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PubMed1982

Distribution of memantine in brain, liver, and blood of the rat.

The distribution of 1,3-dimethyl-5-aminoadamantane (DMAA, D-145, memantine, Memantine), a compound used in the treatment of CNS disorders, is investigated in liver, brain, and blood of the rat. The tissue concentration of memantine is analyzed by gaschromatography after i.p. and p.o. administration. After i.p. application the blood levels are only about 1/10-1/20 of the concentrations found in liver and brain. The highest drug concentration in blood is obtained within the first 15 min, followed by liver and brain, 30 and 60 min after i.p. administration, respectively. The memantine concentration per g brain tissue is almost identical to the dose applied per g body weight. Lower brain levels are obtained if memantine is given p.o. However, in contrast to the rapid decrease after i.p. treatment, the plateau reached 1 h after p.o. administration does not level off within the next 3 h.

Amantadine↗

PubMed1995

Memantine prevents progressive functional neurodegeneration in rats.

The aim of this study was to examine whether the non-competitive NMDA-antagonist memantine might have neuroprotective properties in an animal model of pro-gressive functional neurodegeneration, without producing NMDA-specific learning and memory deficiencies. Rats were subjected to bilateral clamping of the carotid arteries (BCCA) under pentobarbital anaesthesia for 24 min, and 8-10 days later estimates of their escape latency in finding a hidden platform in a Morris water maze indicated a significant increase. This BCCA-induced increase in escape latency is maximally ameliorated by preinjection of 5 mg/kg of memantine, while higher doses have a lesser effect. BCCA for 60 min produces deficiencies in the maze performance during the second experimental day only, when animals were tested 8-10 days after surgery, but results in severe deficits 6 months later. Intraperitoneal injection of 30 mg/kg memantine 10 minutes before BCCA prevents the development of these deficiencies. In parallel experiments, the apomorphine-induced hypersensitivity of the post-synaptic dopamine receptors, observed 12 months after BCCA, was also prevented by the memantine pre-treatment. No neuronal necrosis was observed after BCCA of either 24 minutes' or 60 minutes' duration. The results suggest that memantine complements the therapeutic value of NMDA antagonists. Further, they lend support to the idea that the glutamatergic NMDA-receptor might play a significant role in the BCCA-induced development of progressive "functional neurodegeneration", i.e. behavioural disturbances and dopamine-receptor hypersensitivity.

Analysis of Variance↗

PubMed1998

The NMDA (N-methyl-D-aspartate) receptor antagonist memantine in the treatment of postherpetic neuralgia: a double-blind, placebo-controlled study.

A double-blind, randomized, placebo-controlled trial was conducted to study the analgesic efficacy of the NMDA (N-methyl-D-aspartate) receptor antagonist memantine (1-amino-3,5-dimethyladamantane hydrochloride) in relieving postherpetic neuralgia (PHN). Memantine (or an identical-looking placebon=12/group) was administered at a dose of 10 mg/day for one week, and 20 mg/day for an additional 4 weeks. All patients were required to record their pain level twice daily during the entire study period, with the use of a 0-10 numerical pain scale (NPS). The McGill Pain Questionnaire (MPQ), spontaneous pain, and a series of mechanical and thermal stimuli-induced pain were measured with the use of a 0-100 visual analogue scale (VAS), on six office visits. Quantitative thermal testing (QTT) and routine blood tests were performed at the beginning and at the end of the study. Although reduction in spontaneous pain, mechanical and cold allodynia, mechanical hyperalgesia, and < > like pain were found in both groups, there were no significant differences between memantine and the placebo on any of the outcome measures. No changes were found in either group in MPQ scores or in quantitative thermal thresholds. Although three patients were withdrawn from the memantine group and only one from the control group, no differences in incidence of adverse effects between the two groups were found. Study results show that memantine is ineffective in reducing spontaneous and evoked pain in patients with PHN. Copyright 1998 European Federation of Chapters of the International Association for the Study of Pain.

Journal Article↗

PubMed2025

Donepezil and Memantine Derivatives for Dual-Function and Prodrug Applications in Alzheimer's Disease.

The treatment of Alzheimer's disease by acetylcholinesterase (AChE) and N-methyl-d-aspartate receptor (NMDAR) inhibitors is limited by the narrow therapeutic window and adverse side effects of the drugs. This study aims to increase the efficacy and limit the side effects of donepezil, an AChE inhibitor, and memantine, an NMDAR inhibitor, through the addition of amyloid-β (Aβ)-targeting fragments to create dual-function compounds. The incorporation of the amyloid-targeting fragments successfully produced compounds with affinity for Aβ fibrils, and that can stain amyloid plaques in the brains of 5xFAD mice. The donepezil-based compounds showed significant changes in AChE inhibition compared to donepezil due to the incorporation of the Aβ-targeting fragment and as confirmed by molecular docking studies. The memantine-derived compound showed good brain uptake in 5xFAD mice but lacked compatibility with NMDAR inhibition based on in vitro assays and molecular docking. Importantly, the memantine-derived compound acts as a prodrug in vivo, releasing memantine within a pharmacologically relevant time frame. Overall, these findings suggest that dual-function compounds may be useful as drug delivery agents that can be metabolized to release an active drug in areas of the brain rich in amyloid plaques and thus could lead to improved treatments for Alzheimer's disease.

Animals↗

PubMed2026

Memantine Augmentation for Obsessive-Compulsive Symptoms in Bipolar Disorder: A Randomized, Double-Blind, Placebo-Controlled Trial.

BACKGROUND: Obsessive-compulsive symptoms are frequently observed in patients with bipolar disorder and present a significant therapeutic challenge. This study evaluated the efficacy and safety of memantine as an adjunctive therapy for obsessive-compulsive disorder in patients with bipolar disorder. METHODS: In this randomized, double-blind, placebo-controlled trial, 46 patients with bipolar disorder and obsessive-compulsive disorder, stabilized on quetiapine and lithium, were randomly assigned to receive either memantine (n = 23) or placebo (n = 23) for 6 weeks. RESULTS: The memantine group showed a significant reduction in Yale-Brown Obsessive-Compulsive Scale scores compared with the placebo group (Cohen d = 1.57 vs 0.42, P < 0.001). Nausea was the most common side effect, but overall adverse effects were minimal. CONCLUSION: Memantine appears to be a safe and effective adjunctive treatment for obsessive-compulsive disorder in patients with bipolar disorder, warranting further investigation.

Humans↗

PubMed2003

Memantine: update on the current evidence.

Nine years after the initial approval of a cholinergic drug for the treatment of Alzheimer's Disease in the USA, a compound with a different pharmacological approach, namely the NMDA antagonist memantine, has been approved for the first time in Europe in 2002. This event led to an enhanced perception of a decade of basic research work on its mode of action. At the same time, additional preclinical data, e.g. on memantine's effects on the hyperphosphorylation of tau, and clinical trial results, e.g. on the glutamatergic-cholinergic combination therapy, are being reported. The present paper attempts to provide an update on the currently available pharmacological and clinical evidence on memantine, including earlier clincial data, e.g. in vascular dementia. As the clinical database broadens, and various additional conditions are being tested in ongoing controlled clinical trials, we are approaching an ever more precise profile of memantine's spectrum of safety and tolerability, and also varied efficacy-hopefully resulting in another useful tool in the clinician's hands to fight previously untreatable neurodegenerative disease.

Dementia↗

PubMed1997

Memantine, a noncompetitive NMDA receptor antagonist improves hyperammonemia-induced encephalopathy and acute hepatic encephalopathy in rats.

The aim of this study was to investigate the possible role of N-methyl-D-aspartate (NMDA)-receptor overactivity in two different experimental rat models of encephalopathy: subacute encephalopathy caused by severe hyperammonemia in portacaval-shunted rats (AI-PCS rats) and acute hepatic encephalopathy caused by complete liver ischemia (LIS rats). The effect of the noncompetitive NMDA-receptor antagonist memantine (intraperitoneal [i.p.] 10-20 mg/kg bw or intravenous [i.v.] 5 mg/kg bw) was studied on the severity of encephalopathy by assessment of clinical grading and electroencephalogram (EEG) spectral analysis, on plasma ammonia concentrations, amino acid concentrations in cerebrospinal fluid (CSF), intracranial pressure (ICP), and brain water content. Both rat models developed encephalopathy within 3 to 6 hours, associated with increased CSF glutamate and aspartate concentrations and increased ICP and brain water content. Memantine administration in AI-PCS and LIS rats resulted in a significant improvement in clinical grading and less slowing of EEG activity (P < .05), and smaller increases in CSF glutamate (P < .05) concentrations. Moreover, ICP and brain water content were significantly lower in memantine-treated AI-PCS rats than in untreated AI-PCS rats (P < .05). Memantine had no significant effect on ICP and brain water content in LIS rats, and on ammonia concentrations in both models. These results indicate that NMDA-receptor activation might be involved in the pathogenesis of hyperammonemia-induced encephalopathy and of acute hepatic encephalopathy caused by LIS.

Ammonia↗

PubMed2004

Chronic memantine does not block 3-nitropropionic acid-delayed ischaemic tolerance in rat hippocampal slices ex vivo.

The moderate affinity uncompetitive NMDA receptor antagonist memantine, at concentrations found to be neuroprotective in animal models of chronic excitotoxicity, did not reduce ischaemic tolerance induced chemically with 3 nitropropionic acid (3-NP), but actually tended to enhance this effect ex vivo. Injection of 3-NP (20 mg/kg i.p.)--24 h prior to the in vitro experiment--significantly protected against hypoxia/hypoglycaemia-induced suppression of extracellular field excitatory postsynaptic potentials (fEPSPs) in rat hippocampal slices (62.2% vs. control of 16.8%), whereas 3 days pre-treatment with memantine (20 mg/kg/day--Alzet minipumps) tended to enhance recovery further following 3-NP preconditioning (89.7%). This low dose of memantine had no effect on fEPSPs in the absence of preconditioning. As expected, 3 days pre-treatment with a high dose of (+)MK-801 (dizocilpine; 2 mg/kg/day--Alzet minipumps) tended to reduce ischaemic tolerance following 3-NP preconditioning (45.3%). We conclude that although NMDA receptors do seem to be involved in chemically-induced ischaemic tolerance, semi-chronic pre-treatment with therapeutically-relevant doses of memantine does not block ischaemic tolerance.

Animals↗

PubMed1998

Effects of NMDA receptor channel blockers, dizocilpine and memantine, on the development of opiate analgesic tolerance induced by repeated morphine exposures or social defeats in mice.

Development of tolerance to opiates involves various neurochemically and pharmacologically distinct processes. For instance, the diversity of opiate tolerance has been suggested by experiments comparing the establishment of diminished response to different effects of opiate agonists. Antagonists acting at N-methyl-D-aspartate (NMDA) receptors has become a very useful tool for studying opiate tolerance mechanisms since these drugs have been shown to retard the development of tolerance to analgesic properties of opiates. The present study compared the ability of two NMDA receptor channel blockers, dizocilpine and memantine, to affect the development of tolerance to morphine analgesia induced by repeated social defeat or by repeated morphine administrations. Male BALB/c mice were assessed for the tail-flick response before and after the defeat in five social confrontations, or before and after repeated morphine injections (20 mg/kg, s.c., once daily for 8 days). Repeated morphine injections were explicitly paired with environmental cues. Socially-defeated as well as morphine-treated mice developed significant tolerance to morphine analgesia. Separate groups of mice were exposed to repeated social confrontations or injections of morphine with each defeat or morphine injection followed by administration of either dizocilpine (0.03-0.3 mg/kg, i.p.) or low-affinity channel blocker memantine (3-30 mg/kg, i.p.). Both dizocilpine and memantine were effective in preventing the development of repeated morphine-induced tolerance to acute morphine analgesia. Treatments with NMDA receptor antagonists that retarded development of non-associative tolerance also suppressed the establishment of associative tolerance significantly. Social defeat-induced tolerance was prevented by dizocilpine but not by memantine. Our results suggest some degree of similarity in the mechanisms of morphine analgesic tolerance induced by pharmacological, contextual and social stimuli.

Analgesics, Opioid↗

PubMed2000

Clinically available NMDA receptor antagonists memantine and dextromethorphan reverse existing tolerance to the antinociceptive effects of morphine in mice.

The tail-flick test was used to investigate the effects of chronic administration of the N-methyl-D-aspartate (NMDA) receptor antagonists, dextromethorphan, memantine and MRZ 2/579, on the development and reversal of morphine tolerance in mice in three separate experiments. Experiment 1 investigated the effects of NMDA receptor antagonists on the development of tolerance. Morphine (10 mg/kg for 6 days, twice daily) produced a 5.9-fold rightward shift of the cumulative dose-response curves. Co-administration of dextromethorphan, memantine or MRZ 2/579 between tests 1 and 2 dose-dependently (5-10 mg/kg) inhibited the development of morphine tolerance. In experiment 2, in which the effects on the reversal were investigated, morphine-tolerant mice were treated b.i.d. for an additional 6 days (between tests 2 and 3) with vehicle+vehicle, NMDA receptor antagonist+vehicle, vehicle+morphine or NMDA receptor antagonist+morphine. Morphine-tolerant mice treated with vehicle+vehicle remained morphine tolerant, whereas this residual morphine tolerance was inhibited by administration of all three NMDA antagonists (each 10 mg/kg). Morphine-tolerant mice receiving vehicle+morphine injections demonstrated an unchanged degree of antinociceptive tolerance. In these mice, the co-administration of memantine and MRZ 2/579, but not dextromethorphan, resulted in the reversal of morphine tolerance. In experiment 3, memantine and MRZ 2/579 (10 mg/kg) inhibited the acute antinociceptive effect of morphine, but dextromethorphan did not. These data indicate that low-affinity, clinically available and/or therapeutically promising NMDA receptor antagonists may be used to inhibit ongoing morphine tolerance.

Analgesics, Opioid↗

PubMed1989

Effects of memantine on the twitch tension of mouse diaphragm.

The effects of memantine (50-175 microM) on the post-tetanic potentiation of the twitch tension were studied on the isolated mouse nerve diaphragm preparation. Memantine completely abolished the twitch tension elicited indirectly while it had no effect on the directly elicited twitch tension. Memantine also decreased the post-tetanic potentiation of amplitude of endplate potential and twitch tension. The duration of tetanic stimulation that induced a maximal decrease of twitch tension was 10-20 s. It is suggested that the effect of memantine on post-tetanic potentiation may be due to its voltage- and time-dependent effect on the ion channel-acetylcholine receptor complex.

Amantadine↗

PubMed1991

Memantine is highly potent in protecting cortical cultures against excitotoxic cell death evoked by glutamate and N-methyl-D-aspartate.

The capacity of memantine to protect cultured cerebrocortical cells against N-methyl-D-aspartate (NMDA)- and glutamate-induced cell death was examined. Excitotoxic cell death was evaluated by phase contrast microscopy and quantified by estimating the release of lactic dehydrogenase from damaged cells. Memantine showed a strong, long-lasting and concentration-dependent protective effect against the excitotoxic damage induced by glutamate and NMDA, with almost complete protection being attained at a memantine concentration of 0.1 mM. The present findings indicate that memantine has potential value as a drug against excitotoxic brain damage.

Animals↗

PubMed1994

The effects of the clinically tested NMDA receptor antagonist memantine on carrageenan-induced thermal hyperalgesia in rats.

This study tested the prophylactic and the therapeutic efficacy of memantine (1-amino-3,5-dimethyl-amandate), a clinically tested N-methyl-D-aspartate (NMDA) receptor antagonist, in suppressing carrageenan-induced thermal hyperalgesia in rats. Rats were injected with 0.1 ml of 1% carrageenan solution s.c. into the right hindpaw, and exhibited hyperalgesia in the injected paw as evidenced by a significant reduction of withdrawal latencies from baseline 1, 3, 5, and 24 h following carrageenan. Prophylactic injection of memantine, 10 and 15 mg/kg, significantly suppressed the hyperalgesia 1, 3, and 5 h post-carrageenan, with maximal effects of 70% (10 mg/kg) and 90% (15 mg/kg) at 1 h post-carrageenan. Therapeutic injection of 10 mg/kg of memantine (2.5 h post-carrageenan) had no effect. The 15 mg/kg dose produced a small effect (peak of 44%) at 3.5 h but not at a statistically significant level, and had no effect 5 h post-carrageenan. This study provides evidence that memantine produces primarily a prophylactic effect (and has only a tendency to produce a therapeutic effect) on carrageenan-induced hyperalgesia at doses that do not significantly alter other motor behaviors.

Animals↗

PubMed1996

Infusion of (+) -MK-801 and memantine -- contrasting effects on radial maze learning in rats with entorhinal cortex lesion.

(+)-5-Methyl-10,11-dihydro-5H-dibenzocyclohepten-5,10-imine maleate ((+)-MK-801) and 1-amino-3,5-dimethyladamantane (memantine), two uncompetitive antagonists of the NMDA receptor were tested in an allocentric version of the radial maze test (with four out of eight arms reinforced) both in normal rats and after quinolinic acid-induced entorhinal cortex lesions. Both agents were infused s.c. using Alzet osmotic minipumps in order to assure steady state drug levels in the serum and brain during the experiment. In non-lesioned rats, (+)-MK-801 (0.312 mg/kg per day) produced disturbances in learning of spatial information dependent on reference memory but not that involving working memory. In contrast, memantine (20 mg/kg per day) had no effect in normal rats. In rats with entorhinal cortex lesions, (+)-MK-801 enhanced the lesion-induced deficit in reference memory. In contrast, memantine reversed the lesion-induced increase in reference memory errors. The divergent effects of those two uncompetitive NMDA receptor antagonists could, at least partially, be due to the differences reported in their channel blocking kinetics and voltage dependence. The results indicate that under conditions of pathological impairment of brain structures such as entorhinal cortex lesion, memantine might produce beneficial effects on cognitive functions.

Animals↗

PubMed1992

Antiparkinsonian drugs memantine and trihexyphenidyl potentiate the anticonvulsant activity of valproate against maximal electroshock-induced seizures.

Memantine increased the threshold for electroconvulsions, when administered at 1.0-6.0 mg/kg (i.p.) and given in subthreshold doses of 0.0156, 0.0625, 0.125 and 0.5 mg/kg (i.p.) potentiated the protective efficacy of valproate, against maximal electroshock (50 mA)-induced seizures in mice, lowering the ED50 from 235 to 197, 172, 164 and 130 mg/kg, respectively. Trihexyphenidyl, applied in doses of 30 and 50 mg/kg (i.p.), did not influence the electroconvulsive threshold per se but when combined with valproate, strongly enhanced its anticonvulsant activity against maximal electroshock-induced seizures lowering the ED50 from 206 to 103 and 46 mg/kg, respectively. The chimney test and retention testing in mice revealed that administration of memantine at 0.5 mg/kg (i.p.) or trihexyphenidyl at 30 mg/kg (i.p.) together with valproate in doses of 130 or 103 mg/kg (i.p.), respectively, resulted in motor impairment and caused impairment of long-term memory, similar to the effects of valproate alone, when applied at its ED50 against maximal electroshock. Neither memantine nor trihexyphenidyl altered the total level of valproate in plasma. It may be concluded that the potentiation of the anticonvulsant activity of valproate, by memantine and trihexyphenidyl, is not associated with a pharmacokinetic interaction.

Animals↗

PubMed1992

N-methyl-D-aspartate (NMDA)-mediated muscle relaxant action of memantine in rats.

The present study examined in vivo whether memantine exerts muscle relaxant activity via an antagonistic action at N-methyl-D-aspartate (NMDA) receptors. Intraperitoneal (i.p.) administration of memantine, 50-100 mumol/kg, reduced the tonic activity in the electromyogram recorded from the gastrocnemius muscle of spastic mutant rats. This effect was prevented by coadministration of NMDA. Memantine, while not affecting monosynaptic Hoffmann (H)-reflexes, depressed polysynaptic flexor reflexes in anaesthetized rats following i.p. (6.25-100 mumol/kg) or intrathecal (i.t., 10-500 nmol) administration. The latter effect was prevented by i.t. coadministration of NMDA, but not of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA). These observations suggest that NMDA receptors might be involved in the mediation of the muscle relaxant activity of memantine.

Animals↗

PubMed1995

The clinically tested N-methyl-D-aspartate receptor antagonist memantine blocks and reverses thermal hyperalgesia in a rat model of painful mononeuropathy.

This study tested the prophylactic and therapeutic efficacy of memantine (1-amino-3,5-dimethyl-amandate), a clinically tested N-methyl-D-aspartate (NMDA) antagonist on thermal hyperalgesia in a rat model of painful mononeuropathy. Persistent hyperalgesia induced by chronic constrictive injury (CCI) to the sciatic nerve was significantly reduced for up to 14 days by prophylactic administration of memantine (3.0 mg/kg) via i.p. implanted osmotic micropumps for a period of 7 days. Therapeutic i.p. injections of memantine (10 mg/kg) given on post-injury days 7 and 14 completely reversed existing hyperalgesia for a short period of 1 h. These results provide evidence that memantine produces long-term prophylactic and short-term therapeutic effects on thermal hyperalgesia in a model of painful mononeuropathy.

Animals↗

PubMed1995

Cerebrospinal fluid and serum concentrations of the N-methyl-D-aspartate (NMDA) receptor antagonist memantine in man.

Memantine is an uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist with therapeutic potential in dementia, spasticity and Parkinson's disease. The Ki-value of memantine at the phencyclidine (PCP) binding site of the NMDA receptor is 0.5 microM in human frontal cortex. We investigated whether concentrations of memantine in cerebrospinal fluid (CSF) and serum samples under therapeutic conditions are in the range of its Ki-value at the PCP binding site. The serum levels ranged from 0.025 to 0.529 microM with daily doses between 5 and 30 mg. CSF levels were highly correlated to serum levels and were below serum levels in each patient with a mean CSF/serum ratio of 0.52. Serum and CSF levels were correlated to the daily dose, but not to the duration of treatment. At the concentrations reported here, memantine is expected to specifically interact with the PCP binding site of the NMDA receptor.

Aged↗