (P = 0.06 with the last observa- tion carried forward, P = 0.03 for observed cases), of the activities of daily living (P = 0.02 with the last observation carried forward, P = 0.003 for observed cases), and the Severe Impairment Battery (P � 0.001 with the last observation carried forward, P = 0.002 for observed cases). Memantine was not associated with a signifi cant frequency of adverse events. The conclusions of the authors are well stigmatized by the following sentence: “Antiglutamatergic treatment reduced clinical deterioration in moderate-to-severe Alzheimer’s disease, a phase associated with distress for patients and burden on caregivers, for which other treat- ments are not available” (Bleich et al. 2003). It has been demonstrated a favourable effect of memantine, even in the association with cholines- terase inhibitors. A 24-week, randomised, double- blind, parallel-arm, placebo controlled trial was performed in 37 US centres to study the safety and effi cacy of memantine in patients with moderate to severe AD treated with donepezil (Hartmann et al. 2003). Inclusion criteria of the study were: a diagnosis of probable AD by NINCDS-ADRDA, MMSE (5–14), MRI or CT scan consistent with probable AD, and 6-month daily AChEI (donepe- zil) therapy (stable dose for the past 3 months). Primary outcome assessments were: cognition and function in daily living. A pharmacokinetic study in 24 healthy volunteers showed no pharmacoki- netic or pharmacodynamic interactions and the combination was well tolerated. The global effect was in general favourable to the population who received both the drugs. A postmarketing surveillance study was per- formed in Germany to assess the tolerability of memantine in combination with an AChEI (84% donepezil and 15% rivastigmine) based on 200 questionnaires. The results demonstrate that combining memantine with a commonly used AChEI is safe and superior to the AChEI alone in moderate to severe AD (Tariot et al. 2003; Tariot et al. 2004; Knopman, 2005; Pomara et al. 2004; Sudhir, 2004). To investigate, the cognitive effect of the memantine, a group of scientists (Schmitt et al. 2006) executed a post-hoc exploratory reanalysis of a 24 week randomized, double-blind, placebo- controlled, parallel group clinical trial comparing memantine to placebo in patients with moderate to severe AD receiving treatment with cholinester- ase inhibitor, donepezil. These post-hoc analyses support the benefi cial effects of memantine on cognition observed in a previously reported clini- cal trial. The results suggested an effect of meman- tine on memory, language, and praxis in patients with moderate to severe AD and support the effi - cacy of memantine for the treatment of cognitive defects in AD (Schmitt et al. 2006). A very recent work (Jones et al. 2007) confi rmed the statistically signifi cant benefi ts of memantine given twice-daily to treat moderate to severe AD have already been 80 Moretti et al Drug Target Insights 2008:3 shown by multiple studies in pivotal AD domains (function, cognition and global performance) (Winblad et al. 2006). No clinically relevant dif- ferences in adverse effects or vital signs were observed between the different dosing schedules (Jones et al. 2007). Memantine and Vascular Dementia In course of a cerebrovascular event, there is a run-down of energy in neurons. There are number of microdialysis studies indicating that there is also a consistent increase in extracellular glutamate concentration. In humans, there is also an increase in cerebrospinal fl uid (CSF) and plasma content of glutamate in patients with progressive, but not stable stroke. Thus, other factors may increase neuronal vulnerability to physiological levels of glutamate by, for example, a decrease of resting membrane potential or intracellular buffering of Ca2+ ions. Apart from glutamate, oxidative stress, inflammatory reactions and breakdown of the blood-brain barrier may also play a pivotal role. The toxic effects of glutamate are mediated largely through N-methyl- D-aspartate (NMDA) receptors. Activation of NMDA-associated chan- nels leads to the passage of sodium and chloride into the cell followed by the obligatory movement of water resulting in cytotoxic oedema. If calcium is present early, it tends to pass through the channel into the cell where it recruits second messengers, with concomitant activation of kinases and prote- ases that eventually lead to irreversible injury. This is believed to be the underlying mechanism behind delayed glutamate toxicity. Glutamate excitotoxic- ity can lead to a state of self-amplifi cation, fol- lowed by an increase of intracellular calcium. These events lead to a second messenger activa- tion, giving rise to changes that make the cell more permeable to additional calcium entry and further glutamate release. Glutamate release also gives rise to oxygen free radical production, which main- tains the further release of glutamate. Controversial are the results from animal stud- ies: often short delays (1–3 days) for analysis of infarct size are used. There are data showing that some treatments delay, but do not really prevent neuronal death. Therefore, the protective effects are seen when analyzed at three days but not 7–28 days after insult. Infarct volume or cell damage is not always predictive of functional outcome. There is signifi cant strain and vendor variability of infarct size and neuroprotective efficacy of NMDA receptor antagonists, adding to the already large methodological diversity (Mortimer et al. 1991; Orgogozo et al. 2002). Physiological NMDA receptor activity, however, is also essential for normal neuronal function; potential neuroprotective agents that block virtually all NMDA receptor activity will very likely have unacceptable clinical side effects. For this reason many NMDA receptor antagonists have disappoint- ingly failed advanced clinical trials for a number of diseases including stroke and neurodegenerative disorders such as Huntington’s disease. In contrast, studies by Lipton (2004) were the fi rst to show that memantine preferentially blocks excessive NMDA receptor activity without disrupting normal activity (Orgogozo et al. 2002). Based on the hypothesis of glutamate-induced neurotoxicity (excitotoxicity) in cerebral ischemia, different studies examined the effi cacy and toler- ability of memantine, an uncompetitive N-methyl- D-aspartate antagonist, in the treatment of mild to moderate vascular dementia. In a multicenter, 28-week trial carried out in France, 321 patients received 10 mg/d memantine or placebo twice a day; 288 patients were valid for intent-to-treat analysis. Patients had to meet the criteria for probable vascular dementia and have a Mini-Mental State (MMSE) score between 12 and 20 at inclusion. The 2 primary end points were the cognitive subscale of the Alzheimers Disease Assessment Scale (ADAS-cog) and the global Clinician’s Interview Based Impression of Change (CIBIC-plus) (Wilkock et al. 2002). After 28 weeks, the mean ADAS-cog scores were signifi cantly improved relative to placebo. In the intention-to-treat population, the memantine group mean score had gained an average of 0.4 points, whereas the placebo group mean score had declined by 1.6 points (95% confi dence interval, 0.49 to 3.60). The response rate for CIBIC-plus, defi ned as improved or stable, was 60% with memantine compared with 52% with placebo (P = 0.227, inten- tion to treat). Among the secondary effi cacy param- eters, which were analyzed in the per-protocol subset, MMSE was signifi cantly improved with memantine compared with deterioration with placebo (P = 0.003) (Wilkock et al. 2002). Another work has been conducted on the topic. The aim of the reported trial was to investigate the safety and effi cacy of memantine in mild to moder- ate vascular dementia (VaD) (Jarvis et al. 2002). 81 Memantine: reality and potentiality Drug Target Insights 2008:3 It was a 28-week, double-blind, parallel, randomized controlled trial of memantine 20 mg daily versus placebo, in probable VaD which was conducted in 54 centres in the U.K. Primary effi cacy parameters were cognition and the clinical global impression. A total of 579 patients were randomized and 548 patients with at least one post baseline effi cacy assessment qualifi ed for the intent-to-treat analysis. At endpoint, memantine was shown to improve cognition relative to placebo in VaD: the change of cognition scores from baseline differed by a mean of −1.75 points (95% confi dence intervals −3.023 to −0.49) and a median of 2 points between the two groups, while clinical general impression on the global status rating scores showed no signifi cant differences between treatment groups. Demaerschalk and Wingerchuk (2007) exam- ined in a complete meta-analysis eight relevant systematic reviews and randomized controlled tri- als were identifi ed and served as the principal sources of information. The best evidence to date revealed that donepezil 5 mg/d [number needed to treat (NNT) = 10] was the most effective and best tolerated [number needed to harm (NNH) = 50] of the available agents. Galantamine 24 mg/d (NNT = 7) was also effective but less well tolerated (NNH = 7). Due to insuffi cient evidence, rivastig- mine could not yet be recommended for the treat- ment of vascular dementia. Memantine appeared to be safe and well tolerated but did not demonstrate effectiveness across all cognitive outcomes and clinical global measures. Acetylcholinesterase inhibitors and NMDA receptor antagonists, in gen- eral, displayed promise as treatments for patients with vascular dementia and vascular cognitive impairment. The most effective, evidence-based treatments were donepezil and galantamine Memantine and Parkinson’s Disease Because of its peculiar pharmacological properties, memantine is proposed to be benefi cial, as it blocks excessive NMDA receptors activation, without interfering with their physiological activity. An anti-parkinsonian activity has been described for memantine, in animal models of Parkinson’s disease and in parkinsonian patients (Merello et al. 1999). In addition, memantine prevents cell death induced by 1-methyl-4-phenyl- 1,2,3,6- tetrahydropyridine (Kucheryanu and Kryzhanovskii, 2000). Therefore, an Italian group (Giustizieri et al. 2007) focused our attention onto the action of this drug on the dopamine neurons of the substantia nigra pars compacta (SNc), whose progressive degeneration is a hallmark of Parkinson’s disease. Indeed, several lines of evidence indicate an over- stimulation of glutamate receptors, especially of the NMDA subtype, as the main cause of the pro- gressive loss of this neuronal population (Gardoni and Di Luca, 2006). Memantine has been showed not only to increase the fi ring rate of the dopamine neurons, but also changed occasionally their fi ring mode, from tonic to bursting behavior. This change in the fi ring pattern may have important functional impli- cations, as burst fi ring of the dopamine neurons has been associated to increased release of dopa- mine in the areas of nigral projection (Floresco et al. 2003; Phillips et al. 2003). According to the observations of Giustizieri et al. (2007), memantine does not affect the basal fi ring activity of the dopamine neurons in physi- ological conditions, while, in conditions of meta- bolic stress, a signifi cant effect of memantine emerges, resulting in recovery of fi ring activity of previously silenced dopamine neurons. This prop- erty may be particularly relevant in terms of fi ring dependent dopamine release and in relation to prevention of neuronal loss in Parkinson’s disease. The activity of complex I of the mitochondrial respiratory chain is reduced in dopamine neurons of parkinsonian patients (Schapira, 2001), and drugs acting as inhibitors of complex I, like rote- none or 1-methyl-4-phenyl-1,2,3,6- tetrahydro- pyridine induce dopamine neurons degeneration (Przedborski and Vila, 2003). A recent report by Liss and colleagues (2005) proposed that the selec- tive vulnerability of the SNc dopamine neurons in Parkinson’s disease is casually correlated with the opening of Katp conductances in these neurons; thus, the presence of functional Katp channels promotes the selective loss of SNc dopamine neu- rons in both a genetic model of Parkinson’s disease and in response to mitochondrial complex I inhibi- tion. At present, the mechanism through which Katp channel opening contributes to dopamine neurons degeneration is still unclear. There is evi- dence that increasing neuronal excitability protects dopamine neurons from degeneration (Salthun- Lassalle et al. 2004), for this reason Liss and col- leagues (2005) proposed that drugs acting at KATP channels of SNc dopamine neurons, should cause 82 Moretti et al Drug Target Insights 2008:3 a recovery from their functional silencing, thus providing a clinical benefi t in the treatment of Parkinson’s disease. Indeed, memantine has been shown to prevent cell death associated to Parkinson’s disease (Merello et al. 1999; Kucheryanu and Kryzhanovskii, 2000), although prevention of excitotoxic neuronal dam- age through an uncompetitive inhibition of NMDA receptors has been proposed as its underlying mechanism of action. Giustizieri et al. results (2007) results show that memantine does inhibit NMDA responses in the SNc, however, memantine may also result benefi cial in Parkinson’s disease patients because it reduces dopamine neurons silencing through closure of Katp conductances. Quite balancing the preclinical studies, there are not so consistent data in Parkinson patients in a clinical perspective. An open-fashion study, involv- ing 14 parkinsonian patients with motor fl uctuations taking L-dopa, has been conducted (Rabey et al. 1992); these patients were given a supplement of memantine 30 mg/day. After one month, 10 patients completed the treatment (4 discontinued it due to abdominal pain, psychomotor agitation, confusion and dizziness). In 5 patients, the main parkinsonian features improved signifi cantly (1 point or more on the Webster scale). In 6 patients, “off ” episodes improved (from daily mean of 273 minutes, to 172 minutes). In summary, the authors postulated that memantine addition to parkinsonian features, could form a basis for novel therapeutic strategies directed to neutralize the effects of glutamate at striatal and subthalamic levels. Another work has been conducted quite later (Merello et al. 1999); the aim was to evaluate the effect of Memantine on cardinal symptoms of Parkinson’s disease and on the latency, duration, and magnitude of the response to a single dose of L-Dopa and on drug-induced dyskinesias. Twelve Hoehn-Yahr III-IV patients with idiopathic Parkinson’s disease with motor fl uctuations and drug-induced dyskinesias were randomized to the NMDA antagonist memantine or placebo in a cross-over design. A single-dose L-Dopa challenge was performed after each medication arm. A sig- nifi cant drug effect on the Unifi ed Parkinson’s Disease Rating Scale motor score was observed in “off ” and “on” states (F(1,11) = 13.5; p � 0.003). No signifi cant effect on drug-induced dyskinesias was seen. The results suggest that memantine may improve parkinsonian symptoms independently of dopaminergic drugs and, in contrast to recent fi ndings with amantadine, it has no effect on drug- induced dyskinesias. Very recently, a new study has been conducted to determine the effect of memantine on Parkinson Disease (Seeman et al. 2007), considering that memantine is reported to improve symptoms in moderate cases of Alzheimer’s disease and Parkin- son’s disease, but is also known to trigger psychosis in some Parkinson patients. Because these clinical features suggested a possible dopamine component of memantine action, we measured the potency of memantine on the functional high-affi nity state of dopamine D2 receptors, or D2(High). Using [(3)H]domperidone to label D2 receptors, the memantine dissociation constant at D2(High) was 917 +/− 23 nM for rat striatal D2 receptors and 137 +/− 19 nM for human cloned D2Long receptors. The memantine dissociation constant for striatal N-methyl-D-aspartate (NMDA) receptors labeled by [(3)H] MK 801 was 2200 +/− 400 nM. Meman- tine stimulated the incorporation of [(35)S]GTP- gamma-S into D2-expressing Chinese Hamster Ovary cells with a dissociation constant of 1200 +/− 400 nM. Memantine, between 200 and 2000 nM, directly acted on D2(High) to inhibit the release of prolactin from isolated anterior pituitary cells in culture. Because the memantine potencies at NMDA receptors and dopamine D2(High) receptors are of a similar order of magnitude, it is likely that the clinical features of memantine can be attributed to its action at both types of receptors. Conclusions Memantine protects cultured neurons from excitotoxin-induced cell-death. Memantine exerts neuroprotective effects in several models of brain injury. The drug attenuated loss of cholinergic neurons in the CNS induced by injection of NMDA into the basal forebrain of rats. It has been shown that memantine induced production of brain-derived neurotrophic factor (BDNF), a substance shown to promote survival and differentiation of CNS neu- ron. Due to the preclinical effects of memantine owing to its anti-ischemic and anti-excitotoxic properties, recent clinical effi cacy has been dem- onstrated in patients with advanced dementia of vascular origins. Therefore, it has been employed in different trials, in vascular dementia, showing a potential benefi t and no unbearable side effects. Memantine has a small benefi cial, clinically detectable effect on cognitive function and 83 Memantine: reality and potentiality Drug Target Insights 2008:3 functional decline measured at 6 months in patients with moderate to severe Alzheimer’s Disease (AD). In patients with mild to moderate dementia, the small benefi cial effect on cognition was not clini- cally detectable in those with vascular dementia and barely detectable in those with AD. It is well tolerated (McShane et al. 2007). Main results can be summarized as follows: 1. Moderate to severe AD. Two out of three six month studies show a small benefi cial effect of memantine. Pooled data indicate a benefi cial effect at six months on cognition (2.97 points on the 100 point SIB, 95% CI 1.68 to 4.26, P � 0.00001), activities of daily living (1.27 points on the 54 point ADCS-ADLsev, 95% CI 0.44 to 2.09, P = 0.003) and behaviour (2.76 points on the 144 point NPI, 95% CI 0.88 to 4.63, P = 0.004), supported by clinical impres- sion of change (0.28 points on the 7 point CIBIC+, 95% CI 0.15 to 0.41, P � 0.0001). 2. Mild to moderate AD. Pooled data from three unpublished studies indicate a marginal benef- ical effect at six months on ITT cognition (0.99 points on the 70 point ADAS-Cog, 95% CI 0.21 to 1.78, P = 0.01) which was barely detectable clinically (0.13 CIBIC+ points, 95% CI 0.01 to 0.25, P = 0.03) but no effect on behaviour, activities of daily living or OC analysis of cognition. 3. Mild to moderate vascular dementia. Pooled data from two six month studies indicated a small benefi cial effect of memantine on cognition (1.85 ADAS-Cog points, 95% CI 0.88 to 2.83, P = 0.0002), and behaviour (0.84 95% CI 0.06 to 0.91, P = 0.03) but this was not supported by clinical global measures. 4. Patients taking memantine were slightly less likely to develop agitation (134/1739, 7.7% versus 175/1873, 9.3% OR 0.78, 95% CI 0.61 to 0.99, P = 0.04). This effect was slightly larger, but still small, in moderate to severe AD (58/506 [12%] vs 88/499 [18%]; OR = 0.6, 95% CI 0.42 to 0.86, P = 0.005). There is no evidence either way about whether it has an effect on agitation which is already present. Importantly, however, it does appear that the dementia caused by brain vascular disease may share similar anatomic substrates with AD, supporting the notion of a common substrate to dementia. 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