NMDAR/noncompetitive N-methyl-D-aspartate receptor

Memantine is used to prevent glutamate-mediated excitotoxicity and neurodegeneration in Alzheimer's disease. As glutamine is one of the major source of anabolism in fast growing cancer cells, we aimed to interfere with the cancer cell metabolism in A549 lung cancer cells by using memantine. The effects of memantine on cell cycle progression and cell death in A549 cells were assessed by MTT assay and PI staining. Cells were treated with 0.25 mM memantine for 48 hours and then cell metabolism (AMPKA1, AMPKA2, HIF1A, B-catenin, PKM), apoptosis (p53, p21, Bax, Bcl-XL, NOXA, PUMA) and autophagy related (LC3B-I, LC3B-II, SQSTM1) mRNA and protein expressions were investigated by RT-qPCR and western blotting. Memantine decreased cell viability significantly in a concentration-dependent manner by inducing G0/G1 cell cycle arrest. Our results suggest that memantine activates AMPK1/2 significantly (p=0.039 and p=0.0105) that led cells through apoptosis and autophagy by decreasing cancer cell metabolism regulators like HIF1A, B-catenin and PKM as the consequence of this energetic shift. Memantine represents a useful tool to target metabolism in cancer cells. Therefore, it might be used a new repurposed drug in cancer treatment. [4]

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Memantine decreased cell viability significantly via inducing cell cycle arrest at G0/G1 phase [4]
Memantine's effect on A549 cell viability was investigated at 24 and 48 hours with different memantine concentrations (0.125-4 mM). Memantine decreased cell viability significantly (p=0.0094, two-tailed paired t-test) in MTT assay for both 24 and 48 hours in a dose-dependent manner (Figure 1a(Fig. 1)). At 0.25 mM concentration cell viability was found as 76.58 % for 48 hours. Therefore those concentrations were chosen for further analysis to investigate the molecular mechanism of this anticancer activity. Memantine's effect on cell cycle profile was assessed by propidium iodide staining by flow cytometry. A549 cells were treated with 0.25 mM of memantine for 48 hours and cell cycle profiles were compared with the untreated control cells. Control cells had 0.1 % Sub G1, 62.8 % G0/G1, 9.9 % S and 21.3 % of the cells at G2/M phase whereas memantine treated cells had 0.6 % Sub G1, 82.7 % G0/G1, 3.6 % S and 10.8 % of the cells at G2/M phase. Corresponding cell cycle phases were represented as pie chart graphs in Figure 1b(Fig. 1). Memantine triggered the accumulation of the cells at G0/G1 phase at 48 hours. Memantine activated AMPK1/2 and decreased HIF1A, B-catenin, total PKM protein expressions [4]
We investigated AMPK A1 and AMPK A2 mRNA expression levels after 0.25 mM memantine treatment for 48 h in A549 cells in order to assess memantine's effect on cancer cell metabolism. Memantine activated AMPK A1 and AMPK A2 genes at mRNA level significantly (p=0.039 and p=0.0105) (Figure 2a, 2b(Fig. 2)). Then we checked the potential downstream targets of AMPK activated oncogenic pathway by looking at HIF1A, B-catenin and total PKM protein expression levels. Memantine treatment decreased HIF1A, B-catenin and PKM protein expression levels (Figure 2c, 2d(Fig. 2)). All of these targets are involved in cancer cell metabolism related changes in oncogenic transformation of the cells. Hypoxia-inducible factor 1 (HIF-1) is thought as the master regulator of cancer metabolism by activating glucolytic metabolism. We compared the overall survival of high and low HIF1A expression by Kaplan-Meier survival analysis by using publicly available data set GEPIA. In LUAD (The Cancer Genome Atlas Lung Adenocarcinoma) samples, higher HIF1A expression is found as an indicator of lower overall survival rates (Figure 2e(Fig. 2)). Memantine induced cell death via p53 activation that directed cells into the apoptosis and autophagy [4]
In order to assess memantine's effect on cell death, we investigated its role on p53-dependent pathway of apoptosis. A549 cells were treated with 0.25 mM memantine for 48 h. p53, p21, Bax, Bcl-XL, PUMA and NOXA mRNA expression levels were measured by qRT-PCR. Memantine increased p53 level significantly (p=0.034). Memantine also increased p21 mRNA expression level (Figure 3a(Fig. 3)). In addition to that memantine increased pro-apoptotic gene expression of Bcl-XL, PUMA, NOXA levels significantly (Figure 3b(Fig. 3)). We found that as memantine activated p53 mediated apoptosis, downstream pathway of apoptotic genes are also activated (Bcl-XL, PUMA, NOXA). PUMA is known as “p53 upregulated modulator of apoptosis”. Therefore our results were consistent with the potential activation of P53-dependent pathway of apoptosis.

In hippocampal slices of old rats, memantine (1, 5 and 10, 15 mg/kg; intraperitoneally; daily for 15-20 days) dramatically inhibits big LTP [2]. Tail suspension and forced swim tests show that memantine (1-3 mg/kg; oral (po)) for 14 days dramatically improves depressive-like behavior in olfactory bulbectomized (OBX) mice [3].

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Aberrant depressive-like behaviors in olfactory bulbectomized (OBX) mice have been documented by previous studies. Here, we show that memantine enhances adult neurogenesis in the subgranular zone of the hippocampal dentate gyrus (DG) and improves depressive-like behaviors via inhibition of the ATP-sensitive potassium (KATP) channel in OBX mice. Treatment with memantine (1-3 mg/kg; per os (p.o.)) for 14 days significantly improved depressive-like behaviors in OBX mice, as assessed using the tail-suspension and forced-swim tests. Treatment with memantine also increased the number of BrdU-positive neurons in the DG of OBX mice. In the immunoblot analysis, memantine significantly increased phosphorylation of CaMKIV (Thr-196) and Akt (Ser-473), but not ERK (Thr-202/Tyr-204), in the DG of OBX mice. Furthermore, phosphorylation of GSK3β (Ser-9) and CREB (Ser-133), and BDNF protein expression levels increased in the DG of OBX mice, possibly accounting for the increased adult neurogenesis owing to Akt activation. In contrast, both the improvement of depressive-like behaviors and increase in BrdU-positive neurons in the DG following treatment with memantine were unapparent in OBX-treated Kir6.1 heterozygous (+/-) mice but not OBX-treated Kir6.2 heterozygous (+/-) mice. Furthermore, the increase in CaMKIV (Thr-196) and Akt (Ser-473) phosphorylation and BDNF protein expression levels was not observed in OBX-treated Kir6.1 +/- mice. Overall, our study shows that memantine improves OBX-induced depressive-like behaviors by increasing adult neurogenesis in the DG via Kir6.1 channel inhibition. [3]

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Memantine ameliorates the OBX-induced decrease in adult hippocampal neurogenesis [3]
Mice were injected five times with BrdU 20–24 days after OBX or sham operation, and brains were harvested to assess adult hippocampal neurogenesis 7 days later. To identify BrdU-positive cells, we performed double-staining with antibodies against BrdU and NeuN, a neuronal marker, in hippocampal slices. A moderate number of BrdU/NeuN double-positive cells were identified in the DG of the hippocampus in sham-operated mice (Fig. 2A), but that number was significantly decreased in OBX mice (sham: 152.5 ± 6.4 cells, n = 6; OBX: 78.5 ± 2.6 cells, n = 6) (Fig. 2A, B). Memantine at a dose of 3 mg/kg significantly increased the number of BrdU/NeuN double-positive cells in OBX mice relative to that in untreated OBX controls (151.0 ± 12.1 cells, n = 6) (Fig. 2A, B). Memantine (3 mg/kg) did not affect the number of BrdU/NeuN double-positive cells in sham-operated mice (Fig. 2A, B).

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Memantine increases phosphorylation of CaMKIV (Thr-196), Akt (Ser-473), and downstream substrates in the DG of OBX mice [3]
To determine whether CaMKIV, ERK, and Akt activities are essential for memantine-induced adult hippocampal neurogenesis, we undertook an immunoblot analysis. In sham-operated mice, memantine (3 mg/kg) slightly but significantly increased CaMKIV (Thr-196) phosphorylation (110.3 ± 4.8 %, n = 5) but not Akt (Ser-473) or ERK (Thr-202/Try-204) phosphorylation in the DG (Fig. 3A, B). Interestingly, phosphorylation of CaMKIV (Thr-196), Akt (Ser-473), and ERK (Thr-202/Try-204) in the DG of OBX mice was markedly decreased relative to sham-operated mice (CaMKIV: 57.9 ± 2.1 %, n = 5; Akt: 72.9 ± 3.6 %, n = 5; ERK (Thr-202/Try-204): 42.9 ± 3.3 %, n = 5) (Fig. 3A, B). Memantine (3 mg/kg) significantly increased the phosphorylation of CaMKIV (Thr-196) and Akt (Ser-473) but not ERK (Thr-202/Try-204) in the DG of OBX mice (CaMKIV: 96.2 ± 2.5 %, n = 5; Akt: 82.2 ± 4.5 %, n = 5) (Fig. 3A, B).

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Memantine fails to improve depressive-like behaviors in OBX-operated Kir6.1 heterozygous mice but not Kir6.2 heterozygous mice [3]
We next asked whether memantine improves depressive-like behaviors via Kir6.1 or Kir6.2 channel inhibition, as assessed using the tail-suspension or forced-swim tests. We measured immobility time in the tail-suspension test and compared the times between OBX-operated WT mice, OBX-operated Kir6.1 +/− mice, and OBX-operated Kir6.2 +/− mice with or without repeated memantine treatment. In OBX-operated Kir6.1 +/− mice and OBX-operated Kir6.2 +/− mice, the immobility time in the tail-suspension test (Fig. 4A) or forced-swim test (Fig. 4B) did not change compared to OBX-operated WT mice. Memantine (3 mg/kg) significantly decreased immobility time in OBX-operated WT mice (OBX-operated WT mice: 146.5 ± 5.5 %, n = 5; memantine treated OBX-operated WT mice: 90.7 ± 7.3 %, n = 5) and Kir6.2 +/− mice (OBX-operated Kir6.2 +/− mice: 157.5 ± 14.9 %, n = 5; memantine-treated OBX-operated Kir6.2 +/− mice: 84.7 ± 8.6 %, n = 5), but failed to alter the immobility time in OBX-operated Kir6.1 +/− mice (Fig. 4A).

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Memantine fails to ameliorate the decrease in adult hippocampal neurogenesis observed in OBX-operated Kir6.1 heterozygous mice but not Kir6.2 heterozygous mice [3]
We also assessed adult hippocampal neurogenesis in OBX-operated Kir6.1 +/− mice and OBX-operated Kir6.2 +/− mice with and without repeated memantine exposure. There was no change in the number of BrdU/NeuN double-positive cells in the DG of OBX-operated Kir6.1 +/− mice or OBX-operated Kir6.2 +/− mice relative to that in OBX-operated WT mice (Fig. 5A, B). Repeated memantine treatment (3 mg/kg) significantly increased the number of BrdU/NeuN double positive cells in OBX-operated WT mice and OBX-operated Kir6.2 +/− mice (OBX-operated WT mice: 146.9 ± 6.4 cells, n = 8; OBX-operated Kir6.2 +/− mice: 137.8 ± 2.2 cells, n = 8), but failed to restore the number of BrdU/NeuN double-positive cells in OBX-operated Kir6.1 +/− mice (Fig. 5A, B).

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Memantine failed to increase the phosphorylation of CaMKIV (Thr-196) and Akt (Ser-473) in the DG of OBX-operated Kir6.1 heterozygous mice but not Kir6.2 heterozygous mice [3]
Finally, we assessed whether memantine can increase the phosphorylation of CaMKIV (Thr-196) and Akt (Ser-473) in the DG of OBX-operated Kir6.1 mice or OBX-operated Kir6.2 +/− mice. There was no change in the phosphorylation of CaMKIV (Thr-196) or Akt (Ser-473) in the DG of OBX-operated Kir6.1 mice or OBX-operated Kir6.2 +/− mice relative to OBX-operated WT mice (Fig. 6A, B). Repeated memantine treatment (3 mg/kg) significantly increased the phosphorylation of CaMKIV (Thr-196) and Akt (Ser-473) in OBX-operated WT mice or OBX-operated Kir6.2 +/− mice (CaMKIV: OBX-operated WT mice: 135.3 ± 4.2 %, n = 5; OBX-operated Kir6.2 +/− mice: 131.9 ± 9.6 %, n = 5; Akt: OBX-operated WT mice: 139.9 ± 14.8 %, n = 5; OBX-operated Kir6.2 +/− mice: 143.5 ± 8.9 %, n = 5), but failed to increase CaMKIV and Akt phosphorylation in the DG of OBX-operated Kir6.1 +/− mice (Fig. 6A, B).

Cell culture and chemicals [4]
A549 cells were grown in DMEM medium supplemented with 10 % Fetal bovine serum (FBS). Cells were grown in 5 % CO2 at 37 °C. Cells were treated with 0.125-4 mM Memantine for 24 and 48 hours. Memantine was dissolved in sterile, non-pyrogenic distilled water.

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Cellular cytotoxicity assay [4]
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay was used to evaluate the cytotoxic effect of Memantine. Cells were seeded into the 96 well plate and cultured for overnight. A549 cells were treated with memantine for 24 and 48 hours. MTT solution (5 mg/ml in PBS) was added to each well after treatment and the plate was incubated for 4 h at 37 °C. DMSO was added to solubilize the formazan crystals and the plate was further incubated at 37 °C for 30 min. Absorbance ratio was measured by SpectraMax M3 microplate reader at 570 nm.

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Protein expression profiles by Western blot [4]
After 48 h treatment of A549 cells with Memantine, cells were washed with PBS and scraped into the RIPA lysis buffer containing 1mM PMSF followed by sonication for 15 seconds. Samples were centrifuged for 15 minutes at 14000 rpm at 4 °C and the supernatant was collected. Proteins were quantified by using the BCA Assay Kit. Protein lysates (20 μg) were heated for 5 minutes at 95 °C in LDS non-reducing sample buffer and then loaded to the 10 % Tris-glycin gels. The gels were transferred to the PVDF membrane at 300 mAmp for 90 minutes. Membranes were blocked with 5 % non-fat milk powder in TBS-T for 1 hour at room temperature and incubated overnight at 4 °C with the primary antibodies for HIF1A, B-catenin, total PKM, B-actin, LC3B and SQSTM1 at 1:1000 dilution. Blots were washed with TBS-T subsequently. Protein bands were detected by using the secondary antibody and the blots were visualized by BioVision ECL Western Blotting Substrate Kit

Animal/Disease Models: Male Wistar rat [2]
Doses: 1, 5 and 10, 15 mg/kg
Route of Administration: intraperitoneal (ip) injection; one time/day for 15-20 days
Experimental Results: Dramatically diminished the levels recorded in hippocampal slices of aged animals of large LTP.

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Kir6.1 +/− and Kir6.2 +/− mice [3]
Kir6.1 +/− mice were generated by targeted disruption of the KCNJ8 gene. Kir6.2 −/− mice were generated by targeted disruption of the corresponding gene and similarly backcrossed onto a C57BL/6J background. Mice were backcrossed for more than 10 generations onto a C57BL/6J background. For a detailed protocol for both see Miki et al., 1998, Miki et al., 2002. Kir6.2 +/− mice were generated by crossing both Kir6.2 −/− mice and wild-type (WT) mice.

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Operation & drug treatment [3]
OBX mice were established as described previously (Moriguchi et al., 2006). Mice were treated once a day for 14 days with Memantine starting at 14 days after the OBX operation. Behavioral tests were performed following 12–13 days of drug treatment, and biochemical experiments were measured 13–15 days after drug treatment.

Absorption, Distribution and Excretion
After an oral dose, memantine is well absorbed. Its peak drug concentrations are attained in about 3-7 hours. Memantine shows linear pharmacokinetics when given at normal therapeutic doses. This drug can be taken without regard to food, as there is no effect of food on memantine absorption.
This drug is mainly excreted in the urine. Approximately 48% of administered memantine is excreted unchanged in urine. The remainder of the drug is metabolized to three main metabolites. These metabolites are the N-glucuronide conjugate, 6-hydroxy memantine, and 1-nitroso-deaminated memantine, which show minimal NMDA receptor antagonist activity.
The mean volume of distribution of memantine is 9-11 L/kg.
This drug is cleared by active tubular secretion in the kidneys. Tubular reabsorption of this drug is pH dependent.
Memantine is excreted predominantly (about 48%) unchanged in urine and has a terminal elimination half-life of about 60-80 hours. The remainder is converted primarily to three polar metabolites which possess minimal NMDA receptor antagonistic activity: the N-glucuronide conjugate, 6-hydroxy memantine, and 1-nitroso-deaminated memantine. A total of 74% of the administered dose is excreted as the sum of the parent drug and the N-glucuronide conjugate. Renal clearance involves active tubular secretion moderated by pH dependent tubular reabsorption.
Following oral administration memantine is highly absorbed with peak concentrations reached in about 3-7 hours. Memantine has linear pharmacokinetics over the therapeutic dose range. Food has no effect on the absorption of memantine.
Memantine hydrochloride is well absorbed following oral administration, with peak plasma concentrations achieved in about 3-7 hours. Memantine is eliminated principally in urine, with approximately 57-82% of an administered dose excreted as unchanged drug; the remainder of the dose is converted to metabolites that exhibit minimal NMDA receptor antagonist activity.
Memantine is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist used to treat Alzheimer's disease. We investigated memantine pharmacokinetics after oral, IV and patch administration in rats, and compared memantine pharmacokinetics after multiple- or single-dose oral and transdermal administration. Venous blood was collected at preset intervals in single- and multiple-dose studies. Non-compartmental pharmacokinetics was analysed for all formulations. The oral, IV and patch memantine doses were 10 mg/kg, 2 mg/kg and 8.21 +/- 0.89 mg/kg, respectively. The maximum plasma concentration was lower and the half-life longer after patch administration than oral and IV administration. Memantine bioavailability was 41 and 63% for oral and patch administration, respectively. Steady state was achieved around 24 hr for oral and patch administration. The mean AUC increased after oral or patch administration from single to multiple dose. The memantine patch formulation displayed a longer duration of action and lower peak plasma concentration. However, drug exposure was similar to the oral formulation at each dose. Additionally, the memantine patch formulation displayed a smaller interindividual variability and lower accumulation than the oral formulation.
For more Absorption, Distribution and Excretion (Complete) data for MEMANTINE (6 total), please visit the HSDB record page.

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Metabolism / Metabolites
This drug is partially metabolized in the liver. The hepatic CYP450 enzyme system does not majorly contribute to the metabolism of this drug.
Memantine undergoes partial hepatic metabolism. The hepatic microsomal CYP450 enzyme system does not play a significant role in the metabolism of memantine.
The hepatic microsomal cytochrome P-450 (CYP) isoenzyme system does not play a substantial role in the metabolism of memantine.
Excreted largely unchanged. About 20% is metabolized to 1-amino-3-hydroxymethyl-5-methyl-adamantane and 3-amino-1-hydroxy-5,7-dimethyl-adamantane.
Route of Elimination: Memantine undergoes partial hepatic metabolism. About 48% of administered drug is excreted unchanged in urine; the remainder is converted primarily to three polar metabolites which possess minimal NMDA receptor antagonistic activity: the N-glucuronide conjugate, 6-hydroxy memantine, and 1-nitroso-deaminated memantine. It is excreted predominantly in the urine, unchanged.
Half Life: 60-100 hours

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Biological Half-Life
The terminal elimination half-life of memantine ranges from 60 to 80 hours in humans. Following administration of a single oral dose of 10 mg/kg memantine in rats, the elimination half-life was 2.36 ± 0.20 hours. Following a single intravenous dose of 2 mg/kg in rats, the elimination half-life was 2.28 ± 0.48 hours.
The terminal elimination half-life of memantine is approximately 60-80 hours.

Toxicity Summary
IDENTIFICATION AND USE: Memantine is an oil. It is prescribed as a treatment for moderate to severe Alzheimer's Disease. Memantine functions by blocking the NMDA receptor. HUMAN EXPOSURE AND TOXICITY: Signs and symptoms most often accompanying memantine overdosage in clinical trials and from worldwide marketing experience, alone or in combination with other drugs and/or alcohol, include agitation, asthenia, bradycardia, confusion, coma, dizziness, ECG changes, increased blood pressure, lethargy, loss of consciousness, psychosis, restlessness, slowed movement, somnolence, stupor, unsteady gait, visual hallucinations, vertigo, vomiting, and weakness. Renal impairment and hyperkalaemia possibly associated with memantine administration was described in one patient. Two cases of repeated loss of consciousness were reported after long-term memantine treatment in patients with Alzheimer disease, which resolved after its discontinuation. Little is known about the cardiovascular effects of memantine but there have been reports of bradycardia and reduced cardiovascular survival associated with its use. Memantine produced no evidence of genotoxic potential in vitro in chromosomal aberration test in human lymphocytes. ANIMAL STUDIES: In newborn mice treatment with memantine temporally improves hippocampus-dependent memory formation. In rats memantine administration significantly attenuated the ethanol-associated behavioral alterations in a dose-dependent manner. Memantine produced no evidence of genotoxic potential when evaluated in the in vitro S. typhimurium or E. coli reverse mutation assay, or in vivo cytogenetics assay for chromosome damage in rats, and the in vivo mouse micronucleus assay. The results were equivocal in an in vitro gene mutation assay using Chinese hamster V79 cells.
Memantine exerts its action through uncompetitive NMDA receptor antagonism, binding preferentially to the NMDA receptor-operated cation channels. Prolonged increased levels of glutamate in the brain of demented patients are sufficient to counter the voltage-dependent block of NMDA receptors by Mg²⁺ ions and allow continuous influx of Ca²⁺ ions into cells, ultimately resulting in neuronal degeneration. Studies suggest that memantine binds more effectively than Mg²⁺ ions at the NMDA receptor, and thereby effectively blocks this prolonged influx of Ca²⁺ ions through the NMDA channel whilst preserving the transient physiological activation of the channels by higher concentrations of synaptically released glutamate. Thus memantine protects against chronically elevated concentrations of glutamate. Memantine also has antagonistic activity at the type 3 serotonergic (5-HT₃) receptor with a potency that is similar to that at the NMDA receptor, and lower antagonistic activity at the nicotinic acetylcholine receptor. This drug has no affinity for gamma-aminobutyric acid (GABA), benzodiazepine, dopamine, adrenergic, histamine, or glycine receptors or for voltage-dependent calcium, sodium, or potassium channels.

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Hepatotoxicity
In large placebo controlled trials, the rate of serum enzyme elevations during memantine therapy was similar to that in patients on placebo and no instances of clinically apparent liver injury were reported. Nevertheless, since its introduction into clinical use, memantine has been implicated in at least one report of clinically apparent hepatotoxicity. The time to onset was 3 weeks and the clinical syndrome was that of an acute cholestatic hepatitis which was mild-to-moderate in severity and rapidly reversible upon drug discontinuation (Case 1). Immunoallergic and autoimmune features were not present.
Likelihood score: D (possible rare cause of clinically apparent liver injury).

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Protein Binding
The protein binding for memantine is about 45%.

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Interactions
Protein-bound Drugs: Because plasma protein binding of memantine is low (45%), a pharmacokinetic interaction with drugs that are highly protein bound (e.g., digoxin, warfarin) is unlikely.
Drugs Secreted by Renal Tubular Cationic Transport: Potential pharmacokinetic interaction (altered plasma concentrations of both drugs) when memantine is used with drugs secreted by the same renal cationic system (e.g., cimetidine, hydrochlorothiazide, metformin, nicotine, quinidine, ranitidine, triamterene). However, concomitant use of memantine with a fixed combination of hydrochlorothiazide and triamterene did not affect bioavailability of either memantine or triamterene, and maximum plasma concentrations and area under the plasma concentration-time curve (AUC) of hydrochlorothiazide decreased by only 20%. In addition, concomitant use of memantine with a fixed combination of glyburide and metformin hydrochloride did not affect the pharmacokinetics of memantine, metformin, or glyburide, and the hypoglycemic effects of the glyburide-metformin combination were not affected.
Alkalinizing Agents: Potential decreased memantine clearance with resulting increases in adverse effects when drug is used concomitantly with agents that increase urine pH (e.g., carbonic anhydrase inhibitors, sodium bicarbonate). Use with caution. Memantine clearance was decreased by approximately 80% at alkaline urine conditions (ie, pH 8).
Cholinesterase Inhibitors: Concomitant use of memantine with the acetylcholinesterase inhibitor donepezil did not affect the pharmacokinetics of either drug or substantially alter acetylcholinesterase inhibition by donepezil. In a 24-week clinical study in patients with moderate to severe Alzheimer's disease, adverse effects observed with combination therapy with memantine and donepezil were similar to those observed with donepezil alone. In vitro and animal studies indicate that memantine does not affect the reversible inhibition of acetylcholinesterase produced by donepezil, galantamine, or tacrine.
For more Interactions (Complete) data for MEMANTINE (9 total), please visit the HSDB record page.

[1]. Memantine Derivatives as Multitarget Agents in Alzheimer's Disease. Molecules. 2020;25(17):4005.

[2]. Enhanced LTP in aged rats: Detrimental or compensatory?. Neuropharmacology. 2017;114:12-19.

[3]. Memantine Improves Depressive-like Behaviors via Kir6.1 Channel Inhibition in Olfactory Bulbectomized Mice. Neuroscience. 2020;442:264-273.

[4]. Memantine shifts cancer cell metabolism via AMPK1/2 mediated energetic switch in A549 lung cancer cells. EXCLI J. 2021 Feb 4;20:223–231.

Therapeutic Uses
Antiparkinson Agents; Dopamine Agents; Excitatory Amino Acid Antagonists
/CLINICAL TRIALS/ ClinicalTrials.gov is a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world. The Web site is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each ClinicalTrials.gov record presents summary information about a study protocol and includes the following: Disease or condition; Intervention (for example, the medical product, behavior, or procedure being studied); Title, description, and design of the study; Requirements for participation (eligibility criteria); Locations where the study is being conducted; Contact information for the study locations; and Links to relevant information on other health Web sites, such as NLM's MedlinePlus for patient health information and PubMed for citations and abstracts for scholarly articles in the field of medicine. Memantine is included in the database.
Memantine hydrochloride is used for the palliative treatment of moderate to severe dementia of the Alzheimer's type (Alzheimer's disease). /Included in US product label/
/EXPL THER/ Besides the cognitive impairment and degeneration in the brain, vision dysfunction and retina damage are always prevalent in patients with Alzheimer's disease (AD). The uncompetitive antagonist of the N-methyl-d-aspartate receptor, memantine (MEM), has been proven to improve the cognition of patients with AD. However, limited information exists regarding the mechanism of neurodegeneration and the possible neuroprotective mechanisms of MEM on the retinas of patients with AD. In the present study, by using APPswe/PS1deltaE9 double transgenic (dtg) mice, we found that MEM rescued the loss of retinal ganglion cells (RGCs), as well as improved visual impairments, including improving the P50 component in pattern electroretinograms and the latency delay of the P2 component in flash visual evoked potentials of APPswe/PS1deltaE9 dtg mice. The activated microglia in the retinas of APPswe/PS1deltaE9 dtg mice were also inhibited by MEM. Additionally, the level of glutamine synthetase expressed by Muller cells within the RGC layer was upregulated in APPswe/PS1deltaE9 dtg mice, which was inhibited by MEM. Simultaneously, MEM also reduced the apoptosis of choline acetyl transferase-immunoreactive cholinergic amacrine cells within the RGC layer of AD mice. Moreover, the phosphorylation level of extracellular regulated protein kinases 1 and 2 was increased in APPswe/PS1deltaE9 dtg mice, which was blocked by MEM treatment. These findings suggest that MEM protects RGCs in the retinas of APPswe/PS1deltaE9 dtg mice by modulating the immune response of microglia and the adapted response of Muller cells, making MEM a potential ophthalmic treatment alternative in patients with AD.
For more Therapeutic Uses (Complete) data for MEMANTINE (11 total), please visit the HSDB record page.

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Drug Warnings
FDA Pregnancy Risk Category: B /NO EVIDENCE OF RISK IN HUMANS. Adequate, well controlled studies in pregnant women have not shown increased risk of fetal abnormalities despite adverse findings in animals, or, in the absence of adequate human studies, animal studies show no fetal risk. The chance of fetal harm is remote but remains a possibility./
Not known whether memantine is distributed into human milk. However, since many drugs are distributed into human milk, caution is advised if memantine is administered in nursing women.
Mematine has not been systematically evaluated in patients with a seizure disorder. In clinical studies, seizures occurred in 0.2% of patients receiving memantine and in 0.5% of patients receiving placebo.
Safety and efficacy not established in children.
For more Drug Warnings (Complete) data for MEMANTINE (12 total), please visit the HSDB record page.

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Pharmacodynamics
**General effects** This drug inhibits calcium influx into cells that is normally caused by chronic NMDA receptor activation by glutamate. This leads to the improvement of Alzheimer's dementia symptoms, demonstrated by increased cognition and other beneficial central nervous system effects. **Effects on neuroplasticity** Like other NMDA receptor antagonists, memantine at high doses can reduce neuronal synaptic plasticity that is involved in learning and memory processes. At lower concentrations, which are normally used in the clinical setting, memantine can enhance neuronal synaptic plasticity in the brain, improve memory, and act as a neuroprotectant against the destruction of neurons caused by excitatory neurotransmitters. **Effect on various receptors** Memantine has demonstrated minimal activity for GABA, benzodiazepine, dopamine, adrenergic, histamine, and glycine receptors, as well as voltage-dependent Ca2+, Na+ or K+ channels. This drug has shown antagonist activity at the 5HT3 receptors. Laboratory studies suggest that memantine does not affect the reversible inhibition of the acetylcholinesterase normally caused by donepezil, galantamine, or tacrine.

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Memantine (3,5-dimethyladamantan-1-amine) is an orally active, noncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonist approved for treatment of moderate-to-severe Alzheimer's disease (AD), a neurodegenerative condition characterized by a progressive cognitive decline. Unfortunately, memantine as well as the other class of drugs licensed for AD treatment acting as acetylcholinesterase inhibitors (AChEIs), provide only symptomatic relief. Thus, the urgent need in AD drug development is for disease-modifying therapies that may require approaching targets from more than one path at once or multiple targets simultaneously. Indeed, increasing evidence suggests that the modulation of a single neurotransmitter system represents a reductive approach to face the complexity of AD. Memantine is viewed as a privileged NMDAR-directed structure, and therefore, represents the driving motif in the design of a variety of multi-target directed ligands (MTDLs). In this review, we present selected examples of small molecules recently designed as MTDLs to contrast AD, by combining in a single entity the amantadine core of memantine with the pharmacophoric features of known neuroprotectants, such as antioxidant agents, AChEIs and Aβ-aggregation inhibitors. [1]

C12H21N

179.31

179.167

C, 80.38; H, 11.81; N, 7.81

19982-08-2

Memantine hydrochloride;41100-52-1; 19982-08-2

4054

Off-white to yellow solid powder

1.0±0.1 g/cm3

239.8±8.0 °C at 760 mmHg

153ºC

92.3±9.7 °C

0.0±0.5 mmHg at 25°C

1.554

3.18

1

1

0

13

240

0

CC12CC3CC(C1)(CC(C3)(C2)N)C

BUGYDGFZZOZRHP-UHFFFAOYSA-N

1S/C12H21N/c1-10-3-9-4-11(2,6-10)8-12(13,5-9)7-10/h9H,3-8,13H2,1-2H3

1-Amino-3,5-dimethyladamantane

Ebixza; Memantine; Akatinol; Axura D 145; D-145; NSC 102290; SUN Y7017; 19982-08-2; 3,5-dimethyladamantan-1-amine; 1-Amino-3,5-dimethyladamantane; Memantina; 3,5-Dimethyl-1-adamantanamine; 1,3-Dimethyl-5-adamantanamine; alzantin; Ebixa

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)