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PubMed2006

In vitro galantamine-memantine co-application: mechanism of beneficial action.

Several drugs are in clinical use for symptomatic treatment of Alzheimer's disease patients. Since Alzheimer's disease is known to be associated with down-regulation of the cholinergic and N-methyl-D-aspartate (NMDA) systems, most of these drugs inhibit acetylcholinesterase, potentiate the activity of nicotinic acetylcholine receptors (nAChRs), or modulate NMDA receptors. Galantamine is an anticholinesterase and allosterically potentiates the activity of the nicotinic receptors. We have recently found that galantamine potentiates the activity of NMDA receptors as well. Memantine is unique in that it inhibits the NMDA receptors. We have developed a hypothesis that combining galantamine and memantine will be more effective for improving the patient's conditions than monotherapy with either drug. Patch clamp and intracellular Ca(2+) imaging experiments using rat cortical and hippocampal neurons clearly provided the in vitro bases for our hypothesis. Memantine blocked the extrasynaptic NMDA receptor 100 times more potently than the synaptic NMDA receptor at negative membrane potentials and the block of both types of NMDA receptors was attenuated with depolarization. However, galantamine potentiation of the NMDA receptors was not voltage dependent. Thus, co-application of memantine with galantamine prevented the galantamine potentiation and the activation of extrasynaptic NMDA receptors, but membrane depolarization revealed the galantamine potentiation. Therefore, cell death is expected to be prevented by memantine near the resting potential while the NMDA-mediated synaptic transmission, which is down-regulated in the patients, is maintained and potentiated by galantamine. These results provide in vitro bases for the beneficial actions of galantamine and memantine combinations.

6-Cyano-7-nitroquinoxaline-2,3-dione↗

PubMed2006

Memantine protects against LPS-induced neuroinflammation, restores behaviorally-induced gene expression and spatial learning in the rat.

Neuroinflammation is reliably associated with the pathogenesis of a number of neurodegenerative diseases, and can be detected by the presence of activated microglia. Neuroinflammation can be induced by chronic lipopolysaccharide (LPS) infusion into the 4th ventricle of the rat resulting in region-selective microglia activation and impaired hippocampal-dependent memory. Furthermore, this treatment results in altered behaviorally-induced expression of the immediate early gene Arc, indicating altered network activity. LPS is known to activate microglia directly, leading to increased glutamate release, and in enhanced N-methyl-d-aspartate (NMDA) -dependent signaling. Taken together, the foregoing suggests that decreasing NMDA receptor activation during early stages of chronic neuroinflammation should reduce a) microglia activation, b) overexpression of Arc, and c) spatial memory deficits. Memantine, a low to moderate affinity open channel uncompetitive NMDA receptor antagonist, at low doses was used here to test these hypotheses. Rats were chronically infused into the 4th ventricle for 28 days with LPS alone, vehicle alone (via osmotic minipump) or LPS and memantine (10 mg/kg/day memantine s.c.). The results reported here demonstrate that memantine reduces OX6-immunolabeling for activated microglia, spares resident microglia, returns Arc (activity-regulated cytoskeletal associated protein, protein) -expressing neuronal populations to control levels (as revealed by Arc immunolabeling and fluorescence in situ hybridization), and ameliorates the spatial memory impairments produced by LPS alone. These data indicate that memantine therapy at low doses, recreating plasma levels similar to those of therapeutic doses in human, acts in part through its ability to reduce the effects of neuroinflammation, resulting in normal gene expression patterns and spatial learning. Combined, these findings suggest that low, therapeutically relevant doses of memantine delivered early in the development of neuroinflammation-influenced diseases may confer neural and cognitive protection.

Animals↗

PubMed2006

Memantine increases cardiovascular but not behavioral effects of cocaine in methadone-maintained humans.

Previous work has suggested that maintenance on the noncompetitive N-methyl-d-aspartate (NMDA) antagonist, memantine, increased the subjective effects of smoked cocaine in experienced cocaine users. To determine whether this phenomenon occurs in opioid-dependent individuals, eight (seven male, one female) methadone-maintained cocaine smokers participated in a 47-day inpatient and outpatient study to assess the effects of memantine on smoked cocaine self-administration, subjective effects, and cardiovascular responses. The participants were maintained on memantine (0 mg and 20 mg daily) for 7-10 days prior to laboratory testing, using a double-blind crossover design. Under each medication condition during inpatient phases, participants smoked a sample dose of cocaine base (0, 12, 25, and 50 mg) once, and were subsequently given five choice opportunities, 14 min apart, to self-administer that dose of cocaine or receive a merchandise voucher (US 5.00 dollars). Each cocaine dose was tested twice under each medication condition, and the order of medication condition and cocaine dose were varied systematically. Memantine maintenance did not alter the subjective or reinforcing effects of cocaine. Several cardiovascular responses, however, including peak and initial diastolic pressures following cocaine, were significantly greater during memantine maintenance, although these elevations were not clinically significant. Taken together, these findings corroborate earlier data suggesting that this dose of memantine will not be helpful in the pharmacotherapy of cocaine abuse.

Adult↗

PubMed2002

Neuroprotection by memantine against neurodegeneration induced by beta-amyloid(1-40).

Progressive neuronal loss and cognitive decline in Alzheimer's disease (AD) might be aggravated by beta-amyloid-enhanced excitotoxicity. Memantine is an uncompetitive NMDA receptor antagonist under clinical development for the treatment of AD. Memantine has neuroprotective actions in several in vitro and in vivo models. In the present study, we determined whether memantine protected against beta-amyloid induced neurotoxicity and learning impairment in rats. Twenty Sprague-Dawley rats received vehicle or vehicle plus memantine (steady-state plasma concentrations of 2.34+/-0.23 microM, n=10) s.c. by osmotic pump for 9 days. After 2 days of treatment, 2 microl of water containing beta-amyloid 1-40 [Abeta(1-40)] were injected into the hippocampal fissure. On the ninth day of treatment, animals were sacrificed, and morphological and immunohistochemical techniques were used to determine the extent of neuronal degeneration and astrocytic and microglial activation in the hippocampus. Psychomotor activity and spatial discrimination were tested on the eighth day of treatment. Abeta(1-40), but not water, injections into hippocampus led to neuronal loss in the CA1 subfield, evidence of widespread apoptosis, and astrocytic and microglial activation and hypertrophy. Memantine treated animals had significant reductions in the amount of neuronal degeneration, pyknotic nuclei, and GFAP immunostaining as compared with vehicle treated animals. These data suggest that memantine, at therapeutically relevant concentrations, can protect against neuronal degeneration induced by beta-amyloid.

Alzheimer Disease↗

PubMed1998

Effects of memantine alone and with acute 'binge' cocaine on hypothalamic-pituitary-adrenal activity in the rat.

The effects of memantine, a non-competitive NMDA-receptor antagonist used in the management of dementia, and its coadministration with acute 'binge' pattern cocaine on hypothalamic-pituitary-adrenal axis activity were investigated in the rat. Measurements 3 h after injections showed that memantine alone at 20 mg kg(-1) (i.p.), but not 10 mg kg(-1), increased corticotropin-releasing factor (CRF) mRNA levels in the hypothalamus and both adrenocorticotropic hormone and corticosterone levels in the blood, and decreased type I CRF receptor mRNA in the anterior pituitary. Our previous studies have shown that acute 'binge' cocaine increases CRF mRNA levels in the hypothalamus. In this study, pretreatment with memantine (10 and 20 mg kg(-1), i.p.) did not alter the up-regulation of hypothalamic CRF mRNA induced by acute 'binge' cocaine (3 x 15 mg kg(-1), i.p.). Of interest, pretreatment with memantine at 10 mg kg(-1), which alone had no effect on corticosterone levels, caused a greater elevation of corticosterone levels in combination with 'binge' cocaine than acute 'binge' cocaine alone, indicating that memantine does not attenuate 'binge' cocaine-stimulated hypothalamic-pituitary-adrenal activity. These results indicate that both memantine and acute 'binge' cocaine stimulate hypothalamic-pituitary-adrenal activity by activating CRF neurons in the hypothalamus.

Adrenal Glands↗

PubMed2001

Efficacy and safety of memantine, an NMDA-type open-channel blocker, for reduction of retinal injury associated with experimental glaucoma in rat and monkey.

Glutamatergic excitotoxicity has been implicated as a mechanism for injury in a variety of central nervous system pathologies, including glaucoma. Memantine, an NMDA-type glutamatergic open-channel blocker, has pharmacologic properties that make its efficacy greater under excitotoxic conditions, but lesser under normal conditions. Daily oral dosing for approximately 15 months with 4.0 mg/kg memantine in monkeys yielded plasma concentrations similar to those found in patients who received memantine treatment for Parkinson's disease. This same dose of memantine was not associated with any evidence of an effect on the normal function of the retina and central visual pathways, as indicated by measures of the electroretinogram (ERG) and visually-evoked cortical potential (VECP). Amplitude of the VECP response was reduced in eyes with experimentally induced glaucoma. When compared to vehicle-treated control animals, memantine-treated glaucoma eyes suffered significantly less reduction of VECP amplitude. Preliminary results in a rat model for experimental glaucoma also show that, when compared to control animals, systemic treatment with memantine (10 mg/kg/day) was associated with a significant reduction in glaucoma-induced loss of retinal ganglion cells.

Animals↗

PubMed2003

Possible role for memantine in protecting retinal ganglion cells from glaucomatous damage.

Glaucoma is a neurodegenerative disease typified by progressive loss of retinal ganglion cells (RGCs). Mild excitotoxicity has been implicated as one of the factors contributing to RGC death during the glaucomatous process. This type of excitotoxic cell death is due, at least in part, to somewhat excessive activation of N-methyl-D-aspartate (NMDA)-type glutamate receptors. NMDA-receptor activity, however, is also essential for normal neuronal function. This means that potential neuroprotective agents that block virtually all NMDA-receptor activity will have unacceptable clinical side effects. Studies in our laboratory have shown that the adamantane derivative, memantine, blocks only excessive NMDA-receptor activity without disrupting normal activity. Past clinical use has demonstrated that memantine is safe, and it has recently been approved in Europe for the treatment of Alzheimer's disease and vascular dementia. Clinical studies of the safety and efficacy of memantine in glaucoma are currently underway. A series of second-generation memantine derivatives called nitro-memantines are currently in development and may prove to have even greater neuroprotective properties than does memantine.

Animals↗

PubMed2002

PET studies of 18F-memantine in healthy volunteers.

Previous studies in mice and PET investigations in a Rhesus monkey showed that the regional uptake of 18F-memantine could be blocked by pharmacological doses of memantine and (+)-MK-801. In the present study, the binding characteristics of 18F-memantine was examined in five healthy volunteers. In humans, 18F-memantine was homogeneously distributed in gray matter i.e. cortex and basal ganglia regions, as well as the cerebellum. No radioactive metabolites were detected in plasma during the time-frame of the PET studies. The uptake of 18F-memantine in receptor-rich regions such as striatum and frontal cortex could be well described by a 1-tissue compartment model. The DV" values of all gray matter regions were similar and ranged from 15 to 20 ml/ml. The white matter showed lower DV" values of 15 +/- 1.4 ml/ml. These results suggest that 18F-memantine distribution in human brain does not reflect the regional NMDA receptor concentration, and therefore, this radioligand is not suitable for the PET imaging of the NMDA receptors.

Adult↗

PubMed1999

Brain penetration and in vivo recovery of NMDA receptor antagonists amantadine and memantine: a quantitative microdialysis study.

PURPOSE: To determine free brain concentrations of the clinically used uncompetitive NMDA antagonists memantine and amantadine using microdialysis corrected for in vivo recovery in relations to serum, CSF and brain tissue levels and their in vitro potency at NMDA receptors. METHODS: Microdialysis corrected for in vivo recovery was used to determine brain ECF concentrations after steady-state administration of either memantine or amantadine. Additionally CSF, serum, and brain tissue were analyzed. RESULTS: Following 7 days of infusion of memantine or amantadine (20 and 100 mg/kg/day respectively) whole brain concentrations were 44-and 16-fold higher than free concentrations in serum respectively. The free brain ECF concentration of memantine (0.83 +/- 0.05 microM) was comparable to free serum and CSF concentrations. In case of amantadine, it was lower. A higher in vivo than in vitro recovery was found for memantine. CONCLUSIONS: At clinically relevant doses memantine reaches a brain ECF concentration in range of its affinity for the NMDA receptor and close to its free serum concentration. This is not the case for amantadine and different mechanisms of action may be operational.

Amantadine↗

PubMed2001

The N-methyl-D-aspartate antagonist memantine has no neuroprotective effect during hypothermic circulatory arrest: a study in the chronic porcine model.

BACKGROUND: Glutamate excitotoxicity has an important role in the development of brain injury after prolonged hypothermic circulatory arrest. The goal of the present study was to determine the potential efficacy of memantine, an N -methyl-D -aspartate receptor antagonist, to mitigate cerebral injury after hypothermic circulatory arrest. METHODS: Twenty pigs (23-33 kg) were randomly assigned to receive memantine (5 mg/kg) or placebo in a blinded fashion before a 75-minute period of hypothermic circulatory arrest at 20 degrees C. Hemodynamic, electroencephalographic, and metabolic monitoring were carried out. The intracerebral concentrations of glucose, lactate, glutamate, and glycerol were measured by means of enzymatic methods on a microdialysis analyzer. Daily behavioral assessment was performed until the animals died or were put to death on day 7. Histologic analysis of the brain was carried out in all animals. RESULTS: In the memantine group, 5 of 10 animals survived 7 days compared with 9 of 10 in the placebo group. The median behavioral score at day 7 was 3.5 in the memantine group and 7.5 in the placebo group (P >.2). Among the surviving animals, medians were 9.0 and 8.0 on day 7 (P >.2), respectively. The medians of recovered electroencephalographic bursts were equal in both groups. The median of total histopathologic score was 16 in the memantine group and 14 in the placebo group (P >.2). There was a negative correlation between glutamate levels and electroencephalographic burst recovery (tau = -0.377, P =.043). A positive correlation was found between the highest individual glutamate value and histopathologic score (tau = 0.336, P =.045). CONCLUSIONS: The present study demonstrates that memantine has no neuroprotective effect after hypothermic circulatory arrest in the pig. In addition, we have shown the accuracy of cerebral glutamate measurements to predict histopathologic injury after hypothermic ischemia.

Animals↗

PubMed2006

Salicylate- and quinine-induced tinnitus and effects of memantine.

CONCLUSION: Memantine, an antiglutamatergic drug, has been proposed as a treatment for tinnitus. OBJECTIVES: The purpose of this study was to determine if memantine would prevent salicylate-induced tinnitus. Local field potentials were also recorded from auditory cortex to determine what effect salicylate, memantine, and the combination of both drugs would have on evoked potential amplitudes. MATERIALS AND METHODS: Schedule induced polydipsia-avoidance conditioning was used to identify the doses of salicylate or quinine that reliably induced tinnitus in rats. Rats were trained to lick for water during quiet intervals and avoid licking during sound intervals. RESULTS: Rats injected with saline or a low dose of sodium salicylate or quinine failed to develop tinnitus-like behaviors. However, high doses of salicylate (150-300 mg/kg/day) or quinine (100-150 mg/kg/day) greatly reduced licks-in-quiet, behavior consistent with the presence of tinnitus. Licks-in-quiet increased slightly when memantine (1.5 or 3 mg/kg/day) was co-administered with salicylate; however, the effect was not statistically significant or dose-dependent. These results indicate that memantine does not completely suppress salicylate-induced tinnitus. Cortical auditory evoked potential amplitude increased after salicylate treatment; co-administration of memantine failed to block this salicylate-induced increase.

Analgesics, Non-Narcotic↗

PubMed1993

The clinically available NMDA receptor antagonist memantine is antinociceptive on rat spinal neurones.

In anaesthetized rats antinociceptive effects of the clinically available drug memantine, an NMDA (N-methyl-D-aspartate) antagonist in vitro, were evaluated using extracellular recordings from spinal neurones with knee joint input. Memantine (1-12 mg kg-1) was applied intravenously before (control animals) or after induction of an acute knee joint inflammation which rendered spinal neurones hyperexcitable. Memantine (2 mg kg-1, i.v.) selectively reduced the responses to ionophoretic application of NMDA close to the neurone but not those to AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid). In control animals memantine reduced the neurones' responses to noxious but not to innocuous pressure on to the knee. In rats with acute arthritis memantine reduced the responses to noxious and innocuous pressure. Thus memantine may be useful for the treatment of pain states.

Analgesics↗

PubMedDate not supplied

Pharmacologic rationale for memantine in chronic cerebral hypoperfusion, especially vascular dementia.

Memantine is a moderate-affinity, voltage-dependent, uncompetitive antagonist of N-methyl-D-aspartate (NMDA) receptors. In contrast to competitive NMDA antagonists, Memantine is well tolerated in humans and is being developed for the treatment of dementia. The pathogenesis of vascular dementia (VaD) is largely unknown, and is likely multifactorial, but it involves the impairment of blood circulation as a common denominator. There is broad evidence for the efficacy of Memantine in several animal models of ischemia. Memantine also acts on several secondary, potentially contributing factors in VaD such as neuronal depolarization, removal of magnesium block of NMDA receptors, chronic overstimulation of these receptors, and, possibly, mitochondrial dysfunction. Among others, it also has additional positive effects on long-term potentiation and cognition in standard animal models of impaired synaptic plasticity. Recently, clinical efficacy of Memantine has been shown in an etiologically mixed population of severely demented patients, including those with VaD. Given the difficulties of diagnosing VaD in clinical practice, an optimal antidementive drug should be beneficial in both Alzheimer disease and VaD. Preclinical data presented in this paper indicate that such benefits can be achieved with Memantine. In addition, phase II clinical data in dementia are summarized, and two ongoing pivotal trials in VaD are described. Suggestions for VaD guideline development are made regarding clinical instruments, and etiologies and severity stages are considered.

Brain Ischemia↗

PubMed2002

A double-blind, placebo-controlled multicentre study of memantine in mild to moderate vascular dementia (MMM500).

The aim of the reported trial was to investigate the safety and efficacy of memantine in mild to moderate vascular dementia (VaD). This was a 28-week, double-blind, parallel, randomized controlled trial of memantine 20 mg daily versus placebo which was conducted in 54 centres in the UK. Memantine is a uncompetitive, moderate affinity N-methyl-D-aspartate receptor antagonist. Patients with a diagnosis of probable VaD and Mini Mental State Examination total scores between 10 and 22 were eligible for inclusion. Primary efficacy parameters were the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) and the Clinical Global Impression of Change (CGI-C). A total of 579 patients were randomized and 548 patients with at least one post-baseline efficacy assessment qualified for the intent-to-treat analysis. At endpoint, memantine was shown to improve cognition relative to placebo in VaD: the change of ADAS-cog from baseline differed by a mean of -1.75 points (95% confidence intervals -3.023 to -0.49) and a median of 2 points between the two groups, while CGI-C ratings showed no significant differences between treatment groups. A total of 77% of all memantine-treated patients experienced adverse event, versus 75% of the placebo-treated patients, dizziness being the most frequent adverse event (11% versus 8%, respectively). Memantine was well tolerated and safe.

Aged↗

PubMed1999

Modifications of the behavioral profile of non-competitive NMDA receptor antagonists, memantine, amantadine and (+)MK-801 after chronic administration.

Non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists show antiparkinsonian-like activity in animal models, and possess neuroprotective properties. However they also induce a number of behavioral side effects in rodents at higher doses; these include learning impairment, hyperlocomotion, and ataxia. The present study focused on the possible development of tolerance, or sensitization, to any of these effects after sustained administration, either by repeated injection or continuous infusion. When memantine or (+)MK-801 (20 and 0.31 mg/kg/day respectively) were either infused or repeatedly injected for 14 days, tolerance was observed to their learning impairing effect at high doses, in a passive avoidance test. Tolerance to their ataxic effect developed after repeated administration ((+)MK-801 and memantine), or after infusion (memantine). Sensitization to the locomotor stimulation was seen following repetitive injections of memantine for 14 days, but not seen with (+)MK-801. In animals with an unilateral 6-OHDA lesion of the nigrostriatal system, acute administration of memantine caused ipsilateral rotations, which were augmented following 14 days of infusion. The potency of amantadine to antagonize neuroleptic-induced catalepsy was unchanged following either infusion or repeated injections. The various acute effects of non-competitive NMDA receptor antagonists were modified differently by sustained treatment (i.e. tolerance to learning impairment and ataxia; sensitization to memantine's locomotor stimulation). The anti-cataleptic activity of amantadine remained unaltered. However, differences between drugs and the two treatment regimens (i.e. repetitive versus continuous treatments) were apparent.

Amantadine↗

PubMed1996

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.

Chronic treatment of adult male F-344 rats (9-12 months old) with therapeutically relevant doses of memantine (30 mg/kg/day in chow for > 8 weeks) increased the maintenance of long-term potentiation of field excitatory postsynaptic potentials from perforant path-granule cell hippocampal synapses recorded in the fascia dentata in vivo. In contrast, there was no effect of memantine on baseline synaptic responses or population spikes. Likewise, short-term exploratory modulation of these hippocampal evoked responses was not different between memantine-treated and control rats. Both groups of rats were able to learn the spatial version of the Morris water task equally well, but the memantine-treated group showed a strong tendency to show more selective spatial search patterns in the training quadrant of the water pool during a final probe trial. As such, these studies provide the first electrophysiological evidence that memantine can increase the durability of synaptic plasticity and provide preclinical confirmation of the cognitive improvement seen with memantine in the treatment of demented patients.

Animals↗

PubMed2005

Memantine prolongs survival in an amyotrophic lateral sclerosis mouse model.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease which results from selective loss of upper and lower motor neurons. Mouse models of ALS, such as one carrying the G93A mutant of the human Cu-Zn superoxide dismutase gene[SOD1(G93A)], develop motor neuron pathology and clinical symptoms similar to those observed in ALS patients. There is compelling evidence that both direct and indirect glutamate toxicity contribute to the pathogenesis of motor neuron degeneration. However, the therapeutic effect of various glutamate receptor antagonists has not been clearly demonstrated. Memantine is a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist. It has been shown to protect neurons against NMDA- or glutamate-induced toxicity in vitro and in animal models of neurodegenerative diseases. In the current study, we have examined the therapeutic efficacy of memantine in an ALS mouse model carrying a high copy number of SOD1(G93A). Memantine treatment significantly delayed the disease progression and increased the life span of SOD1(G93A) mice, from 121.4 +/- 5.5 to 129.7 +/- 4.5 days (P = 0.032). Furthermore, NMDA receptor subunits were reliably detected in the spinal cord of SOD1(G93A) mice and their expression levels were similar to those in the wild-type littermate control. Therefore, the neuroprotective effect of memantine in SOD1(G93A) mice is most probably due to the inhibition of spinal cord NMDA receptors. In view of the long-term usage of memantine for dementia patients, with excellent tolerance and safety, these data suggest that memantine may be used in ALS patients alone or in combination with other therapies to prolong survival.

Amyotrophic Lateral Sclerosis↗

PubMed1996

Effects of memantine on recombinant rat NMDA receptors expressed in HEK 293 cells.

1. The actions of the uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists, memantine (1-amino-3,5-dimethyladamantane) and (+)-MK-801 ((+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate, dizocilpine), on recombinant NMDA receptors has been studied by use of the whole-cell patch clamp technique. 2. Human embryonic kidney (HEK) 293 cells were transiently transfected with different NMDA receptor subunit combinations (NR1a/NR2A, NR1a/NR2B and NR1a/NR2D). A mutant form of the green fluorescent protein (GFP) cotransfected with the NMDA receptor subunits to enable the visualization of transfected cells. 3. Memantine (0.3-30 microM) blocked L-glutamate (100 microM)-mediated currents in a concentration-dependent manner in NR1a/NR2A, NR1a/NR2B and NR1a/NR2D transfected cells with IC50 values (at -70 mV) of 0.93 +/- 0.15 microM, 0.82 +/- 0.12 microM and 0.47 +/- 0.06 microM (mean +/- s.c. mean), respectively. 4. The memantine-induced block was strongly voltage-dependent. Alteration of the holding potential from -70 mV to +60 mV resulted in an e-fold increase in the IC50 values per 30-33 mV change in membrane potential, for all 3 subunit combinations investigated. 5. The kinetics of the actions of memantine (30 microM) were investigated for the NR1a/2A combination, in 6 cells (13-15 determinations). At -70 mV, the block and recovery from block were both best described by two exponentials with time-constants of 201 +/- 23 ms (81 +/- 2%) and 3.9 +/- 0.6 s and 597 +/- 94 ms (18 +/- 1%) and 18.6 +/- 2.4 s, respectively. The predominant effect of depolarization was to increase the weight of the faster recovery time-constant. Kinetic analysis suggests that these results are consistent with previously proposed Markov models. 6. (+)-MK-801 was studied briefly for comparative purposes. (+)-MK-801 (200 nM) preferentially blocked NMDA receptor currents (at -70 mV) in NR1a/NR2A and NR1a/NR2B (82 +/- 10% and 93 +/- 2% depressions) compared to NR1a/NR2D (38 +/- 7%) transfected cells. (+)-MK-801 appeared to be less voltage-dependent than memantine on all three receptor combinations. 7. In conclusion, memantine was a voltage-dependent antagonist of recombinant rat NMDA receptors expressed in HEK 293 cells but showed little selectivity between the subunits investigated. Its actions on these recombinant receptor combinations are similar to its actions on native NMDA receptors.

Binding, Competitive↗