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PubMed1998

Memantine is neuroprotective in a rat model of pressure-induced retinal ischemia.

PURPOSE: To quantify vitreous amino acid concentrations in pressure-induced retinal ischemia and to evaluate the neuroprotective effect of memantine, a N-methyl-D-aspartate (NMDA) antagonist, administered before and at two time intervals after ischemia. METHODS: Retinal ischemia was induced in 10 rats by elevating the intraocular pressure to 120 mm Hg. The concentrations of the amino acids of vitreous samples were measured by high-pressure liquid chromatography. In another series of 56 rats, ischemia was induced in a similar fashion. Fifteen rats received 20 mg/kg x day memantine by a subcutaneous osmotic pump starting 2 days before ischemia, 13 rats received 10 mg/kg memantine intraperitoneally (ip) 0.5 and 4.5 hours after reperfusion, 13 rats received 10 mg/kg memantine ip 3.5 and 7.5 hours after reperfusion, and 15 rats received the vehicle alone. Ischemic damage was histologically quantified 14 days after ischemia. RESULTS: Compared with the nonischemic fellow eyes, there was an elevation (P < 0.05) in the mean vitreous concentration of glutamate (223%+/-41%) and glycine (428%+/-92%). The percentage of surviving neurons in the ganglion cell layer was 33%+/-3% in the controls, 61%+/-5% (P < 0.001) when memantine was infused subcutaneously before ischemia, 52%+/-5% (P < 0.05) when memantine was injected ip 0.5 and 4.5 hours after ischemia, and 48%+/-5% (P > 0.05) when injected ip 3.5 and 7.5 hours after ischemia. CONCLUSIONS: Retinal ischemia increased vitreous concentrations of glutamate and glycine. Both amino acids were agonists at the NMDA receptor. The NMDA receptor antagonist memantine reduced ganglion cell loss when given systemically before or within 30 minutes of retinal ischemia.

Animals↗

PubMed2006

A 24-week open-label extension study of memantine in moderate to severe Alzheimer disease.

BACKGROUND: This study is an extension of a 28-week, randomized, double-blind, placebo-controlled study of memantine in 252 patients with moderate to severe Alzheimer disease. OBJECTIVE: To evaluate long-term memantine treatment in moderate to severe Alzheimer disease. DESIGN, SETTING, AND PATIENTS: Open-label, 24-week extension trial. Raters remained blind to the patients' initial study treatment. Patients (n = 175) were enrolled from the previous double-blind study in an outpatient setting. INTERVENTION: Twenty mg of memantine was given daily. MAIN OUTCOME MEASURES: Efficacy assessments from the double-blind study were continued and safety parameters were monitored. RESULTS: Patients who switched to memantine treatment from their previous placebo therapy experienced a significant benefit in all main efficacy assessments (functional, global, and cognitive) relative to their mean rate of decline with placebo treatment during the double-blind period (P<.05). The completion rate for the extension phase of the study was high (78%) and the favorable adverse event profile for memantine therapy was similar to that seen in the double-blind study. CONCLUSION: These results extend previous findings that demonstrated the efficacy and safety of memantine in the treatment of patients with moderate to severe Alzheimer disease.

Aged↗

PubMed2004

Memantine enhances autonomy in moderate to severe Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is the leading cause of dementia and its course renders patients functionally disabled. Memantine is the first drug to demonstrate a clinical benefit in the treatment of patients with moderately-severe to severe AD. OBJECTIVES: Our objective was to illustrate the benefits of memantine on functional disability. METHODS: We classified 252 patients from a randomised 28-week clinical trial of memantine vs placebo according to their Activities of Daily Living capabilities measured by the ADCS-ADLsev scale. The scale was divided into two sub-scores: basic and instrumental. The relevance of this classification was validated by comparing clinical and socio-demographic parameters between the different autonomy classes (autonomous and dependent). The effect of memantine was estimated by using a logistic regression model on the autonomy status of patients at week 28, controlling for confounding factors (Observed Cases analysis). RESULTS: Our results showed that dependent patients (n = 106) had significantly longer disease duration, poorer cognition, greater severity, more behavioural alterations and higher total societal costs compared with autonomous patients (n = 146). When controlling for autonomy and severity at baseline, memantine-treated patients were three times more likely [Odds Ratio (OR) = 3.03; 95% Confidence Intervals (CI) = (1.38, 6.66)] to remain autonomous after 28 weeks. Analysis of the Treated Per Protocol set and the use of Last Observation Carried Forward analyses confirmed this finding. CONCLUSIONS: Memantine enhances autonomy in patients with moderately-severe to severe AD by increasing the probability of their remaining autonomous, therefore delaying transition to the dependent stage.

Activities of Daily Living↗

PubMed2001

The neuroprotective agent memantine induces brain-derived neurotrophic factor and trkB receptor expression in rat brain.

Memantine is a medium-affinity uncompetitive N-methyl-d-aspartate receptor antagonist and has been clinically used as a neuroprotective agent to treat Alzheimer's and Parkinson's diseases. We have examined the effect of memantine (ip 5-50 mg/kg; 4 h) on the expression of brain-derived neurotrophic factor (BDNF) and trkB receptor mRNAs in rat brain by in situ hybridization. Memantine at a clinically relevant dose markedly increased BDNF mRNA levels in the limbic cortex, and this effect was more widespread and pronounced at higher doses. Effects of memantine on BDNF mRNA were also reflected in changes in BDNF protein levels. Moreover, memantine induced isoforms of the BDNF receptor trkB. Taken together, these data suggest that the neuroprotective properties of memantine could be mediated by the increased endogenous production of BDNF in the brain. These findings may open up new possibilities of pharmacologically regulating the expression of neurotrophic factors in the brain.

Animals↗

PubMed1995

Chronic treatment with the uncompetitive NMDA receptor antagonist memantine influences the polyamine and glycine binding sites of the NMDA receptor complex in aged rats.

Receptor binding studies on rat cortical membranes were used to characterize the NMDA receptor in aged rats (22 months) treated for 20 months with a memantine containing diet delivering 30 mg/kg/day in comparison to aged and young/adult rats treated with control-diet. Spatial memory impairing effects of (+)-MK-801 (0.16 mg/kg) in the radial maze was not altered within the course of memantine-treatment (up to 16 months). However, chronic memantine-treatment significantly increased the number of [3H]MK-801 binding sites and the affinity of [3H]glycine. A non-significant trend to such changes was also seen in aged-control rats. Glycine-dependent [3H]MK-801 binding (functional binding under non-equilibrium conditions at a fixed L-glutamate concentration) revealed that a decreased ability of glycine to stimulate channel opening in aged rats was partially attenuated by the long-term memantine treatment. Furthermore, an increased ability of spermidine to enhance [3H]MK-801 binding in aged-control rats was even more pronounced in the aged memantine-treated group. Together these findings may indicate that changes in functional receptor-channel properties during the process of aging occur prior to a detectable loss of binding sites and that memantine enhances an endogenous compensatory mechanism triggered by glutamatergic hypofunction which is suggested to take place in aging.

Aging↗

PubMed2002

Inhibitory effects of MPEP, an mGluR5 antagonist, and memantine, an N-methyl-D-aspartate receptor antagonist, on morphine antinociceptive tolerance in mice.

RATIONALE: Inhibition of N-methyl- D-aspartate (NMDA) receptors by memantine, an NMDA-receptor antagonist, and other antagonists of ionotropic receptors for glutamate inhibit the development of opiate antinociceptive tolerance. The role of metabotropic receptors for glutamate (mGluR) in opiate tolerance is less known. OBJECTIVE: In the present study, we examined the effect of 2-methyl-6-(phenylethynyl)-pyridine (MPEP), the mGluR type-I (subtype mGluR5) antagonist, as well as the effect of co-administration of low doses of memantine and MPEP on morphine antinociceptive tolerance in mice. METHODS: Morphine antinociceptive activity was tested twice, before and after chronic morphine administration, in the tail-flick test using a cumulative dose-response protocol. Tolerance was induced by six consecutive days of b.i.d. administration of morphine (10 mg/kg, s.c.). Saline, memantine (7.5 mg/kg and 2.5 mg/kg, s.c.), MPEP (30 mg/kg and 10 mg/kg, i.p.) and the combination of both antagonists at low doses was given 30 min prior to each morphine injection during its chronic administration. A separate experiment assessed the effects of memantine, MPEP and their combination on acute morphine antinociception using a tail-flick test. RESULTS: MPEP (30 mg/kg but not 10 mg/kg) as well as memantine (7.5 mg/kg but not 2.5 mg/kg) attenuated the development of tolerance to morphine-induced antinociception. When given together, the low doses of MPEP (10 mg/kg) and memantine (2.5 mg/kg) also significantly attenuated opiate tolerance. None of the treatments with glutamate antagonists produced antinociceptive effects or significantly affected morphine-induced antinociception. CONCLUSIONS: The data suggest that both mGluR5 and NMDA receptors may be involved in the development of morphine antinociceptive tolerance.

Analgesics, Opioid↗

PubMed2006

Effects of memantine, haloperidol, and cocaine on primary and conditioned reinforcement associated with cocaine in rhesus monkeys.

RATIONALE: The N-methyl-D-aspartate (NMDA) receptor has been implicated in mediating the reinforcing effects of abused drugs. Some reports indicate the uncompetitive NMDA antagonist, memantine, modulates the conditioned and unconditioned effects of stimulants in rats. OBJECTIVE: The objective of this study was to evaluate the effects of memantine on the primary and conditioned reinforcing effects of cocaine in the rhesus monkey. METHODS: Rhesus monkeys were trained to press levers reinforced with either cocaine-associated stimuli (brief stimuli, BS) or 30-microg/kg cocaine infusion during daily, 75-min experimental sessions in which the reinforcers were independently available in separate components according to identical progressive ratio (PR) schedules. Memantine (0.3-10 mg/kg), and as comparators, haloperidol (0.001-0.1 mg/kg) and cocaine (0.01-1 mg/kg), were administered 5 min before experimental sessions. RESULTS: Memantine (0.3-3 mg/kg) produced decreases in responding maintained by BS presentations at some doses which failed to affect cocaine self-administration when measured during equivalent periods early in the experimental session. Memantine (3 mg/kg) increased cocaine self-administration, however, later in the session. A low dose of haloperidol (0.001 mg/kg) increased the number of BS presentations, whereas higher doses decreased their number. Cocaine self-administration was not significantly affected by haloperidol until a behaviorally suppressant dose (0.1 mg/kg) was administered. Pretreatment with high doses of cocaine (0.3 and 1 mg/kg) decreased responding maintained by both reinforcers. CONCLUSION: These results suggest that while memantine may attenuate the conditioned reinforcing effects of cocaine-associated stimuli, it may also occasion increase levels of cocaine self-administration. These findings support the hypothesis that the NMDA receptor can play a role in modulating the conditioned and primary reinforcing effects of cocaine.

Animals↗

PubMed2000

Effects of the non-competitive NMDA-receptor antagonist memantine on morphine- and cocaine-induced potentiation of lateral hypothalamic brain stimulation reward.

RATIONALE: NMDA-receptor antagonists may be of potential therapeutic use in several states of disease. It has been reported that drugs like MK-801 can potentiate the rewarding effects of other drugs, which may complicate the therapeutic use of this class of drugs. However, since MK-801 appears to be an "atypical" drug in several respects, other NMDA-receptor antagonists may not share this effect of MK-801. OBJECTIVES: We tested the effects of memantine, a clinically used NMDA-receptor antagonist, in a paradigm that has previously shown the reward-potentiating effects of MK-801 to see if this drug would yield qualitatively comparable results. METHODS: The effects of memantine on morphine- and cocaine-induced potentiation of brain stimulation reward were examined, using the rate-free curve-shift paradigm. RESULTS: Low doses of morphine (2.5 mg/kg) and cocaine (5 mg/kg) produced moderate decreases in the reward threshold frequency reflected in moderate leftward shifts of the function relating response rate to stimulation frequency. These effects were not altered by co-administration of an intermediate dose of memantine (5 mg/kg), but maximum response rate was significantly increased by these drug combinations. Higher doses of morphine (7.5 mg/kg) and cocaine (10 mg/kg) had stronger effects on the rate-frequency function and reward threshold. These effects were enhanced by co-administration of a high dose of memantine (10 mg/kg), while the effects on maximum response rate were less pronounced. CONCLUSIONS: These results demonstrate that fairly high doses of memantine and morphine or cocaine have to be combined in order to observe an enhancement of the latter drugs' potentiation of brain stimulation reward. In this respect, memantine differs markedly from MK-801, another non-competitive NMDA-receptor antagonist which has been shown to interact with morphine and cocaine at very low doses.

Analgesics, Opioid↗

PubMed1999

Protective effects of memantine against ischemia-reperfusion injury in spontaneously hypertensive rats.

Memantine, an uncompetitive NMDA open-channel blocker, has been shown to be effective in preventing neuronal damage after permanent focal cerebral ischemia. Reperfusion after a long period of ischemia may aggravate the progression of neuronal damage. Those drugs that show protective effects after permanent cerebral ischemia, therefore, might fail to do so against ischemia-reperfusion injury. In this study we evaluated the effects of memantine on brain edema formation and ischemic injury volume after transient cerebral ischemia. Male Spontaneously Hypertensive Rats (SHR) weighing 250-300 g were anesthetized with halothane and subjected to 1 hour of temporary middle cerebral artery occlusion by an intraluminal suture. 20 mg/kg of memantine or saline were injected intraperitoneally 5 min. after the induction of ischemia. Physiological parameters and regional cerebral blood flow were monitored during the surgical procedure. Brain water content and ischemic injury volume were measured with the wet dry method and 2,3,5-triphenyl tetrazolium chloride monohydrate (TTC) staining, respectively, at 24 hours after occlusion. There were no statistically significant differences between the groups regarding physiological parameters during the procedure. Memantine treatment (n=9) reduced the brain water content significantly in the cortex compared to saline treatment (n=8; 83. 1+/-0.7% vs. 84.5+/-1.5%, respectively, p<0.05). The total volume of ischemic brain injury was 300+/-49 mm(3) in the animals treated with saline (n=13). Treatment with 20 mg/kg memantine (n=14) reduced the ischemic injury volume to 233+/-61 mm(3) (P<0.01). These results demonstrate that the harmful effects of recirculation after a period of ischemia can be attenuated by the treatment of memantine, perhaps by its action at the NMDA receptors.

Animals↗

PubMed2005

The effects of memantine on lipid peroxidation following closed-head trauma in rats.

Memantine is an uncompetitive N-methyl-D: -aspartate (NMDA) receptor antagonist. Unlike other NMDA antagonists, it has been used clinically for years for the treatment of Parkinson's disease, spasticity, and dementia without serious side effects. We aimed to investigate the therapeutic efficacy of memantine on a closed head trauma model. A total of 132 adult male Sprague-Dawley rats were randomly divided into four groups: sham-operated, control (closed head trauma), sham-vehicle (closed head trauma + saline), treatment (closed head trauma + memantine, 10 mg/kg, i.p.). A cranial impact was delivered to the skull, just in front of the coronal suture, over the left hemisphere, from the height of 7 cm. Saline or memantine were applied 15 min after trauma. Rats were euthanased 0.5, 1, 2, 6, 24, 48 h after trauma. Brain tissue samples were taken 5 mm away from the left frontal pole and also from the corresponding point of the contralateral hemispheres. Malondialdehyde activity (MDA) was considered to reflect the degree of lipid peroxidation. The MDA levels continued to increase for the first 2 h after the injury, then started to decrease gradually. Memantine treatment significantly reduced lipid peroxidation levels in the treatment group compared with other groups (P<0.01). The findings of the present study indicate that memantine provides beneficial effects after closed head trauma in rats.

Animals↗

PubMed2006

Pharmacokinetics and disposition of memantine in the arterially perfused bovine eye.

PURPOSE: To develop an improved ((1)This is to clearly acknowledge that we have tried to improve an existing model.) arterially perfused bovine eye model and investigate the general ocular disposition of memantine. MATERIALS AND METHODS: Fresh bovine eyes were prepared by exposing and cannulating one ciliary artery, placing the eye into a perfusion chamber and slowly increasing the rate of perfusion to 1.0 ml/min. Analysis of the arterial perfusion pressure (APP), intraocular pressure (IOP), venous perfusate for glucose consumption and lactate dehydrogenase (LDH) activity, and histopathology ensured viability. Memantine was administered with the perfusate (simulated systemic access), by an intravitreal injection and by topical infusion. At the appropriate time points, the cornea, aqueous humour, sclera, iris-ciliary body, choroid/RPE, retina and vitreous humour were harvested and analysed for memantine. RESULTS: The preparation remained viable for at least 9 h. At this time, histopathological examination showed mild to moderate deterioration of retinal layers. However, all retinal layers remained well defined and the integrity of the inner limiting membrane and Bruch's membrane were preserved. Glucose consumption, LDH levels and constant APP and IOP showed that correct cannulation and viability was maintained. After administration, memantine accumulated in the melanin rich iris-ciliary body and choroid/RPE. Results following topical administration indicate that substantial concentrations of memantine are present in the retina and choroid/RPE. CONCLUSIONS: The arterial perfused bovine eye system proved to be a useful system for ocular drug delivery studies. The experimental results indicate that memantine will accumulate in the posterior segment when delivered by the topical route and that melanin-binding may support sustaining significant concentrations in the retina.

Animals↗

PubMed1990

Neuroprotective effect of memantine demonstrated in vivo and in vitro.

The purpose of the present study was to test whether the anticonvulsant, memantine (1-amino-3,5-dimethyladamantane), can protect neurons against hypoxic or ischemic damage. To this end, we used a rat model of transient forebrain ischemia and cultured neurons from chick embryo cerebral hemispheres. Ischemia was induced for 10 min by clamping both carotid arteries and lowering the mean arterial blood pressure to 40 mm Hg; the rats were allowed to recover for 7 days. Cultured neurons were made hypoxic with 1 mmol/l NaCN added to the incubation medium for 30 min followed by a recovery period of 3 days. The possible effects of memantine were compared with those produced by a typical non-competitive NMDA antagonist, dizocilpine. Similar effects were obtained with both drugs. The drugs reduced the damage caused by transient ischemia to neurons of the hippocampal CA1 subfield. Memantine (10 and 20 mg/kg) had a dose-dependent effect when administered intraperitoneally to the rats 1 h before ischemia. Dizocilpine was active in this model at a dosage of 1 mg/kg. When administered after ischemia, 10 mg/kg memantine significantly protected CA1 neurons against ischemic damage. Furthermore, the drugs protected cultured neurons against hypoxic damage. The lowest effective concentration was 0.1 mumol/l for dizocilpine and 1 mumol/l for memantine. Thus, memantine possesses neuroprotective activity but is less potent than dizocilpine.

Adenosine Triphosphate↗

PubMed1990

Memantine reduces repetitive action potential firing in spinal cord nerve cell cultures.

(1) The anticonvulsant effects of memantine were examined and compared with those of baclofen in monolayer primary cultures of murine nerve cells using conventional intracellular recordings. (2) Memantine and baclofen (each 10-100 microM) decreased spontaneous synaptic activity when action potential frequencies exceeded 6 Hz. Neurons firing action potentials at frequencies below 6 Hz (about 90% of all impaled cells), however, were not affected by the drugs. (3) Memantine reduced the duration of strychnine-elicited bursts and the firing rate of action potentials within a burst. In contrast, baclofen lowered the frequency of the bursts without reducing intra-burst firing. The duration of the bursts was increased. (4) Memantine, but not baclofen, reduced the extent of sustained repetitive firing evoked by pulses of depolarizing current. (5) In the presence of memantine, the second of two electrically evoked action potentials increasingly failed to appear as the intervals between successive stimulating pulses were shortened. Such an effect was not seen when baclofen was applied. Thus, both antispastic agents, memantine and baclofen, reduce hyperactivity of spinal cord neurons in culture, although their mechanisms of action are different.

Action Potentials↗

PubMed1996

Memantine reduces functional and morphological consequences induced by global ischemia in rats.

In this study the effect of memantine, an antagonist at the N-methyl-D-aspartate receptor, on spatial learning deficit and on neuronal damage following transient cerebral ischemia was evaluated. Global ischemia was induced by four-vessel-occlusion (4VO) for 20 min in rats. Memantine was administered 20 min before induction of ischemia at a dose of 10 or 20 mg/kg. One week after surgery spatial learning was tested in the Morris water maze. Treatment with the higher dose of memantine reduced the increase in escape latency and in swim distance induced by 4VO. Neuronal damage in the CA1 sector of the hippocampus and in the striatum produced by 4VO was significantly attenuated by 20 mg/kg memantine. Treatment with the lower dose of memantine had no influence on the deficit in spatial learning and the neuronal damage resulting from ischemia. The present data demonstrate that treatment with a neuroprotective agent like memantine can reduce functional as well as morphological sequelae induced by ischemia.

Animals↗

PubMed2005

Effects of memantine and donepezil on amyloid beta-induced memory impairment in a delayed-matching to position task in rats.

We investigated the effects of memantine and donepezil on amyloid beta (Abeta)-induced memory impairment in rats, which was assessed by a delayed-matching to position (DMPT) paradigm in three-lever operant chambers. Aggregated Abeta1-40 was microinjected bilaterally (1 nmol/side) into both CA1 and CA3 subfields of the hippocampus in rats that had previously performed the DMTP task. Memantine (20 mg/(kg day), s.c.) was continuously infused by an osmotic minipump for 4 weeks from 3 days before the microinjection of Abeta. Donepezil (2.5 mg/kg, p.o.) was administered 60 min before the DMTP test session. Bilateral microinjections of Abeta1-40 into the hippocampus resulted in a delayed, but persistent impairment of DMTP performance, which appeared more than 50 days after the injection. Memantine prevented the development of Abeta-induced memory impairment, while donepezil symptomatically alleviated the deficits. Because of a ceiling effect, the combination of donepezil with memantine failed to produce any additive or synergic effects. These results support the clinical data showing that memantine and donepezil are effective for the treatment of Alzheimer's disease. Moreover, it is suggested that memantine is effective for preventing Abeta-induced short-term memory impairment.

Amyloid beta-Peptides↗

PubMed2006

Evidence for the involvement of L-arginine-nitric oxide-cyclic guanosine monophosphate pathway in the antidepressant-like effect of memantine in mice.

This study investigated the involvement of the L-arginine-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) pathway in the antidepressant-like effect of an acute administration of memantine in the forced swimming test (FST) in mice, since this signaling pathway is supposed to play a significant role in depression. The antidepressant-like effect of memantine (3 mg/kg, i.p.) was prevented by pretreatment with L-arginine (750 mg/kg, i.p.) or S-nitroso-N-acetyl-penicillamine (SNAP, 25 microg/site, i.c.v.), but not with d-arginine (750 mg/kg, i.p.).The treatment of mice with NG-nitro-L-arginine (L-NNA, 0.03 and 0.3 mg/kg, i.p.) potentiated the effect of a subeffective dose of memantine (0.3 mg/kg, i.p.) in the FST. Moreover, the pretreatment of mice with (1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one) (ODQ, 30 pmol/site, i.c.v.) produced a synergistic antidepressant-like effect with subeffective doses of memantine (0.3 and 1 mg/kg, i.p.) in the FST. Furthermore, the reduction in the immobility time elicited by memantine (3 mg/kg, i.p.) in the FST was prevented by pretreatment with sildenafil (5 mg/kg, i.p.). Taken together, the results demonstrate that memantine produced an antidepressant-like effect in the FST that seems to be mediated through an interaction with the L-arginine-NO-cGMP pathway.

Analysis of Variance↗

PubMed2005

Memantine inhibits ethanol-induced NMDA receptor up-regulation in rat hippocampal neurons.

The present study examined the effect of memantine, an uncompetitive NMDA receptor antagonist, on ethanol-induced NMDA receptor up-regulation. Primary glutamatergic rat hippocampal neurons were exposed to ethanol and memantine for 5 days. The ethanol-sensitive NMDA receptor subunits NR1, NR2A and NR2B were quantified by Western immunoblot analysis. Exposure to ethanol (50 mM) caused an increase in the levels of NR1 (137 +/- 11% of untreated control, P = 0.009), NR2A (128 +/- 14%, P = 0.022) and NR2B (136 +/- 19%, P = 0.012). Coincubation with memantine (10 microM) completely blocked the ethanol-induced up-regulation of NR1 (102 +/- 4%), NR2A (95 +/- 7%) and NR2B (105 +/- 13%). No effect of memantine on NR subunit expression was observable, except for NR2A, where a decrease (79 +/- 6%, P = 0.034) was noted. Neither ethanol nor memantine alone or in combination were toxic in the concentrations tested. These results may provide a molecular explanation for beneficial effects of memantine on ethanol-induced glutamatergic hyperexcitability reflected in the ethanol withdrawal syndrome and on the development of ethanol dependence.

Analysis of Variance↗

PubMed2005

Mechanism of action of memantine.

Memantine is a clinically useful drug in many neurological disorders, including Alzheimer's disease. The principal mechanism of action of memantine is believed to be the blockade of current flow through channels of N-methyl-d-aspartate (NMDA) receptors--a glutamate receptor subfamily broadly involved in brain function. Surprisingly, other drugs that block NMDA receptor channels, such as ketamine, exhibit serious deleterious effects. The unusual therapeutic utility of memantine probably results from inhibitory mechanisms shared with ketamine, combined with actions specific to memantine. These potentially important differences between memantine and ketamine include effects on gating of blocked channels and binding of memantine to two sites on NMDA receptors. Because modulation of NMDA receptor activity can increase or decrease excitability of neuronal circuits, subtle differences in the mechanisms of action of NMDA receptor antagonists can strongly impact on their clinical effects.

Alzheimer Disease↗