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PubMed2005

[Efficacy of memantine in the treatment of Alzheimer's disease].

Alzheimer's disease (AD) is a neurodegenerative disorder clinically characterized by cognitive loss with impairment of daily living activities. The benefits presently observed with the approved treatments are mainly symptomatic without clear evidence of neuroprotection. N-methyl-D-aspartate (NMDA) glutamate receptor antagonists have very extensive therapeutic potential in several central nervous system disorders and can be used in chronic neurodegenerative diseases and in other neurological diseases such as epilepsy. Memantine, a moderate-low affinity, uncompetitive NMDA receptor antagonist, is the only antiglutamatergic drug currently approved for the treatment of moderate to severe AD. Several studies have demonstrated that treatment with memantine has cognitive and functional benefits through all disease stages, while it is safe and well tolerated. Additionally, memantine generates an indirect positive effect on the caregiver, which results in some social benefits. This fact, together with a delay on the transition towards a greater dependence stage is probably associated with a decrease in the number of patients institutionalized. From a socio-economic perspective, these effects mean lower global cost of disease, therefore being a cost-effective drug.

Alzheimer Disease↗
PubMed1977

[Effects of intravenous administration of memantine in parkinsonian patients (author's transl)].

After a preliminary study in 6 parkinsonian patients concerning the effectiveness and tolerance of 1,3-dimethyl-5-aminoadamantane hydrochloride (memantine) an investigation to assess its short-term effects was performed. In an unselected group of 12 parkinsonian patients 40 mg of memantine diluted in 500 ml of laevulose were applied i.v. within 2 h. The patients were examined under standardized conditions before, immediately after and 2, 4 and 24 h, respectively, using a program of physchological tests. The results give evidence for a favourable influence on rigor and tremor in Parkinson's syndrome as well as on motor drive. In comparative studies memantine showed a better tolerance than adamantylaminosulfate. The short-time effects of the drug could be differentiated from placebo and learning effects.

Adult↗
PubMed1982

[The Effect of memantine on spinal alpha-motoneurons and on the content of dopamine, noradrenaline and serotonin in the striatum and lumbar spinal cord].

In the present paper the pharmacological effect of 1,3-dimethyl-5-aminoadamantane (DMAA, D-145, memantine, Memantine was investigated on the reflex activity of spinal alpha-motoneurones of the cat and on spontaneous hyperactivity of alpha-motoneurones of spastic Han-Wist rats. The activity of both systems is reduced by the drug. Furthermore the content of dopamine, noradrenaline, and serotonin of striatum and lumbar spinal cord of normals and mutants is dose dependently decreased. It is assumed that memantine depresses the activation of central nervous membranes and reduces repetitive discharges of axons and in addition acts by release of neurotransmitters.

Amantadine↗
PubMed1995

Microdialysis studies with amantadine and memantine on pharmacokinetics and effects on dopamine turnover.

Amantadine and memantine are in clinical use for the treatment of neurodegenerative diseases such as M. Parkinson and dementia syndrome. In order to contribute to the understanding of the interaction of these uncompetitive NMDA-antagonists with the dopaminergic system in the striatum, the pharmacokinetics and the effects of amantadine and memantine on the dopaminergic system were examined in a microdialysis study in anaesthetized rats. Both substances achieved extracellular fluid concentrations in the striatum known to block NMDA receptors, supporting the assumption that NMDA receptor antagonism is their primary mechanism of action. Both, memantine, and to a lesser degree, amantadine induce a modest dopamine overflow not paralleled by HVA or DOPAC. The small increase in dopamine overflow cannot add substantially to the drugs' action and may be generated indirectly via their NMDA-antagonistic properties.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1993

Delayed administration of memantine prevents N-methyl-D-aspartate receptor-mediated neurotoxicity.

Increasing evidence supports the hypothesis that escalating levels of excitatory amino acids (EAAs) are responsible for neuronal cell death in a variety of acute neurological conditions including hypoxia/ischemia, trauma, seizures, and hypoglycemia. EAAs may also contribute to several chronic neurodegenerative diseases including Huntington's disease, parkinsonism, and acquired immunodeficiency syndrome dementia. A predominant form of neurotoxicity appears to be mediated by excessive activation of the N-methyl-D-aspartate subtype of glutamate receptor. This laboratory recently reported that memantine, an antiparkinsonian drug, is a potent N-methyl-D-aspartate antagonist capable of preventing the death of central neurons both in vitro and in vivo when given coincident to an EAA insult. In the present study, we found that 12 microM memantine prevented the death of neonatal rat retinal ganglion cells in primary culture when administered up to 4 hours after the initiation of N-methyl-D-aspartate receptor-mediated neurotoxicity.

Animals↗
PubMed2004

The N-methyl-D-aspartate antagonist memantine retards progression of Huntington's disease.

According to the excitotoxicity hypothesis, neurotoxicity due to glutamate is regarded as potential factor in the progredient neurodegeneration of Huntington's disease (HD). Memantine, as a glutamate receptor antagonist, should counteract this mechanism. Its effectiveness (up to 30 mg/day) with regard to retardation of progression was thus examined in 27 HD patients in a two year, open and multicentre trial. The results suggest that memantine treatment of HD may be useful in terms of retardation of the progression of the disorder.

Activities of Daily Living↗
PubMed1980

Distribution of metabolism of the potential anti-parkinson drug memantine in the human.

GC-MS of tissue extracts obtained from a parkinsonian patient who died from secondary causes during memantine (1-amino-3.5-dimethyladamantane) treatment showed the drug to be largely unmetabolized. In the kidney and liver a second peak corresponded to less than 1% of the main temporal lobe, hypothalamus and pons. Thus treatment with 2 X 10 mg memantine/day reveals an accumulation of the drug in microM concentrations in the brain. This is probably high enough to explain the ameliorating effect of memantine treatment in patients suffering from Parkinson's disease.

Aged↗
PubMed1995

Assessment of primary neuronal culture as a model for soman-induced neurotoxicity and effectiveness of memantine as a neuroprotective drug.

An in vitro mammalian model neuronal system to evaluate the intrinsic toxicity of soman and other neurotoxicants as well as the efficacy of potential countermeasures was investigated. The link between soman toxicity, glutamate hyperactivity and neuronal death in the central nervous system was investigated in primary dissociated cell cultures from rat hippocampus and cerebral neocortex. Exposure of cortical or hippocampal neurons to glutamate for 30 min produced neuronal death in almost 80% of the cells examined at 24 h. Hippocampal neurons exposed to soman for 15-120 min at 0.1 microM concentration caused almost complete inhibition (> or = 90%) of acetylcholinesterase but failed to show any evidence of effects on cell viability, indicating a lack of direct cytotoxicity by this agent. Acetylcholine (ACh, 0.1 mM), alone or in combination with soman, did not potentiate glutamate toxicity in hippocampal neurons. Memantine, a drug used for the therapy of Parkinson's disease, spasticity and other brain disorders, significantly protected hippocampal and cortical neurons in culture against glutamate and N-methyl-D-aspartate (NMDA) excitotoxicity. In rats a single dose of memantine (18 mg/kg) administered 1 h prior to a s.c. injection of a 0.9 LD50 dose of soman reduced the severity of convulsions and increased survival. Survival, however, was accompanied by neuronal loss in the frontal cortex, piriform cortex and hippocampus.

Acetylcholine↗
PubMed2004

Effect of memantine on the alpha 7 neuronal nicotinic receptors, synaptophysin- and low molecular weight MAP-2 levels in the brain of transgenic mice over-expressing human acetylcholinesterase.

Transgenic mice over-expressing human acetylcholinesterase (hAChE-Tg) display memory impairments, cholinergic deficits and reduced dendritic branching. In this study, we found a reduced number of N-Methyl-D-Aspartate (NMDA) binding sites and reduced levels of low molecular weight (LMW) microtubule associated protein 2 (MAP-2), in addition to an increased number of alpha4 and alpha7 nicotinic receptor (nAChR) binding sites in the brain of hAChE-Tg mice. Treatment with memantine, 20 mg/kg/day during 14 days, significantly increased the number of [(125)I]alphabungarotoxin (alpha7 nAChR) binding sites in the frontal- and retrosplenial cortex of hAChE-Tg mice and synaptophysin- and LMW MAP-2 levels in the cortex of both hAChE-Tg and FVB/N controls. The findings reveal an alteration of the glutamatergic system in hAChE-Tg mice. Whether the effect of memantine on alpha7 nAChRs, synaptophysin- and LMW MAP-2 levels is a direct effect, or an indirect effect via the NMDA receptors, has to be further evaluated.

Acetylcholinesterase↗
PubMed2000

Memantine and the amino-alkyl-cyclohexane MRZ 2/579 are moderate affinity uncompetitive NMDA receptor antagonists--in vitro characterisation.

There is general agreement that moderate affinity uncompetitive NMDA receptor antagonists combine good efficacy and tolerability in animal models of disturbances in glutamatergic transmission. There are several theories on which properties are important for this profile including 1, rapid access to the channel at the start of pathological overactivity 2, rapid, voltage-dependent relief of blockade during physiological synaptic activation and 3, partial untrapping. Merz has developed a series of novel uncompetitive NMDA receptor antagonists based on the cyclohexane structure. In cultured hippocampal neurones MRZ 2/579 (1-amino-1,3,3,5,5-pentamethylcyclohexane) shows similar blocking kinetics to memantine (Kon 10.7 * 10(4)M(-1)sec(-1), Koff 0.20sec(-1) at -70mV) and binds at the same depth in the NMDA receptor channel (delta = 0.8). The potency of MRZ 2/579 assessed as Kd = Koff/Kon = 1.87microM agrees well with the IC50 of 1.29microM against steady-state currents in cultured hippocampal neurones (at -70mV) and with the Ki in [3H]-MK-801 binding of 0.65microM. MRZ 2/579 protected cultured cortical neurones against glutamate toxicity with an IC50 of 2.16microM and was also effective in protecting hippocampal slices against hypoxia/hypoglycaemia-induced reduction of fEPSP amplitude in CA1 with an EC50 of 7.01microM. MRZ 2/579 has similar potency and bio-availability to memantine in vivo assessed using microdialysis, microiontophoresis and MES-induced seizures. Initial characterization in animal models provides strong support for the assumption that MRZ 2/579 could be a useful therapeutic in morphine/alcohol dependence, inhibition of morphine tolerance, chronic pain and as a neuroprotective agent.

Animals↗
PubMed1994

Over-additive anticonvulsant effect of memantine and NBQX in kindled rats.

We investigated the anticonvulsant and adverse effects of various dose combinations of the AMPA receptor antagonist NBQX (2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(F)quinoxaline) and the low-affinity, rapidly channel blocking NMDA receptor antagonist memantine in the kindling model of epilepsy. While memantine was ineffective when given alone, co-administration with NBQX markedly potentiated the increase in focal seizure threshold induced by NBQX alone. This synergistic (i.e. over-additive) interaction was seen at doses of both drugs which did not induce behavioural adverse effects. The data substantiate that combinations of AMPA and NMDA receptor antagonists provide a new strategy for the treatment of epileptic seizures.

Animals↗
PubMed1996

Learning deficits induced by chronic intraventricular infusion of quinolinic acid--protection by MK-801 and memantine.

The NMDA receptor agonist quinolinic acid (9 mM) was infused i.c.v. via ALZET osmotic minipumps for 2 weeks. This treatment produced a persistent, short-term memory deficit in the T-maze. Autoradiography revealed a decrease in the density of choline uptake sites in the hippocampus. Parallel s.c. infusion by another minipump of the uncompetitive NMDA receptor antagonist memantine (1-amino-3,5-dimethyladamantane, 20 mg/kg per day) or (+)-5-methyl-10,11-dihydro-5H-dibenzocyclohepten-5,10-imine maleate ((+)-MK-801, 0.31 mg/kg day) prevented the learning deterioration induced by quinolinic acid. The treatment with memantine resulted in steady-state serum levels of 1.2 mu M which, based on in vitro data, should assure inhibition of NMDA receptors and are similar to levels seen in the serum of demented patients treated with this agent. In naive animals this treatment had no effect on either learning or on ex vivo induction of long-term potentiation, indicating that under chronic conditions it is possible to obtain neuroprotective effects with NMDA receptor antagonists without negative effects on memory processes. This contrasts to some acute insults (e.g. ischaemia) where high doses of NMDA receptor antagonists that produce side effects are required.

Analysis of Variance↗
PubMed1996

MK-801 and memantine inhibit a centrally induced increase in myocardial oxygen demand in rabbits.

Electrical stimulation of the paraventricular nucleus of the hypothalamus in the anaesthetized rabbit induces an increase in indexes of myocardial oxygen demand. This increase in myocardial oxygen demand is due to the activation of sympathetic pathways which include glutamatergic relays. In this model, systemic injection of dizolcipine (MK-801) and memantine inhibited these responses. Because these drugs have only one pharmacological property in common i.e. blockade of the NMDA receptor channel complex, these results fit with our previous results concerning the possible involvement of NMDA receptors in the central control of sympathetic activation. Memantine appears to be an interesting prototype for centrally acting cardioprotective drugs devoid of serious side effects.

Animals↗
PubMed1996

Memantine abrogates neurological deficits, but not CNS inflammation, in Lewis rat experimental autoimmune encephalomyelitis.

Memantine, a clinically employed drug with N-methyl-D-aspartate (NMDA) receptor antagonistic effects, dose-dependently ameliorates neurological deficits in Lewis rat experimental autoimmune encephalomyelitis (EAE). Interestingly, this therapeutic effect was not due to dampened CNS inflammation, as assessed by immunohistochemical evaluation of spinal cord tissue. Furthermore, numbers of interferon gamma (IFN gamma) mRNA expressing cells were not decreased, as assessed by in situ hybridization. Systemic immunity in terms of numbers of IFN gamma secreting cells in response to immunodominant myelin basic protein (MBP) peptides ex vivo was not reduced, and non-toxic doses of memantine did not affect lymphocyte proliferation or IFN gamma secretion in vitro. Considering these findings, we hypothesize that effector mechanisms responsible for reversible neurological deficits in EAE may involve NMDA receptors, and this highlights neurons as targets during autoimmune neuroinflammation.

Animals↗
PubMed1992

Prophylactic and therapeutic efficacy of memantine against seizures produced by soman in the rat.

Male Sprague-Dawley rats injected sc with a single sublethal dose of the organophosphate nerve agent, soman (100 micrograms/kg), had motor limbic seizures within 5-15 min. Pretreatment with a single dose of memantine HCl (MEM, 18 mg/kg, sc), alone or in combination with atropine sulfate (ATS, 16 mg/kg, sc), before soman prevented seizures without sedation or ataxia. Rats appeared normal or demonstrated increased exploratory activity. Excessive salivation, a peripheral manifestation of soman intoxication, was decreased by ATS, but pretreatment with ATS alone did not prevent seizures. After seizure onset, MEM +/- ATS, but not ATS, abolished seizures. Acetylcholinesterase (AChE) activity in several brain regions (cortex, stem, striatum, and hippocampus) was markedly reduced by soman, but not by MEM, ATS, or MEM + ATS. Preadministration of MEM + ATS in vivo significantly protected AChE from inhibition by soman. Memantine reduced inhibition of AChE activity in crude brain homogenates by soman, but not by edrophonium (anionic site inhibitor) or decamethonium (peripheral site inhibitor). Thus, MEM may bind to a different modulatory site, not yet characterized, to protect AChE. When given after onset of soman-induced seizures, treatment with MEM +/- ATS did not reactivate AChE although seizures were controlled, suggesting additional anticonvulsant mechanisms of action. At concentrations (10(-4) to 5 x 10(-4) M) which did not significantly alter the spontaneous firing of action potentials (APs), MEM limited sustained high frequency repetitive firing (SRF) induced by depolarization of spinal cord (mouse and rat) and neocortical (mouse) neurons in monolayer-dissociated cell culture. In the same range of concentrations, ATS both limited SRF and suppressed spontaneous activity, suggesting toxicity. In addition, MEM and ATS reversibly produced use-dependent block of depolarizing responses to acetylcholine (ACh) applied by pressure ejection to spinal cord neurons. Thus, the anticonvulsant efficacy of MEM, with or without ATS, may have resulted from a combination of actions, including protection of AChE from inhibition by soman, limitation of high frequency firing of APs, and blockade of excitatory postsynaptic responses to ACh.

Animals↗
PubMed1991

Antidystonic effects of the NMDA receptor antagonists memantine, MK-801 and CGP 37849 in a mutant hamster model of paroxysmal dystonia.

The effects of competitive and noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists were evaluated in an inbred line of Syrian golden hamsters, in which sustained dystonic postures of limbs and trunk can be initiated by handling or mild environmental stimuli. In this model of paroxysmal dystonia, the noncompetitive NMDA receptor antagonists memantine and MK-801 (dizocilpine) delayed the progression of dystonic attacks in a dose-dependent fashion. The novel competitive NMDA receptor antagonist CGP 37849 (DL-[E]-2-amino-4-methyl-5-phosphono-3-pentenoic acid) was more effective than memantine and MK-801, because it retarded not only the progression but also reduced the severity of the dystonic movements. All compounds exhibited antidystonic effects at doses which did not cause marked ataxia or sedation. The data indicate that NMDA receptor antagonists might be interesting candidates for treatment of dystonia.

2-Amino-5-phosphonovalerate↗
PubMed1992

gp120 of HIV-1 induces apoptosis in rat cortical cell cultures: prevention by memantine.

After incubation of rat cortical cell cultures with the human immunodeficiency virus type 1 (HIV-1) coat protein gp120 for 12 h, cells showed fragmentation of DNA at internucleosomal linkers, the characteristic feature of apoptosis. In a quantitative approach, it was determined that the percentage of DNA fragmentation increased from 7%, in the absence of gp120, to 62% following incubation with 24 ng/ml of gp120. Simultaneously, the percentage of viable cells decreased from 94% to 33%. Memantine (1-amino-3,5-dimethyladamantane), a drug currently used in the therapy of spasticity and Parkinson's disease as well as the NMDA antagonist MK-801 both prevented the effects of gp120 at micromolar concentrations. In human cultured astrocytes, gp120 was ineffective with respect to DNA fragmentation and cell toxicity. From these data, we conclude that the gp120-induced apoptosis may contribute to the neurological complications frequently associated with the immunodeficiency syndrome. The cytoprotective effect of memantine in cortical cell cultures may qualify the drug for the treatment of AIDS-related dementia.

Animals↗
PubMed2003

Memantine attenuates the increase in striatal preproenkephalin mRNA expression and development of haloperidol-induced persistent oral dyskinesias in rats.

Tardive dyskinesia (TD) is a serious motor side effect of long-term neuroleptic treatment that may persist after drug withdrawal. Alterations in striatal enkephalinergic neurons due to excessive glutamatergic activity is a possible pathogenetic mechanism. We studied the effect of the NMDA antagonist memantine in a rat model of TD, in which vacuous chewing movements (VCM) were induced by 20 weeks of haloperidol administration. The striatal density of preproenkephalin mRNA was measured and the number of neurons estimated. Haloperidol induced persistent VCM that was associated with increased striatal expression of preproenkephalin mRNA. Memantine inhibited the development of haloperidol-induced persistent VCM and attenuated the increase in preproenkephalin mRNA expression. This suggests that glutamate-mediated up-regulation of striatal enkephalin plays a role in the development of haloperidol-induced persistent oral dyskinesias.

Analysis of Variance↗