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
Memantine is well absorbed after oral administration. Peak plasma concentrations are reached in approximately 3–7 hours. At normal therapeutic doses, the pharmacokinetics of memantine are linear. Since food does not affect the absorption of memantine, food intake does not affect the administration of this drug. The drug is primarily excreted in the urine. Approximately 48% of administered memantine is excreted unchanged in the urine. The remaining drug is metabolized into three major metabolites: N-glucuronide conjugate, 6-hydroxymemantine, and 1-nitrosodeaminememantine, which have very low antagonistic activity against NMDA receptors. The mean volume of distribution of memantine is 9–11 L/kg. The drug is cleared by active renal tubular secretion. Renal tubular reabsorption of the drug is affected by pH. Memantine is primarily excreted unchanged (approximately 48%) in the urine, with a terminal elimination half-life of approximately 60–80 hours. The remainder is primarily converted into three polar metabolites with very low NMDA receptor antagonistic activity: N-glucuronide conjugate, 6-hydroxymemantine, and 1-nitrosodeaminememantine. 74% of the administered dose is excreted as the combined amount of the parent drug and N-glucuronide conjugate. Renal clearance is primarily via active tubular secretion and is regulated by pH-dependent tubular reabsorption. Memantine is rapidly absorbed after oral administration, reaching peak plasma concentrations in approximately 3–7 hours. Within the therapeutic dose range, the pharmacokinetics of memantine are linear. Food has no effect on memantine absorption. Memantine hydrochloride is well absorbed after oral administration, reaching peak plasma concentrations in approximately 3–7 hours. Memantine is primarily excreted in the urine, with approximately 57–82% of the administered dose excreted unchanged; the remaining dose is converted into metabolites, which have virtually no NMDA receptor antagonistic activity. Memantine is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist used to treat Alzheimer's disease. We investigated the pharmacokinetics of memantine in rats after oral, intravenous, and transdermal administration, and compared the pharmacokinetics of memantine after single or multiple oral administrations with transdermal administration. Venous blood was collected at pre-defined time intervals in both single and multiple-dose studies. All formulations were analyzed using a non-compartmental model. The oral, intravenous, and transdermal doses of memantine were 10 mg/kg, 2 mg/kg, and 8.21 ± 0.89 mg/kg, respectively. Peak plasma concentrations and a longer half-life were observed after transdermal administration of memantine compared to oral and intravenous administration. The bioavailability of memantine after oral and transdermal administration was 41% and 63%, respectively. Steady-state plasma concentrations were reached approximately 24 hours after both oral and transdermal administration. The mean AUC increased after single or multiple oral administration. The transdermal memantine patch had a longer duration of action and a lower peak plasma concentration. However, at various doses, drug exposure is similar to that of the oral formulation. Furthermore, inter-individual variability in memantine patches is small, and accumulation is lower than in oral formulations.
For more complete data on absorption, distribution, and excretion of memantine (6 types), 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 contributes little to the metabolism of this drug.
Memantine is partially metabolized in the liver. The hepatic microsomal CYP450 enzyme system plays a minor role in the metabolism of memantine.
The hepatic microsomal cytochrome P-450 (CYP) isoenzyme system plays a minor role in the metabolism of memantine.
Primarily excreted unchanged. Approximately 20% is metabolized to 1-amino-3-hydroxymethyl-5-methyladamantane and 3-amino-1-hydroxy-5,7-dimethyladamantane.
Elimination pathway: Memantine is partially metabolized in the liver. Approximately 48% of the administered drug is excreted unchanged in the urine; the remainder is primarily converted into three polar metabolites with very low antagonistic activity against NMDA receptors: N-glucuronide conjugate, 6-hydroxymemantine, and 1-nitrosodeaminomemantine. These are also primarily excreted unchanged in the urine.
Half-life: 60-100 hours

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Biological Half-life
The terminal elimination half-life of memantine in humans is 60 to 80 hours. In rats, after a single oral administration of 10 mg/kg memantine, the elimination half-life was 2.36 ± 0.20 hours. In rats, after a single intravenous injection of 2 mg/kg memantine, 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 Uses: Memantine is an oil-based medication. It is used to treat moderate to severe Alzheimer's disease. Memantine works by blocking NMDA receptors. Human Exposure and Toxicity: Clinical trials and global market experience indicate that the most common signs and symptoms of memantine overdose (alone or in combination with other medications and/or alcohol) include: agitation, weakness, bradycardia, confusion, coma, dizziness, ECG changes, elevated blood pressure, drowsiness, loss of consciousness, psychosis, restlessness, bradykinesia, somnolence, stupor, unsteady gait, visual hallucinations, vertigo, vomiting, and weakness. One patient has reported renal impairment and hyperkalemia possibly associated with memantine administration. Two Alzheimer's patients have been reported to have experienced recurrent loss of consciousness after long-term memantine use, with symptoms resolving upon discontinuation. Little is known about the cardiovascular effects of memantine, but its use has been reported to be associated with bradycardia and reduced cardiovascular survival. In human lymphocyte chromosome aberration assays, memantine showed no in vitro genotoxicity. Animal studies: In newborn mice, memantine treatment temporarily improved the formation of hippocampal-dependent memories. In rats, memantine administration significantly reduced ethanol-related behavioral changes in a dose-dependent manner. Memantine showed no genotoxicity in in vitro Salmonella or E. coli reverse mutation assays, in vivo cytogenetic assays of chromosome damage in rats, and in vivo micronucleus assays in mice. Results of in vitro gene mutation assays using Chinese hamster V79 cells were unclear. Memantine exerts its effect through non-competitive NMDA receptor antagonism, preferentially binding to NMDA receptor-activated cation channels. Long-term elevated glutamate levels in the brains of dementia patients are sufficient to counteract the voltage-dependent blockade of NMDA receptors by Mg²⁺ ions, allowing continuous influx of Ca²⁺ ions into cells, ultimately leading to neuronal degeneration. Studies have shown that memantine binds more strongly to NMDA receptors than to Mg²⁺ ions, effectively blocking the continuous influx of Ca²⁺ ions through NMDA channels while preserving the transient physiological activation of the channel by synaptic-released glutamate. Therefore, memantine can protect the brain from the effects of chronically elevated glutamate levels. Memantine exhibits antagonistic activity against type 3 serotonin (5-HT3) receptors, with potency similar to its antagonistic activity against NMDA receptors, but lower antagonistic activity against nicotinic acetylcholine receptors. The drug has no affinity for γ-aminobutyric acid (GABA), benzodiazepines, dopamine, adrenergic, histamine, or glycine receptors, as well as voltage-dependent calcium, sodium, or potassium channels.
Hepatotoxicity
In large placebo-controlled trials, the incidence of elevated serum enzymes during memantine treatment was similar to that in the placebo group, and no clinically significant cases of liver injury were reported. However, since mimantine was introduced into clinical use, at least one clinically significant case of hepatotoxicity has been reported in connection with this drug. The onset time was 3 weeks, with clinical manifestations of acute cholestatic hepatitis, mild to moderate in severity, which was rapidly reversible upon discontinuation of the drug (Case 1). No immune hypersensitivity or autoimmune features were observed. Probability score: D (likely a rare cause of clinically significant liver injury). Protein binding: The protein binding rate of mimantine is approximately 45%. Interactions: Protein-bound drugs: Due to the low plasma protein binding rate of mimantine (45%), pharmacokinetic interactions with drugs with high protein binding rates (e.g., digoxin, warfarin) are unlikely.
Drugs secreted via the renal tubular cation transport system: When memantine is co-administered with drugs secreted via the same renal cation transport system (e.g., cimetidine, hydrochlorothiazide, metformin, nicotine, quinidine, ranitidine, triamterene), pharmacokinetic interactions may occur (altering the plasma concentrations of both drugs). However, co-administration of memantine with fixed-dose formulations of hydrochlorothiazide and triamterene did not affect the bioavailability of memantine or triamterene; the peak plasma concentration and area under the plasma concentration-time curve (AUC) of hydrochlorothiazide decreased by only 20%. Furthermore, co-administration of memantine with fixed-dose formulations of glibenclamide and metformin hydrochloride did not affect the pharmacokinetics of memantine, metformin, or glibenclamide, and the hypoglycemic effect of the glibenclamide-metformin combination was also unaffected.
Alkalinizing agents: When memantine is used in combination with drugs that can increase urine pH (e.g., carbonic anhydrase inhibitors, sodium bicarbonate), the clearance of memantine may be reduced, thereby increasing the incidence of adverse reactions. Caution should be exercised when using this medication. Under alkaline urine conditions (i.e., pH 8), the clearance of memantine is reduced by approximately 80%.
Cholinesterase inhibitors: The combination of memantine and the acetylcholinesterase inhibitor donepezil does not affect the pharmacokinetics of either drug, nor does it significantly alter the inhibitory effect of donepezil on acetylcholinesterase. In a 24-week clinical study in patients with moderate to severe Alzheimer's disease, the adverse reactions observed with memantine in combination with donepezil were similar to those observed with donepezil alone. In vitro and animal studies have shown that memantine does not affect the reversible inhibitory effect of donepezil, galantamine, or tacrine on acetylcholinesterase.
For more complete data on memantine (9 drug interactions), 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
Anti-Parkinson's disease drugs; dopaminergic drugs; excitatory amino acid antagonists. ClinicalTrials.gov is a registry and results database that lists human clinical studies funded by public and private institutions worldwide. The website is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each record on ClinicalTrials.gov includes a summary of the study protocol, including: the disease or condition; the intervention (e.g., the medical product, behavior, or procedure under investigation); the title, description, and design of the study; participation requirements (eligibility criteria); the location of the study; contact information for the study location; and links to relevant information from other health websites, such as the NLM's MedlinePlus (for providing patient health information) and PubMed (for providing citations and abstracts of academic articles in the medical field). Memantine is listed in the database. Memantine hydrochloride is used to relieve symptoms of moderate to severe Alzheimer's disease (AD) dementia. /US Product Label Includes/
/Therapeutic Use/ Besides cognitive impairment and brain degeneration, visual impairment and retinal damage are also common in Alzheimer's disease (AD) patients. Memantine (MEM), a non-competitive antagonist of the N-methyl-D-aspartate receptor, has been shown to improve cognitive function in AD patients. However, information regarding the neurodegenerative mechanisms of MEM on the retina in AD patients and its possible neuroprotective mechanisms is currently limited. In this study, using APPswe/PS1deltaE9 double transgenic (dtg) mice, we found that meropenem (MEM) can rescue the loss of retinal ganglion cells (RGCs) and improve visual impairment, including increasing the latency of the P50 component in pattern electroretinography (PEG) and the P2 component in visual evoked potentials (VEP). MEM also inhibits activated microglia in the retina of APPswe/PS1deltaE9 dtg mice. Furthermore, MEM inhibited the level of glutamine synthase expressed in Müller cells in the RGC layer of APPswe/PS1deltaE9 dtg mice. Simultaneously, MEM reduced apoptosis of cholinergic adenoid cells that were immunoreactive in choline acetyltransferase in the RGC layer of AD mice. Additionally, in APPswe/PS1deltaE9 dtg mice, phosphorylation levels of extracellular regulated protein kinases 1 and 2 were elevated, and mimantine treatment blocked this elevation. These findings suggest that mimantine protects the RGC in the retina of APPswe/PS1deltaE9 dtg mice by modulating the immune response of microglia and the adaptive response of Müller cells, making mimantine a potential ophthalmic treatment alternative for AD patients.
For more complete data on the therapeutic uses of mimantine (out of 11), please visit the HSDB record page.
Drug Warning
FDA Pregnancy Risk Category: B/No evidence of risk to humans. Although adverse reactions have been observed in animals, adequate, well-controlled studies in pregnant women have not shown an increased risk of fetal malformations; or, in the absence of adequate human studies, animal studies have shown no fetal risk. The possibility of fetal harm is small, but it still exists. It is unclear whether memantine is excreted into breast milk. However, because many drugs are excreted into breast milk, caution is advised for breastfeeding women taking memantine. Memantine has not been systematically evaluated in patients with epilepsy. In clinical studies, 0.2% of patients taking memantine and 0.5% of patients taking placebo experienced seizures. The safety and efficacy of memantine in children have not been established. For more complete data on drug warnings for memantine (12 of them), please visit the HSDB record page. Pharmacodynamics General Actions This drug inhibits the influx of calcium ions into cells, which is normally caused by chronic activation of NMDA receptors by glutamate. This may improve symptoms of Alzheimer's disease dementia, manifested as cognitive enhancement and other beneficial central nervous system effects. Effects on Neuroplasticity Like other NMDA receptor antagonists, high-dose memantine can reduce synaptic plasticity in neurons involved in learning and memory. At clinically used lower concentrations, memantine can enhance synaptic plasticity in the brain, improve memory, and provide neuroprotection against neuronal damage caused by excitatory neurotransmitters. Effects on Multiple Receptors Memantine exhibits very low activity against GABA, benzodiazepine, dopamine, adrenergic, histamine, and glycine receptors, as well as voltage-dependent Ca2+, Na+, or K+ channels. The drug has antagonistic activity against 5HT3 receptors. Laboratory studies have shown that memantine does not affect the reversible inhibition of acetylcholinesterase typically induced by donepezil, galantamine, or tacrine. Memantine (3,5-dimethyladamantane-1-amine) is an orally potent, non-competitive N-methyl-D-aspartate receptor (NMDAR) antagonist approved for the treatment of moderate to severe Alzheimer's disease (AD), a neurodegenerative disease characterized by progressive cognitive decline. However, memantine, along with other approved acetylcholinesterase inhibitors (AChEIs) for AD, only alleviate symptoms. Therefore, a pressing need in AD drug development is to develop disease-modifying therapies, which may require targeting multiple pathways or multiple targets simultaneously. Indeed, mounting evidence suggests that modulating only a single neurotransmitter system is an oversimplification for addressing the complexity of AD. Memantine is considered a specific NMDAR-targeting structure and is therefore a core component in various multi-target ligand (MTDL) designs. This article reviews some recent examples of MTDL small molecules designed to combat Alzheimer's disease (AD), which combine the amantadine core structure of memantine with the pharmacophore features of known neuroprotective agents such as antioxidants, acetylcholinesterase inhibitors and Aβ aggregation inhibitors in a single entity. [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.)