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PubMed2002

Synergistic effect of uncompetitive NMDA receptor antagonists and antidepressant drugs in the forced swimming test in rats.

In spite of intensive research, the problem of treating antidepressant-resistant depressive patients has not yet been solved. The authors previously reported that combined administration of imipramine and the uncompetitive NMDA receptor antagonist amantadine reduced immobility time in the forced swimming test in rats to a much greater extent than either treatment alone. The present paper investigates the possibility of synergistic interactions between three antidepressants (imipramine, venlafaxine, fluoxetine) with three uncompetitive NMDA receptor antagonists (amantadine, memantine and neramexane). Most combinations resulted in synergistic (hyperadditive) antidepressive-like effects in the forced swim test. Most interesting was the observation that fluoxetine, which was inactive when given alone, showed a positive effect when combined with amantadine (10 and 20 mg/kg), memantine (2.5 and 5 mg/kg) or neramexane (2.5 and 5 mg/kg). The specificity of these observations is supported by control open field studies, which demonstrated no significant increase, or even a decrease in general locomotion after coadministration of the compounds. The present results suggest that the combination of traditional antidepressant drugs and NMDA receptor antagonists may produce enhanced antidepressive effects, and this is of particular relevance for antidepressant-resistant patients.

Animals↗
PubMed1997

Anxiolytic activity of glycine-B antagonists and partial agonists--no relation to intrinsic activity in the patch clamp.

On the basis of animal models, anxiety was one of the first suggested clinical applications of partial agonists of the glycineB site coupled to the NMDA receptor. It is not certain, however, whether these findings can be extended to full glycineB antagonists and what is the relation between intrinsic activity (degree of NMDA receptor antagonism) and anxiolytic effect. In the present study several NMDA receptor antagonists, including several glycineB antagonists/partial agonists, were tested for anxiolytic activity in the Vogel conflict test and the elevated plus-maze. Additionally, the intrinsic activities of the glycineB partial agonists used [ACPC, (R,+)-HA-966 and D-cycloserine] were compared in patch-clamp experiments in cultured neurones. In the plus-maze the most striking increase in the time spent in open arms (index of anxiolytic effect) was seen after diazepam and D-cycloserine (at doses that did not change locomotion). Also reliable (dose-dependent), although weaker, anxiolytic activity was produced by the uncompetitive NMDA receptor antagonist (+)MK-801 and the competitive antagonist CGP 39551. Modest anxiolytic-like effect in the plus-maze was also observed after the glycineB antagonist L-701,324 and the partial agonist (+,R)-HA-966. Uncompetitive antagonists memantine and amantadine, the glycineB partial agonist ACPC (up to 600 mg/kg) or the full antagonists MRZ 2/570, MRZ 2/571 and MRZ 2/576 had no effect. In the Vogel conflict test neither memantine, nor any of the full glycineB antagonists tested (L-701,324 and MRZ 2/576), showed anxiolytic activity. Patch-clamp studies revealed that the intrinsic activity of (+,R)-HA-966, D-cycloserine and ACPC was 13, 57 and 92%, respectively, as compared to that of glycine itself (100%). In conclusion, for the agents tested there is no clear relation between the levels of intrinsic activity, i.e. degree of NMDA receptor inhibition, and anxiolytic activity. Moreover, L-701,324 and MRZ-type glycineB full antagonists do not exchibit anxiolytic activity in the elevated plus-maze and Vogel conflict test.

Animals↗
PubMedDate not supplied

Competitive and noncompetitive NMDA antagonist effects in rats trained to discriminate lever-press counts.

The glutamate activated N-methyl-D-aspartate (NMDA) receptor may play a role in short-term memory processing. Among the evidence for this is that NMDA antagonists can impair accuracy in fixed consecutive number (FCN) tasks. This study was designed to further characterize this effect by examining NMDA antagonists differing in their cellular mechanisms of action. Rats were trained to respond under an FCN operant schedule, which required eight presses on one lever (counting lever) before one press at an alternate lever (reinforcement lever) would produce food reinforcement. The effects of three noncompetitive [MK-801 (0.01-0.56 mg/kg); phencyclidine (0.3-3.0 mg/kg); memantine (1-10 mg/kg)] and two competitive [SDZ EAA 494 (0.3-3.0 mg/kg) and NPC 17742 (2.0-16 mg/kg)] NMDA antagonists were analyzed. MK-801 and phencyclidine decreased accuracy at doses not reducing response rates. Memantine, and both of the competitive antagonists, also reduced accuracy, but did so only at doses that markedly reduced response rates. These results suggest that both the affinity and the site bound on the NMDA glutamate receptor by antagonists can determine their effects on FCN performance. Subsequent studies investigated whether SCH 23390, a dopamine D1 receptor antagonist, and NMDA could modulate the effects by phencyclidine and SDZ EAA 494, respectively, on FCN performance.

Animals↗
PubMed1999

Role of Na+/H+ exchangers, excitatory amino acid receptors and voltage-operated Ca2+ channels in human immunodeficiency virus type 1 gp120-mediated increases in intracellular Ca2+ in human neurons and astrocytes.

Human immunodeficiency virus type 1 (HIV-1) dementia is the commonest form of dementia in North American people less than 60 years of age. HIV-1 envelope glycoprotein gp120 has been implicated in the neurotoxicity observed in, and the pathogenesis of, HIV-1 dementia. Recombinant gp120 (gp120) was pressure-applied on to cultured human fetal neurons and astrocytes and, by using single-cell calcium imaging, we determined the mechanisms responsible for gp120-induced increases in the levels of intracellular calcium ([Ca2+]i). Significant dose-related increases in [Ca2+]i were observed in neurons and astrocytes. In neurons, 5 pM gp120 increased [Ca2+]i by 290+/-13 nM and increases of 2210+/-211 nM were found at 209 nM, the highest concentration of gp120 tested. The apparent EC50 value for gp120 of 223+/-40 pM in neurons was not significantly different from that in astrocytes. Immunoelution of gp120 with polyclonal anti-gp120 and Ca2+-free conditions blocked increases in [Ca2+]i by gp120. Increases in [Ca2+]i were significantly (P < 0.005) attenuated by the Na+/H+ exchange blocker 5-(N-methyl-N-isobutyl)-amiloride in neurons and astrocytes. The L-type calcium channel blockers nimodipine, diltiazem and CdCl2 + NiCl2 significantly (P < 0.005) reduced increases in [Ca2+]i in neurons, but not astrocytes. Increases in [Ca2+]i by gp120 were not significantly affected by blockers of N-, P- and Q-type calcium channels. The N-methyl-D-aspartate receptor antagonists (+/-)-2-amino-5-phosphonopentanoic acid (AP5), memantine and dizocilpine significantly (P < 0.01) lowered gp120-induced increases in [Ca2+]i in neurons. AP5 and memantine, but not dizocilpine, significantly (P < 0.01) reduced increases in [Ca2+]i by gp120 in astrocytes. Gp120 appears to activate astrocyte Na+/H+ exchangers to release glutamate and potassium and, subsequent to this, increases in [Ca2+]i in neurons and astrocytes result from activation of excitatory amino acid receptors on astrocytes and neurons, and voltage-operated calcium channels on neurons. Drugs that block gp120-induced changes in [Ca2+]i in neurons and astrocytes may help in the treatment of HIV-1 dementia.

Astrocytes↗
PubMed2004

Evidence-based pharmacotherapy of Alzheimer's disease.

Dementia is an acquired global impairment of cognitive capacities. Approximately 5% of people aged over 65 yr are affected by dementia, and some 70% of cases are thought to be due primarily to Alzheimer's disease. Descriptions of the clinical manifestations of Alzheimer's disease have been increasingly refined in the last decade but there is no diagnostic test for what remains fundamentally a pathologically defined condition. At the present time interventions for Alzheimer's disease are limited to those that modify the manifestations of the disease, and foremost amongst the candidates available are the cholinesterase inhibitors. The rationale for the use of cholinergic drugs for Alzheimer's disease lies in enhancing the secretion of, or prolonging the half-life of, acetylcholine in the brain. Several potential compounds have been tested, but short half-lives and a high incidence of cholinergic and other adverse effects have eliminated most. Only three are widely licensed for use, donepezil, galantamine and rivastigmine. Their efficacy is relatively modest. These drugs have been tested in 32 randomized, placebo-controlled trials. The trials assess cognitive function primarily, and in addition they may assess global function, activities of daily living, quality of life and behavioural disturbance typically over 3 or 6 months. The performance of each drug is summarized in a Cochrane review, a systematic review carried out according to strict guidelines. There was a significant benefit in favour of treatment compared with placebo for cognition and activities of daily living, but withdrawals due to adverse events were significantly higher for treatment than placebo for all three drugs. There is little evidence from direct comparisons between the three drugs. There are several economic analyses of the cost-effectiveness of these drugs, but the findings cannot be considered robust owing to inadequate data. A range of other pharmacological treatments have been tested, including selegiline, piracetam, vitamin E, Ginkgo biloba, anti-inflammatory drugs and hormone replacement therapy, but, so far, Cochrane reviews have not established the efficacy of these interventions for Alzheimer's disease. A Cochrane review of memantine shows benefits on cognitive and global function of the same order of magnitude as seen for the cholinesterase inhibitors. Memantine has been licensed in Europe for treatment of patients with moderately severe to severe Alzheimer's disease.

Aged↗
PubMed2004

Comparison of the anticonvulsive activities of organic mono- and dications with their abilities to inhibit NMDA and AMPA glutamate receptors.

The abilities of mono- and dicationic adamantane and phenylcyclohexyl derivatives to (a) block open NMDA and AMPA glutamate receptors in isolated rat brain neurons and (b) prevent convulsions induced in mice by intraventricular NMDA or kainate were studied. Monocations inhibited NMDA receptors in vitro and produced corresponding protection against NMDA-induced convulsions in vivo, but lacked the ability to block AMPA receptors or prevent kainate-induced convulsions. Dications (IEM-1754 and IEM-1925), which inhibited both NMDA and AMPA receptors, were highly effective at protecting against kainate convulsions and were more effective than the corresponding monocations in preventing NMDA convulsions. The origin of convulsions induced by NMDA appears to be based on a component mediated by activation of AMPA receptors. The anticonvulsive activity of IEM-1754 and IEM-1925 were comparable with those of the known NMDA receptor blockers memantine and MK-801. This was combined with an almost complete absence of the side effects characteristic of memantine and MK-801. The complete correspondence between the in vitro data and in vivo results seen with some of the study compounds is evidently associated with their pharmacokinetic properties.

Adamantane↗
PubMed2001

Uncompetitive antagonists of the N-methyl-D-aspartate (NMDA) receptors alter the mRNA expression of proteins associated with the NMDA receptor complex.

N-methyl-D-aspartate (NMDA) receptor function appears to be under complex control during physiological and pharmacological states. We have investigated the effects of acute administration of uncompetitive NMDA receptor antagonists on mRNA levels of NMDA receptor subunits and on molecules known to cluster or phosphorylate the receptor utilizing in situ hybridization on rat brain sections. A high dose (5 mg/kg; 4 hr) of dizocilpine (MK-801) decreased mRNA levels of NMDA receptor subunits NR2C and NR2B in the entorhinal and parietal cortices, respectively. MK-801 increased mRNA levels of synapse-associated protein-90/postsynaptic density-95 (SAP90/PSD-95) and a gamma-isoform of protein kinase C (PKCgamma) in cortical regions. Synapse-associated protein-97 (SAP97) mRNA levels were increased in the entorhinal cortex layer III after MK-801 or after relatively high doses of other uncompetitive NMDA receptor antagonists: phencyclidine (15 mg/kg; 6 hr) and memantine (50 mg/kg; 6 hr). Memantine also increased SAP97 mRNA expression in other cortical regions, but this effect was not observed with MK-801 or phencyclidine. NMDA receptor uncompetitive antagonists alter the expression of multiple receptor components and such events may ultimately play a role in adaptation or toxic responses.

Adaptor Proteins, Signal Transducing↗
PubMed2002

Morphine tolerance and reward but not expression of morphine dependence are inhibited by the selective glutamate carboxypeptidase II (GCP II, NAALADase) inhibitor, 2-PMPA.

Inhibition of glutamate carboxypeptidase II (GCP II; NAALADase) produces a variety of effects on glutamatergic neurotransmission. The aim of this study was to investigate effects of GCP II inhibition with the selective inhibitor, 2-PMPA, on: (a) development of tolerance to the antinociceptive effects, (b) withdrawal, and (c) conditioned reward produced by morphine in C57/Bl mice. The degree of tolerance was assessed using the tail-flick test before and after 6 days of twice daily (b.i.d.) administration of 2-PMPA and 10 mg/kg of morphine. Opioid withdrawal was measured 3 days after twice daily morphine (30 or 10 mg/kg) administration, followed by naloxone challenge. Conditioned morphine reward was investigated using conditioned place preference with a single morphine dose (10 mg/kg). High doses of 2-PMPA inhibited the development of morphine tolerance (resembling the effect of 7.5 mg/kg of the NMDA receptor antagonist, memantine) while not affecting the severity of withdrawal. A high dose of 2-PMPA (100 mg/kg) also significantly potentiated morphine withdrawal, but inhibited both acquisition and expression of morphine-induced conditioned place preference. Memantine inhibited the intensity of morphine withdrawal as well as acquisition and expression of morphine-induced conditioned place preference. In addition, 2-PMPA did not affect learning or memory retrieval in a simple two-trial test, nor did it produce withdrawal symptoms in morphine-dependent, placebo-challenged mice. Results suggest involvement of GCP II (NAALADase) in phenomena related to opioid addiction.

Animals↗
PubMed2006

The selective mGlu5 receptor antagonist MTEP, similar to NMDA receptor antagonists, induces social isolation in rats.

It has repeatedly been shown that uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists can mimic certain aspects of positive and negative symptoms of schizophrenia in human volunteers and laboratory animals. The purpose of the present study was to expand these findings and to determine whether the selective metabotropic glutamate receptor subtype 5 (mGluR5) antagonist, MTEP (3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine), could induce similar effects in Wistar rats. First, MTEP (1.0-10.0 mg/kg; intraperitoneally) after acute and subchronic (daily for 5 days) administration as well as the uncompetitive antagonists of the NMDA receptor of either high affinity, phencyclidine (0.5-4.0 mg/kg; subcutaneously (s.c.)) and (+)-MK-801 (0.03-0.25 mg/kg; s.c.), or low-moderate affinity, ketamine (2.0-16.0 mg/kg; s.c.) and memantine (0.15-20.0 mg/kg; s.c.), following daily administration for 3 days were tested in the social interaction test to determine their ability to reproduce the negative and positive symptoms measured by social isolation and stereotyped behavior, respectively. Second, the compounds were tested in the motility test following acute administration to determine their ability to induce locomotor hyperactivity reflecting the positive symptoms. In line with previous findings, all examined NMDA receptor antagonists produced social interaction deficits, locomotor hyperactivity, and stereotypy except memantine. Notably, this study found that MTEP following both acute and subchronic administration dose-dependently induced social isolation, but did not cause either locomotor hyperactivity or stereotypy. These data demonstrate that social behavior deficits in rats can be caused by both the blockade of the NMDA receptor and the inhibition of mGluR5, whereas mGluR5 antagonists may not independently be able to mimic the positive symptoms.

Analysis of Variance↗
PubMed2002

Continuous brachial plexus analgesia and NMDA-receptor blockade in early phantom limb pain: a report of two cases.

OBJECTIVE: To provide a mechanism-based acute pain management strategy for early phantom limb pain following traumatic amputations and to collect first evidence of its acute and potentially preventative effects on the formation and maintenance of phantom limb pain. The combination of continuous brachial plexus analgesia and prolonged block of N-methyl-D-aspartate (NMDA) receptors over 4 weeks aimed to attenuate peripheral and central sensitization, currently thought to be substantially involved in establishing and maintaining phantom limb pain. CASE REPORT: Two patients, after traumatic upper limb amputations and early phantom limb pain, were treated on the second and fifth day following amputation by continuous brachial plexus analgesia with ropivacaine 0.375% (30 ml for the initial block, continuous infusion rate = 5 ml/h) for 5 (Patient 1) and 9 days (Patient 2). Both patients received oral memantine (a noncompetitive NMDA-receptor antagonist) in increasing doses from 10 to 30 mg/d over a 4-week period. Ropivacaine only produced minor motor block, with almost unimpaired motor function. Memantine was well tolerated and no relevant side effects were observed. In both patients the treatment prevented the establishment of phantom limb pain, which did not reappear during follow-up of 1 year. CONCLUSIONS: The combination of long-term regional analgesia with prolonged block of NMDA receptors might be effective for treatment and prevention of phantom limb pain following traumatic amputations. The absence of clinically relevant side effects, together with maintained motor function suggests this treatment to be a promising preventive strategy for phantom limb pain following traumatic amputations.

Journal Article↗
PubMed2001

Role of peripheral N-methyl-D-aspartate (NMDA) receptors in visceral nociception in rats.

BACKGROUND & AIMS: N-methyl-D-aspartate (NMDA) receptors are ligand-gated ion channels that have an important role in long-term potentiation and memory processing in the central nervous system. The aims in this study were to determine whether NMDA receptors are expressed in the peripheral nervous system and identify their role in mediating behavioral pain responses to colonic distention in the normal gut. METHODS AND RESULTS: Immunohistochemical localization of the NR1 subunit showed that NMDA receptors are expressed on the cell bodies and peripheral terminals of primary afferent nerves innervating the colon. Dorsal root ganglia neurons retrogradely labeled from the colon in short-term culture responded to addition of NMDA with increased intracellular [Ca2+]. Activation of peripheral NMDA receptors in colonic tissue sections caused Ca2+-dependent release of the proinflammatory neuropeptides, calcitonin gene-related peptide and substance P. Behavioral pain responses to noxious mechanical stimulation were inhibited in a reversible, dose-dependent manner by intravenous administration of memantine, a noncompetitive antagonist of the NMDA receptor. Single fiber recordings of decentralized pelvic nerves showed that colorectal distention responsive afferent nerve activity was inhibited by memantine. CONCLUSIONS: Peripheral NMDA receptors are important in normal visceral pain transmission, and may provide a novel mechanism for development of peripheral sensitization and visceral hyperalgesia.

Amino Acid Sequence↗
PubMed2005

Pharmacology of vertigo/nystagmus/oscillopsia.

PURPOSE OF REVIEW: To describe recent developments in the pharmacological treatment of vertigo and nystagmus while focusing on vestibular neuritis, Meniere's disease, downbeat nystagmus, periodic alternating nystagmus, acquired pendular nystagmus, and superior oblique myokymia. RECENT FINDINGS: In the last 2 years several studies have been published on possible pharmacological treatment options for nystagmus and oscillopsia. In the treatment of vestibular neuritis two studies showed that cortisone treatment was effective for restoring labyrinthine function. This benefit seems more likely if treatment is started within the first 2 days of onset. For recurrent vertigo attacks due to Meniere's disease, the titration technique with daily or weekly doses of intratympanic gentamicin until onset of vestibular symptoms, change in vertigo or hearing loss rated best for complete vertigo control. A new pharmacological treatment option for downbeat nystagmus is the administration of potassium channel blockers (e.g. 4-aminopyridine). They are thought to reinforce the inhibitory action of cerebellar Purkinje cells. Several case reports have proven the beneficial effect of baclofen on periodic alternating nystagmus, of gabapentin and memantine on acquired pendular nystagmus, and of carbamazepine and gabapentin on superior oblique myokymia. SUMMARY: There have been several new developments in the treatment of nystagmus and vertigo over the last 2 years. These include potassium channel blockers for the treatment of downbeat nystagmus, early cortisone treatment to improve recovery of the labyrinth function in vestibular neuritis, and intratympanic gentamicin treatment for Meniere's disease. Other pharmacological treatment options are baclofen for periodic alternating nystagmus, gabapentin and memantine for acquired pendular nystagmus, and carbamazepine for superior oblique myokymia.

Amines↗
PubMed2007

Treatment of vascular dementia and vascular cognitive impairment.

OBJECTIVE: In patients with vascular dementia and vascular cognitive impairment, are acetylcholinesterase inhibitors (donepezil, galantamine, and rivastigmine) and N-methyl-d-aspartate (NMDA) receptor antagonists (memantine) effective in improving cognitive function over placebo? METHODS: The question was addressed with a structured, evidence-based, clinical, neurologic practice review. Participants included consultant and resident neurologists, clinical epidemiologists, medical librarians, and clinical content experts. A critically appraised topic format was employed, with a clinical scenario, structured question, search strategy, appraisal, results, summary of evidence, commentary, and bottom-line conclusions. RESULTS: Eight relevant systematic reviews and randomized controlled trials were identified and served as the principal sources of information. The best evidence to date revealed that donepezil 5 mg/d [number needed to treat (NNT) = 10] was the most effective and best tolerated [number needed to harm (NNH) = 50] of the available agents. Galantamine 24 mg/d (NNT = 7) was also effective but less well tolerated (NNH = 7). Due to insufficient evidence, rivastigmine could not yet be recommended for the treatment of vascular dementia. Memantine appeared to be safe and well tolerated but did not demonstrate effectiveness across all cognitive outcomes and clinical global measures. CONCLUSION: Acetylcholinesterase inhibitors and NMDA receptor antagonists, in general, displayed promise as treatments for patients with vascular dementia and vascular cognitive impairment. The most effective, evidence-based treatments were donepezil and galantamine.

Aged↗
PubMed2005

Treatments for Alzheimer disease.

As our population ages, the incidence and prevalence of Alzheimer disease (AD) will increase dramatically. A number of therapies have been investigated for the treatment and prevention of AD. Clinicians should be prepared to provide evidence-based answers to inquiries regarding AD treatment. There is insufficient evidence to recommend ginkgo biloba, estrogen, statins, or nonsteroidal anti-inflammatory drugs for the prevention or treatment of AD. The use of vitamin E is supported by a single randomized controlled trial, while data on other antioxidants is mixed. There is good evidence that cholinesterase inhibitors and memantine are modestly effective in the treatment of AD. Cholinesterase inhibitors appear to be effective throughout the spectrum of AD, while memantine, alone or in combination with cholinesterase inhibitors, is effective in late stage disease. There is insufficient evidence to suggest superiority of one cholinesterase over another.

Alzheimer Disease↗
PubMed2006

Current pharmacotherapy for Alzheimer's disease.

Alzheimer's disease (AD) is an age-related neurodegenerative disease that affects approximately 4.5 million people in the United States. The mainstays of current pharmacotherapy for AD are compounds aimed at increasing the levels of acetylcholine in the brain, thereby facilitating cholinergic neurotransmission through inhibition of the cholinesterases. These drugs, known as acetylcholinesterase inhibitors (AChEIs), were first approved by the U.S. Food and Drug Administration (FDA) in 1995 based on clinical trials showing modest symptomatic benefit on cognitive, behavioral, and global measures. In 2004 the FDA approved memantine, an NMDA antagonist, for treating dementia symptoms in moderate to severe AD cases. In clinical practice, memantine may be co-administered with an AChEI, although neither drug individually or in combination affects the underlying pathophysiology of dementia. Dementia in AD results from progressive synaptic loss and neuronal death. As knowledge of the mechanisms responsible for neurodegeneration in AD increases, it is anticipated that neuroprotective drugs to slow or prevent neuronal dysfunction and death will be developed to complement current symptomatic treatments.

Alzheimer Disease↗
PubMed2003

Treatment of dementia with neurotransmission modulation.

The prevalence of dementia is growing in developed countries where elderly patients are increasing in numbers. Neurotransmission modulation is one approach to the treatment of dementia. Cholinergic precursors, anticholinesterases, nicotine receptor agonists and muscarinic M(2) receptor antagonists are agents that enhance cholinergic neurotransmission and that depend on having some intact cholinergic innervation to be effective in the treatment of dementia. The cholinergic precursor choline alfoscerate may be emerging as a potential useful drug in the treatment of dementia, with few adverse effects. Of the anticholinesterases, donepezil, in addition to having a similar efficacy to tacrine in mild-to-moderate Alzheimer's disease (AD), appears to have major advantages; its use is associated with lower drop-out rates in clinical trials, a lower incidence of cholinergic-like side effects and no liver toxicity. Rivastigmine is efficacious in the treatment in dementia with Lewy bodies, a condition in which the other anticholinesterases have not been tested extensively to date. Galantamine is an anticholinesterase and also acts as an allosteric potentiating modulator at nicotinic receptors to increase the release of acetylcholine. Pooled data from clinical trials of patients with mild-to-moderate AD suggest that the benefits and safety profile of galantamine are similar to those of the anticholinesterases. Selective nicotine receptor agonists are being developed that enhance cognitive performance without influencing autonomic and skeletal muscle function, but these have not yet entered clinical trial for dementia. Unlike the cholinergic enhancers, the M(1) receptor agonists do not depend upon intact cholinergic nerves but on intact M(1) receptors for their action, which are mainly preserved in AD and dementia with Lewy bodies. The M(1) receptor-selective agonists developed to date have shown limited efficacy in clinical trials and have a high incidence of side effects. A major recent advancement in the treatment of dementia is memantine, a non-competitive antagonist at NMDA receptors. Memantine is beneficial in the treatment of severe and moderate-to-severe AD and may also be of some benefit in the treatment of mild-to-moderate vascular dementia. Drugs that modulate 5-HT, somatostatin and noradrenergic neurotransmission are also being considered for the treatment of dementia.

Animals↗
PubMed2001

Potential and current use of N-methyl-D-aspartate (NMDA) receptor antagonists in diseases of aging.

The N-methyl-D-aspartate (NMDA) receptor complex is a subtype of glutamate receptor and its dysfunction is involved in many neurological disorders associated with aging, including chronic pain, depression, stroke and Parkinson's disease. Multiple clinical trials using NMDA receptor antagonists have been aborted mainly due to the severe psychomimetic adverse effects of these drugs that occur before concentrations can reach an adequate level in the brain. In this review, we present the evidence that clinically safer NMDA antagonists such as memantine and nitroglycerin, and the combination drug nitro-memantine, are promising as drugs in treating neurodegenerative diseases.

Aged↗
PubMed2002

Amino-alkyl-cyclohexanes as a novel class of uncompetitive NMDA receptor antagonists.

Because of its widespread involvement in the physiology and pathology of the CNS, the glutamatergic system has gained considerable attention as a potential target for development of new agents for a number of therapeutic indications. In this respect, the glutamate receptor subtype of the NMDA type has been most intensively studied. The present review describes the rational for developing amino-alkyl-cyclohexanes, as new uncompetitive NMDA receptor antagonists based on our positive experience with memantine which has been used clinically for many years for the treatment of neurodegenerative dementia. Many amino-alkyl-cyclohexane derivatives have been evaluated in vitro and in animal models, and in turn, one structure, namely neramexane HCl (MRZ 2/579) was selected for further development. This agent shows some similarity to memantine e.g. channel blocking kinetics, voltage dependency, and affinity. Preclinical tests indicated particularly good activity in animal models of alcoholism (self-administration, withdrawal-induced audiogenic seizures etc.) and pain (chronic pain, inhibition of tolerance to the analgesic effects of morphine). It turn, this agent has recently entered phase II of clinical trials in alcoholism after a favourable profile seen in phase I studies.

Animals↗