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PubMed2006

Cognitive dysfunction induced by sequential injection of amyloid-beta and ibotenate into the bilateral hippocampus; protection by memantine and MK-801.

Aggregated 40-residue amyloid-beta peptide (beta40, 4 microg/microl), and 2 days later, ibotenate (NMDA receptor agonist, 0.3 microg/0.5 microl), were bilaterally injected into the hippocampus of rats. Five to six weeks after the beta40 injection, the rats showed learning deficits in the Morris water maze task and neuronal damage in the hippocampus, although the injection of beta40 or ibotenate alone did not result in cognitive deficits and hippocampal damage. Memantine (10, 20 mg/kg/day s.c. infusion for 6 weeks starting 24 h before the beta40 injection) significantly prevented learning deficits as measured for 4 days from 5 weeks after the beta40 injection, while a lower dose of memantine (5 mg/kg/day) and MK-801 (0.312, 0.624 mg/kg/day) did not have inhibitory effects on the learning deficits. The neuronal damage in the hippocampus, assessed as an elevation of the levels of the peripheral-type benzodiazepine-binding site (a gliosis marker for neuronal damage) produced by sequential intra-hippocampal injections of beta40 and ibotenate, at 6 weeks (39 days) after the beta40 injection, was significantly attenuated by memantine (10, 20 mg/kg/day) and MK-801 (0.624 mg/kg/day). These protective effects were also confirmed by histochemical examination (Cresyl violet staining of brain slices). In naive rats, MK-801 produced a significant learning impairment in the water maze task at a dose of 0.624 mg/kg/day, while memantine (20 mg/kg/day s.c. infusion) did not, although the beta40 plus ibotenate-induced hippocampal damage was lessened by both treatments. These results suggest that memantine and MK-801 exert protective effects on progressive neuronal damage, but that only memantine prevents memory impairment in hippocampal-lesioned rats, and that memantine may be a beneficial agent for the treatment of progressive cognitive dysfunction including Alzheimer's disease-type dementia.

Amyloid beta-Peptides↗

PubMed2026

Effects of adjunctive memantine on executive function and global cognition in bipolar disorder (BD): A randomized, double-blind, placebo-controlled clinical trial.

BACKGROUND: Cognitive impairment contributes substantially to disability in bipolar disorder (BD), but effective pharmacologic options remain limited. This trial evaluated whether adjunctive memantine improves global cognition and executive function in BD. METHODS: In this double-blind, placebo-controlled randomized trial, patients with bipolar I disorder (B1D) receiving lithium and olanzapine were assigned to memantine or placebo. Memantine was titrated to 20 mg/day over 6 weeks. Cognitive outcomes were assessed at baseline, week 6, and week 18. Global cognition was measured with the Neurocognitive Assessment Battery (NuCog), and executive function with the Frontal Assessment Battery (FAB). Data were analyzed using generalized estimating equations and Bonferroni-adjusted post-hoc tests. RESULTS: Sixty-three participants were randomized (memantine, n = 31; placebo, n = 32), and all completed follow-up. Groups were comparable at baseline for demographic and clinical variables and for most cognitive measures. Both groups improved over time (P < 0.001), but improvement was greater with memantine for global cognition at week 6 (MD = 9.32; 95% CI, 4.84-13.81; P < 0.001) and week 18 (MD = 12.69; 95% CI, 8.67-16.71; P < 0.001). FAB total scores favored memantine at week 18 (MD = 2.68; 95% CI, 1.76-3.61; P < 0.001), but not at week 6. Domain analyses showed significant benefits for NuCog attention, visuoconstructional ability, memory, and executive function, and for several FAB subscales by week 18. CONCLUSIONS: Adjunctive memantine improved global cognition and, over longer follow-up, executive function in BD. These findings support NMDA receptor modulation as a potential strategy for cognitive dysfunction in BD.

Humans↗

PubMed2004

Co-administration of memantine has no effect on the in vitro or ex vivo determined acetylcholinesterase inhibition of rivastigmine in the rat brain.

Rivastigmine, a cholinesterase inhibitor, is successfully used for the symptomatic therapy of Alzheimer's disease (AD) in the clinic. The drug has a very low potential for drug-drug interactions, as has been demonstrated within large clinical trials. Memantine, recently approved by the FDA for the treatment of moderate to severe AD, acts as a low affinity, non-competitive NMDA-antagonist, on a completely different neurotransmitter system, the glutamatergic system. Given the different sites of action, the possibility to combine a cholinergic with a glutamatergic intervention as potentially superior AD therapy has recently been proposed. In vitro studies have demonstrated that memantine, when added to reversible AChE inhibitors, such as tacrine, donepezil or galantamine, did not interfere with the inhibitory action of any of these drugs. The results from the present study provide evidence that rivastigmine as a pseudo-irreversible (or slow-reversible) AChE inhibitor shares this property described for reversible inhibitors, since memantine (1-100 microM), irrespective of whether given prior to or after rivastigmine did not influence rivastigmine's AChE inhibition in vitro. A similar observation was also made under in vivo conditions (ex vivo measurements): following a 21 day chronic, oral administration of 6 micromol/kg rivastigmine alone or of a combination of rivastigmine plus memantine (6 micromol/kg p.o. of either of the two compounds), an identical degree of AChE inhibition was observed. The concentrations of rivastigmine, its metabolite NAP 226-90 and memantine were measured in the brain of the same animals. Following an equimolar oral dose (6 micromol/kg) of both compounds, the brain level of memantine exceeded that of rivastigmine + metabolite, by a factor of around 30, when measured 2 h after the final dosing, irrespective of the duration of treatment (acute, for 3 or 21 days). This indicates that neither of the two drugs showed accumulation but also, and more importantly, that memantine does not modulate the prime therapeutic action of rivastigmine (AChE inhibition) in vitro or in vivo. Clinical trials using a combination of both drugs will provide a final proof of whether a combination therapy would lead to an increased efficacy in AD patients.

Acetylcholinesterase↗

PubMed1996

Memantine induces heat shock protein HSP70 in the posterior cingulate cortex, retrosplenial cortex and dentate gyrus of rat brain.

High-affinity N-methyl-D-aspartate (NMDA) receptor antagonists like MK-801 are known to induce the heat shock protein, HSP70, in the posterior cingulate cortex and retrosplenial cortex of rat brain. Memantine, which is a low affinity uncompetitive NMDA receptor antagonist, has been used in the treatment of Parkinson's disease in Europe. The faster kinetics of memantine in blocking and unblocking the NMDA receptor-operated ion channel as opposed to high-affinity NMDA antagonists like MK-801 has been thought to account for the safety of memantine. The present study evaluated the neurotoxic potential of memantine and amantadine using the induction of HSP70 immunoreactivity in rat brain. Memantine (25, 50, 75 mg/kg) induced HSP70 in the posterior cingulate, retrosplenial cortex and dentate gyrus of rat brain. In contrast, amantadine (50, 100, 200 mg/kg) did not induce HSP70 in the rat brain. These results suggest that memantine has an antagonistic effect at NMDA receptor in vivo, and raises the possibility that high doses of memantine may cause neuronal damage similar to those observed with other high-affinity NMDA receptor antagonists.

Animals↗

PubMed1999

Neuroprotection by the NMDA receptor-associated open-channel blocker memantine in a photothrombotic model of cerebral focal ischemia in neonatal rat.

Excessive accumulation of glutamate or other excitatory amino acids and the subsequent overactivity of NMDA receptors is currently thought to lead to neuronal injury in cerebral ischemia. Therefore, antagonists of the NMDA receptor may offer an approach for the treatment of ischemic brain injury. Dizocilpine (MK-801), an NMDA receptor-associated channel blocker, protects neurons in several rodent stroke models. However, this drug has numerous side effects and causes apoptosis of neonatal neurons. Recently, another NMDA receptor-associated channel blocker, memantine, has been shown to ameliorate NMDA-receptor mediated neurotoxicity in neuronal cell cultures and in focal cerebral ischemia models in adult rats without substantial side effects. Memantine has been used clinically in the treatment of Parkinson's disease and spasticity for a number of years. Here we tested the effects of memantine on focal stroke caused by photochemical thrombosis in neonatal rats and demonstrated a neuroprotective effect of memantine in this model. We also found excellent correlation between infarct size determined by magnetic resonance imaging (MRI) and histopathological analysis in the same animals. A single pre-ischemic dose of memantine (20 mg/kg) given 15 min prior to induction of stroke reduced the infarct size by 36.3% when compared to control animals treated with normal saline (P < 0.0001). At this dosage, memantine manifests few, if any, neurobehavioral side effects. Thus memantine appears to be both safe and effective in neonatal as well as adult animal models of stroke.

Animals↗

PubMed1999

Memantine for prevention of spinal cord injury in a rabbit model.

BACKGROUND: This study was conducted to investigate the effect of memantine, a noncompetitive N-methyl-d-aspartate receptor antagonist, on the neurologic outcome of spinal cord ischemia after aortic occlusion. MATERIALS AND METHODS: New Zealand White rabbits were anesthetized and spinal cord ischemia was induced for 40 minutes by infrarenal aortic occlusion. Animals were randomly allocated to 3 groups. Group 1 (n = 8, control) received no pharmacologic intervention, group 2 (n = 8) received intra-aortic memantine infusion (20 mg/kg) after aortic crossclamping, and group 3 (n = 8) was treated with systemic memantine infusion (20 mg/kg) 45 minutes before aortic occlusion. Neurologic status was scored by the Tarlov system (in which 4 is normal and 0 is paraplegia) at 12, 24, 36, and 48 hours after the operation. Lumbar spinal root stimulation potentials and motor evoked potentials from lower limb muscles were monitored before, during, and after the operation. After the animals were killed, the spinal cords were studied histopathologically. RESULTS: All potentials disappeared shortly after aortic crossclamping. They returned earlier in both memantine-treated groups than in the placebo group. Histologic examination of spinal cords revealed a few abnormal motor neurons in memantine-treated rabbits but found extensive injury in the control group. At 12 hours the median Tarlov scores were 0 in the control group (group 1), 2 in the intra-aortic memantine group (group 2, P =.001 versus control), and 3 in the systemic group (group 3, P =.0002 versus control). At 24 hours median Tarlov scores were 0, 2.5 (P =.0002), and 4 (P =. 0002), respectively. Finally, at both 36 and 48 hours median Tarlov scores were 0, 3 (P =.0006), and 4 (P =.0002), respectively. CONCLUSION: Memantine significantly reduced neurologic injury related to spinal cord ischemia and reperfusion after aortic occlusion.

Animals↗

PubMedDate not supplied

Memantine reduces alterations to the mammalian retina, in situ, induced by ischemia.

The aim of the study was to determine whether memantine could slow down the changes seen in the rabbit and rat retina following ischemia/reperfusion. A "suction cup procedure," which raises the intraocular pressure, was used to give an ischemic insult to the rabbit retina. The electroretinogram was recorded before ischemia and after 2 days of reperfusion. Memantine or saline (10 microl) was injected into the eye before ischemia. Immunohistochemistry was used to study the effect of ischemia/reperfusion on the GABA, ChAT, and alphaPKC immunoreactivities. Ischemia/reperfusion injury to the rat retina was induced by raising the intraocular pressure above the systolic blood pressure for 60 min, followed by reperfusion of 3-14 days. Memantine (5 mg/kg) or saline was injected i.p. at the onset of ischemia or reperfusion. Immunohistochemistry was used to study the effect of ischemia/reperfusion on the ChAT, alphaPKC, and Thy-1 immunoreactivities. In addition, morphometric analysis was carried out to determine the effects of ischemia/reperfusion on the thickness of the retina. Ischemia for 75 min caused a change in the nature of the normal GABA and ChAT immunoreactivities in the rabbit retina and a reduction in the b-wave of the electroretinogram. When memantine was injected into the vitreous humour at the onset of an ischemic insult, the changes in the GABA and ChAT immunoreactivities were reduced and the recovery of the reduced b-wave of the electroretinogram after 2 days reperfusion was enhanced significantly. Ischemia for 60 min followed by 3 days reperfusion showed a clear change in ChAT immunoreactivity in the rat retina. The Thy-1 immunoreactivity was only clearly altered after a reperfusion period of 7 days. Moreover, a measurable change in the thickness of the inner retinal layers was detected after 14 days of reperfusion. When given at the onset of ischemia, memantine counteracted the effect of ischemia/reperfusion to varying degrees. However, when memantine was given at the onset of the reperfusion this was not the case. The combined data show that a single injection of memantine given i.p. or intravitreally will protect the retina from a subsequent ischemic insult.

Animals↗

PubMed1998

Influence of urine pH and urinary flow on the renal excretion of memantine.

AIMS: The present study assessed the influence of urinary flow rate and urine pH on the renal excretion of the NMDA-receptor antagonist memantine. METHODS: In a randomized, open, four-period cross-over trial, 12 healthy male volunteers received 10 mg memantine daily for 43 days. After reaching steady state conditions the volunteers were allocated to four different regimens to alter urine pH and urinary flow, which were each separated by a 1 week period while the study medication continued (A: acidification of urine pH, low urinary flow; B: acidification of urine pH, high urinary flow; C: alkalinization of urine pH, low urinary flow; D: alkalinization of urine pH, high urinary flow). RESULTS: The renal clearance of memantine (CL(R)) in regimen A and B was 7-10 fold higher in comparison with regimen C and D (P<0.05). There were small but statistically significant differences of CL(R) between the two regimens with acidic urine pH (A: median: 210.2 ml min(-1) vs B: median: 218.7 ml min(-1)) and between the two regimens with alkaline urine pH (C: median: 19.4 ml min(-1) vs D: median: 30.5 ml min(-1)). The amount of memantine excreted into the urine within one regimen (Ae0-24h) was 5.7-7.4 fold higher in regimens A and B than C and D (P< 0.05). Differences of the AUC(0,24 h) and Cmax/AUC(0,24 h) were significant (P<0.05) between each of the regimens with acidic urine pH (A, B) and regimens (C, D) with alkaline urine pH (A vs C, A vs D, B vs C, B vs D) but not between regimens A vs B or C vs D. CONCLUSIONS: The present study demonstrated a considerable effect of urine pH, whereas no clinically relevant change of the renal excretion of memantine with urinary flow could be detected. As the renal excretion of memantine may have an impact on therapeutic efficacy changes of dietary habits that may alter urine pH should be avoided during treatment with memantine.

Adult↗

PubMed1997

No protective effect of the NMDA antagonist memantine in experimental spinal cord injuries.

We have investigated the effect of memantine, a clinically used NMDA receptor antagonist, in two experimental animals models of spinal cord injury. The lesions were laser-induced photothrombosis to induce focal spinal cord ischemia and clip compression to mimic traumatic spinal cord injury. Pre- or posttreatment of rats with a dose of memantine (20 mg/kg ip) previously shown to be neuroprotective in cerebral ischemia, failed to affect both the neurological and morphological outcome of ischemic spinal cord injury. Likewise, memantine had no effects on neurological and morphological outcome after experimental traumatic injury. In view of the regional heterogeneity of NMDA receptors, the affinity of memantine for spinal cord NMDA receptors was also determined by studying displacement of [3H] (+)-5-methyl-10,11-dihydro-5-H-dibenzo[a,d]cyclohepten-5-10-imine (MK-801) to rat and human spinal cord homogenates. We found that memantine had an affinity for NMDA receptors in the spinal cord (Ki = 0.58 microM) that was significantly lower compared to that of the cerebral cortex (Ki = 0.23 microM) and that the affinity for NMDA receptors in human spinal cord was even lower. We conclude that in view of available data, memantine should not be chosen for clinical studies on neuroprotection in spinal cord injuries and that the lack of protective effect is most likely due to insufficient affinity of memantine for spinal cord NMDA receptors.

Adult↗

PubMedDate not supplied

Treatment effect size of memantine therapy in Alzheimer disease and vascular dementia.

The purpose of this paper is to assess the clinical relevance of the significant results reported in clinical trials of memantine therapy for Alzheimer disease (AD) and vascular dementia. We sought to understand what clinically detectable changes would be evident to the patient with dementia, their caregivers, and the treating physician during a trial of memantine therapy. A literature search was performed on MedLine, PsycInfo, and the Cochrane database. The statistically significant findings from the memantine literature were reviewed using treatment effect size as a measure of clinical meaningfulness. There have been 3 phase 2 studies of memantine in dementia, and 6 phase 3 studies published as of August 1, 2005. Of the 6 published phase 3 trials of memantine in dementia; 2 were in mild-moderate vascular dementia, 1 in mild-moderate AD, 2 in moderate-severe AD, and 1 in severe dementia (both AD and vascular dementia). The most convincing evidence of a clinically meaningful treatment effect of memantine therapy is in the moderate-severe AD patient population. Cognition, as measured by the Severe Impairment Battery, had an effect size of 0.32 and 0.49 in the 2 published trials, indicating a small-to-medium effect of the medication. Global, functional, and behavioral scales also showed a small-to-medium response to memantine.

Alzheimer Disease↗

PubMed2005

A comparison of the predictive therapeutic and undesired side-effects of the NMDA receptor antagonist, memantine, in mice.

Memantine (1-amino-3,5-dimethyl-adamantane) is the only clinically used NMDA (N-methyl-D-aspartate) glutamate receptor antagonist. The present experiments were carried out to compare the dose-response for memantine's predictive therapeutic and side-effects in a variety of tests in C57BL/6J/Han mice, and to elucidate if tolerance may develop to them. Memantine produced a dose-dependent (2.5-15 mg/kg) antidepressant-like effect in the tail-suspension test (TST); this anti-immobility effect of 15 mg/kg of memantine appeared to persist with its sub-chronic administration (3 days, twice daily). Treatment with the same doses of memantine produced no effects on locomotor activity, and sub-chronic treatment with 15 mg/kg did not affect locomotor activity. Exploratory activity was assessed in the open field. Given acutely 5 min before the test, memantine reduced rearing (1.875-30 mg/kg), ambulation (7.5 and 30 mg/kg) and grooming (30 mg/kg). These effects were more pronounced 35 min after its administration. As measured in three different tests, ataxia and stereotypy appeared only at the single dose of 30 mg/kg, 5 and 35 min after administration. In mice treated sub-chronically with 30 mg/kg, the dose of 30 mg/kg increased ambulation, and continued to decrease rearing and grooming, but no signs of ataxia and stereotypy were detected. The present data indicate that different doses of memantine are required for the purportedly therapeutic and side-effects, and that tolerance may develop to the ataxic, but not anti-immobility actions.

Animals↗

PubMed2002

Neuroprotective effect of memantine in different retinal injury models in rats.

PURPOSE: To evaluate the neuroprotective effect of memantine, an NMDA receptor channel blocker, in two retinal ganglion cell (RGC) injury models in rats. METHODS: Neuroprotective effect of memantine was tested in partial optic nerve injury and chronic ocular hypertensive models. In the optic nerve injury model, memantine (0.1 - 30 mg/kg) was injected intraperitoneally immediately after injury. Two weeks later, optic nerve function was determined by measuring compound action potential and surviving RGC was determined by retrograde labeling with dextran tetramethyl rhodamine. Chronic ocular hypertension was attained by laser photocoagulation of episcleral and limbal veins. Memantine (5 or 10 mg/kg) was administered continuously each day with an osmotic pump, either immediately after or 10 days after first laser photocoagulation, for 3 weeks, after which RGC survival was determined. RESULTS: Two weeks after partial optic nerve injury, there was approximately 80% reduction in RGC number. Memantine (5 mg/kg) caused a twofold increase in compound action potential amplitude and a 1.7-fold increase in survival of RGCs, respectively. In the chronic ocular hypertension model there was 37% decrease in RGCs after 3 weeks of elevated intraocular pressure. Memantine (10 mg/kg daily) reduced ganglion cell loss to 12% when applied immediately after first laser photocoagulation, and prevented any further loss when applied 10 days after first laser photocoagulation. CONCLUSION: The protective effect of memantine suggests that excessive stimulation of NMDA receptors by glutamate is involved in causing cell damage in these RGC injury models.

Action Potentials↗

PubMed2006

Neuroprotective properties of memantine in different in vitro and in vivo models of excitotoxicity.

The pathogenesis of stroke, trauma and chronic degenerative diseases, such as Alzheimer's disease (AD), has been linked to excitotoxic processes due to inappropriate stimulation of the N-methyl-D-aspartate receptor (NMDA-R). Attempts to use potent competitive NMDA-R antagonists as neuroprotectants have shown serious side-effects in patients. As an alternative approach, we were interested in the anti-excitotoxic properties of memantine, a well-tolerated low affinity uncompetitive NMDA-R antagonist presently used as an anti-dementia agent. We explored in a series of models of increasing complexity, whether this voltage-dependent channel blocker had neuroprotective properties at clinically relevant concentrations. As expected, memantine protected neurons in organotypic hippocampal slices or dissociated cultures from direct NMDA-induced excitotoxicity. However, low concentrations of memantine were also effective in neuronal (cortical neurons and cerebellar granule cells) stress models dependent on endogenous glutamate stimulation and mitochondrial stress, i.e. exposure to hypoxia, the mitochondrial toxin 1-methyl-4-phenylpyridinium (MPP+) or a nitric oxide (NO) donor. Furthermore, memantine reduced lethality and brain damage in vivo in a model of neonatal hypoxia-ischemia (HI). Finally, we investigated functional rescue (neuronal capacity to migrate along radial glia) by memantine in cerebellar microexplant cultures exposed to the indirect excitotoxin 3-nitropropionic acid (3-NP). Potent NMDA-R antagonists, such as (+)MK-801, are known to block neuronal migration in microexplant cultures. Interestingly, memantine significantly restored the number of neurons able to migrate out of the stressed microexplants. These findings suggest that inhibition of the NMDA-R by memantine is sufficient to block excitotoxicity, while still allowing some degree of signalling.

Animals↗

PubMed2001

Memantine inhibits efferent cholinergic transmission in the cochlea by blocking nicotinic acetylcholine receptors of outer hair cells.

Memantine is a blocker of Ca(2+)-permeable glutamate and nicotinic acetylcholine receptors (nAChR). We investigated the action of memantine on cholinergic synaptic transmission at cochlear outer hair cells (OHCs). At this inhibitory synapse, hyperpolarization of the postsynaptic cell results from opening of SK-type Ca(2+)-activated K(+) channels via a highly Ca(2+)-permeable nAChR containing the alpha 9 subunit. We show that inhibitory postsynaptic currents recorded from OHCs were reversibly blocked by memantine with an IC(50) value of 16 microM. RT-PCR revealed that a newly cloned nAChR subunit, alpha 10, is expressed in OHCs. In contrast to homomeric expression, coexpression of alpha 9 and alpha 10 subunits in Xenopus laevis oocytes resulted in robust acetylcholine-induced currents, indicating that the OHC nAChR may be an alpha 9/alpha 10 heteromer. Accordingly, nAChR currents evoked by application of the ligand to OHCs and currents through alpha 9/alpha 10 were blocked by memantine with a similar IC(50) value of about 1 microM. Memantine block of alpha 9/alpha 10 was moderately voltage dependent. The lower efficacy of memantine for inhibition of inhibitory postsynaptic currents (IPSCs) most probably results from a blocking rate that is slow with respect to the short open time of the receptor channels during an IPSC. Thus, synaptic transmission in OHCs is inhibited by memantine block of Ca(2+) influx through nAChRs. Importantly, prolonged receptor activation and consequently massive Ca(2+) influx, as might occur under pathological conditions, is blocked at low micromolar concentrations, whereas the fast IPSCs initiated by short receptor activation are only blocked at concentrations above 10 microM.

Animals↗

PubMed2003

A placebo-controlled study of memantine (Ebixa) in dementia of Wernicke-Korsakoff syndrome.

We evaluated the responses of 16 patients to preliminarily explore the spectrum of effectiveness and tolerability of the memantine, and NMDA antagonist, in the treatment of dementia in Wernicke-Korsakoff syndrome. In this study, for the first time in dementia of Wernicke-Korsakoff syndrome, the response to memantine was assessed. 16 patients with median age of 64 years and median body weight of 77 kg were treated with memantine 10 mg twice daily for up to 28 weeks. Clinical global impressions (CGI), and Mini Mental Status Examination (MMSE) were performed during the treatment period (after 2, 4, and 28 weeks). Efficacy measures also included the ADCS-Activities of Daily Living scale (ADCS-ADL). At 28 weeks, the ADCS-ADL showed significantly less deterioration in memantine treated patients compared with placebo (-2.3 compared with -4.3: p = 0.005). The results of MMSE demonstrate a significant and clinically relevant benefit for memantine relative to placebo as shown by positive outcomes in cognitive and functional assessments. Memantine (10 mg) was safe and well tolerated. The preliminarily findings of this study with 16 patients suggested that memantine is effective in the treatment of dementia in Wernicke-Korsakoff syndrome.

Dementia↗

PubMed2003

Memantine: new preparation. Poor evaluation and uncertain benefit in Alzheimer's disease.

(1) The standard treatment for mild to moderately severe Alzheimer's disease is donepezil, an anticholinesterase with some beneficial effects (progression is slowed in about 10% of patients, by six months on average) and mainly gastrointestinal adverse effects. (2) Memantine, a drug first developed several decades ago, belongs to the family of NMDA glutamate receptor inhibitors. Marketing authorisation was recently granted for memantine in moderately severe and severe Alzheimer's disease. (3) The clinical evaluation dossier on memantine is poor. Marketing approval was obtained thanks to only one placebo-controlled trial. It included only 252 patients treated for 28 weeks. Patients with moderately severe Alzheimer's disease were not analyzed separately from those with severe forms, even though the response criteria are different for the two categories of patients. (4) According to the chosen endpoint, 5% to 19% of patients were clinically improved by memantine. It is not known whether this benefit persists beyond six months. (5) The report of a trial comparing memantine + donepezil with placebo + donepezil does not analyse the response rate. Use of this combination is not currently justified. (6) In clinical trials the main adverse effects of memantine were neurological (dizziness and headache). Fairly lengthy pharmacovigilance data from Germany are relatively reassuring. (7) In practice, donepezil remains the reference option for moderately severe Alzheimer's disease. Memantine is a second-line option, as its adverse effects differ from those of anticholinesterases. There is still no drug offering a clear benefit for patients with severe forms of the disease.

Alzheimer Disease↗

PubMed1995

Effects of memantine on synaptic transmission in the hippocampus in vitro.

CA1 pyramidal cell response (population spike) in the hippocampal slice preparation was monitored after electrical stimulation of the Schaffer collaterals at CA2 in the presence of different concentrations of memantine (1-amino-3,5-dimethyladamantane, Akatinol Memantine, CAS 41100-52-1) currently being prescribed for the treatment of e.g. dementia. Memantine increased the amplitude of the population spike by 100% compared to the predrug level with an EC50 of approximately 8 mumol/l. Long-term potentiation induced by a brief theta stimulus was likewise increased by a factor of 2. The concentration dependent action of D-serine, an agonist acting at the strychnine insensitive glycine-site of the NMDA (N-methyl-d-aspartic acid) receptor was enhanced in the presence of 1 mumol/l of memantine. These effects of memantine were antagonized completely by very low concentrations of the selective non-NMDA receptor antagonist NBQX (2,3-dihydroxy-6-nitro-7-sulfamoyl-benzoe (F) quinoxyline) as well as by less selective antagonists such as DNQX (6,7-dinitroquinoxaline-2,3-dione) and CNQX (6-cyano-7-nitroquinoxaline-2,3-dione). In contrast, dizocilpine tested under identical conditions and in concordance with the literature decreased long-term potentiation. Thus, memantine clearly has different effects on glutamatergic synaptic transmission compared to dizocilpine. The ability of memantine to enhance synaptic transmission in the hippocampus is in concordance with the reported positive influence on cognition deficits in humans.

Animals↗

PubMed1996

Chronic low-dose glutamate is toxic to retinal ganglion cells. Toxicity blocked by memantine.

PURPOSE: It is well known that acute exposure to high concentrations of glutamate is toxic to central mammalian neurons. However, the effect of a chronic, minor elevation over endogenous glutamate levels has not been explored. The authors have suggested that such chronic exposure may play a role in glaucomatous neuronal loss. In the current study, they sought to explore whether a chronic, low-dose elevation in vitreal glutamate was toxic to retinal ganglion cells and whether this toxicity could be prevented with memantine, a glutamate antagonist. METHODS: Rats were injected serially and intravitreally with glutamate to induce chronic elevations in glutamate concentration. A second group of rats was treated with intraperitoneal memantine and glutamate. Control groups received vehicle injection with or without concurrent memantine therapy. After 3 months, the animals were killed, and ganglion cell survival was evaluated. RESULTS: Intravitreal injections raised the intravitreal glutamate levels from an endogenous range of 5 to 12 microM glutamate to 26 to 34 microM. This chronic glutamate elevation killed 42% of the retinal ganglion cells after 3 months. Memantine treatment alone had no effect on ganglion cell survival. However, when memantine was given concurrently with low-dose glutamate, memantine was partially protective against glutamate toxicity. CONCLUSIONS: These data suggest that minor elevations in glutamate concentration can be toxic to ganglion cells if this elevation is maintained for 3 months. Furthermore, memantine is efficacious at protecting ganglion cells from chronic low-dose glutamate toxicity.

Animals↗