Effects Of Memantine Research Articles

Anxiogenic and anxiolytic effects of memantine injected into the ventral hippocampus in male stressed mice.

The effects of intra-ventral hippocampal memantine administration in male NMRI stressed mice were studied. Two stainless steel gauge 23 guide cannulas were placed in the middle part of the mice ventral hippocampus using stereotaxic coordination. Seven days later, the animals were undergone to the stress protocol as follows: They experience four consecutive electro-foot shock stress sessions lasting for 10min. Five or 30min before each stress session, the animals received intra-ventral hippocampal (0.1, 1 and, 5µg/mouse) or intraperitoneal (1,5, and 10mg/kg) memantine respectively. Eight days after stress termination, the animals were tested either for the maintenance of either anxiety (elevated plus maze) or depression (forced swimming test). Animals show anxiety eight days after stress termination. Intra-ventral hippocampal infusion of memantine (5µg/mouse) 5min before stress inhibited the anxiety-like behaviors. However, other doses of the drug exacerbate the stress effect. The drug, when injected peripherally exacerbated the stress effect in all doses. The drug by itself had no effect. In addition, animals also show depression nine days after stress termination and memantine (0.1, 1, and 5µg/mouse) reduced the stress effect. The drug (0.1µg/mouse) by itself induced depression in the animals. However, the drug when injected peripherally reduced the stress effect in all doses. It could be concluded that NMDA glutamate receptors in the ventral hippocampus may play a pivotal role in the mediation of maintenance of anxiety and depression induced by stress in the mice.

Effect of memantine on the survival of an ischemic random skin flap and the underlying mechanism

BackgroundSkin flap transplantation is a common wound repair method in orthopedic surgery, but skin flap necrosis remains problematic. Memantine, an excitatory amino acid receptor antagonist, is currently used in the treatment of moderate to severe Alzheimer's disease, due to its ability to promote angiogenesis and reduce oxidative stress. This study investigated the effect of memantine on the survival of random skin flaps in Sprague-Dawley (SD) rats. Materials and methodsThirty six male SD rats were divided into control, high-dose (20 mg/kg per day), and low-dose (10 mg/kg per day) groups and underwent a McFarland flap procedure. Seven days later, the survival of the flap was evaluated, The microvascular density and neutrophil density were measured by hematoxylin and eosin staining. Lead angiography was used to detect angiogenesis, and laser Doppler was used to detect blood perfusion. Expression levels of vascular endothelial growth factor (VEGF), interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, Toll-like receptor (TLR) 4, nuclear factor kappa B(NF-κB) and Mitogen-activated protein kinase（MAPK）were detected by immunohistochemistry. Oxidative stress was evaluated by measuring the levels of malondialdehyde (MDA) and superoxide dismutase (SOD). ResultsCompared with the control group, the flap survival area of memantine group, especially the high-dose group, was larger, VEGF expression, microvascular density, angiogenesis, blood perfusion, and superoxide dismutase in the flap were higher in the Memantine-H group than in the Memantine-L and control groups (P < 0.01). In addition, levels of neutrophil density, IL-1β, IL-6, TNF-α, TLR4, NF-κB, MAPK and malondialdehyde decreased significantly in the Memantine-H group (P < 0.01). ConclusionsMemantine can promote the survival of skin flap in rats by improving the blood supply, promoting angiogenesis, inhibiting the inflammatory response, and reducing ischemia-reperfusion injury.

Neurocognitive Outcomes from Memantine: A Pilot, Double-Blind, Placebo-Controlled Trial in Children with Autism Spectrum Disorder.

Objective: Studies interrogating therapeutics which alter the excitation-inhibition balance in the treatment of autism spectrum disorder (ASD) have reported mixed results on social and behavioral outcomes. Methods: The aim of this randomized, double-blind placebo-controlled pilot trial was to evaluate neurocognitive effects of memantine over a 24-week trial. Twenty-three children ages 6-12 years old with ASD were randomized to memantine or placebo. Primary outcomes included measures of apraxia and expressive language with evaluations at midpoint (week 12) and endpoint (week 24). Secondary outcomes included memory and adaptive behavior measures. Exploratory outcomes included changes in overall cognitive functioning and behavior (e.g., Aberrant Behavior Checklist). Results: Results suggest that memantine was well-tolerated. Dropout rates were high across groups with only 14 participants completing the 6-month trial. Memantine was not associated with improvements in apraxia and expressive language. Treatment with memantine was associated with improvements in verbal recognition memory as measured by the Narrative Memory-Recognition (NEPSY-II) (F = 5.05, p = .03). In addition, exploratory analyses of changes in Intelligence quotient (IQ) suggest improvements on verbal IQ (d = 1.8). Conclusions: Results suggest future studies of memantine in ASD may benefit from shifting treatment targets from social and behavioral outcomes to exploration of effects of memantine on cognition, potentially as an adjunct to learning and educational interventions. ClinicalTrials.gov: NCT01372449.

Sleep-Prolonging Effect of Memantine for Short Periods and Low Doses

Among the antidementia drugs, only memantine has a sedative effect. In addition, it also has the effect of prolonging sleep time. However, there are no reports of prolonging sleep time upon commencement of the drugs. Therefore, this study was conducted to investigate the effect of memantine on sleep time for short periods and low doses upon commencement of the drugs. Patients included in this retrospective study were those who commenced therapy taking either memantine 5 mg once daily or galantamine 4 mg twice daily during hospitalization. Galantamine was used as a comparison. The evaluation was made by averaging the sleep time scores (1 to 5 points) for 3 days before and after commencement of the drugs. There was no difference in sleep time scores before commencement between the two groups [memantine group 4.3 (3.7–4.7)/galantamine group median 4.7 (interquartile range 3.3–4.7): p = 0.838]. The memantine group had significantly higher scores after commencement [memantine group 4.7 (4.3–5.0) galantamine group 4.3 (3.0–4.7): p = 0.036]. Memantine may have a sleep-prolonging effect for short periods and low doses.

Potentiation of cognitive enhancer effects of Alzheimer’s disease medication memantine by alpha7 nicotinic acetylcholine receptor agonist PHA-543613 in the Morris water maze task

RationaleThere are controversial pieces of evidence whether combination therapies using memantine and cholinesterase inhibitors are beneficial over their monotreatments. However, results of preclinical studies are promising when memantine is combined with agonists and allosteric modulators of the alpha7 nicotinic acetylcholine receptor (nAChR).ObjectivesHere, we tested the hypothesis that cognitive enhancer effects of memantine can be potentiated through modulating alpha7 nAChRs in a scopolamine-induced amnesia model.MethodsMonotreatments, as well as co-administrations of selective alpha7 nicotinic acetylcholine receptor agonist PHA-543613 and memantine were tested in the Morris water maze task in rats. The efficacy of the co-administration treatment was observed on different domains of spatial episodic memory.ResultsLow dose of memantine (0.1 mg/kg) and PHA-543613 (0.3 mg/kg) successfully reversed scopolamine-induced short-term memory deficits both in monotreatments and in co-administration. When recall of information from long-term memory was tested, pharmacological effects caused by co-administration of subeffective doses of memantine and PHA-543613 exceeded that of their monotreatments.ConclusionOur results further support the evidence of beneficial interactions between memantine and alpha7 nAChR ligands and suggest a prominent role of alpha7 nAChRs in the procognitive effects of memantine.

Effect of NMDA-receptors antagonist on serum lipid level under experimental hyperhomocysteinemia in diabetic hamsters

Background and Aims: Hyperhomocysteinemia is a common condition in a course of diabetes, obesity, metabolic syndrome and atherosclerosis. It is observed hyperstimulation of pancreatic NMDA-receptors by endogenous glutamate under metabolic disorders which intensified by another NMDA-agonist homocysteine, that impairs β-cell glucose-dependent insulin secretion. Insulin signal disorders and chronical hyperglycemia provoke atherogenic dyslipidemia. In current study, we have investigated the effect of NMDA-receptor antagonist memantine on lipids level in diabetic hamsters under experimental hyperhomocysteinemia.

Protective Effect of Memantine on Bergmann Glia and Purkinje Cells Morphology in Optogenetic Model of Neurodegeneration in Mice.

Spinocerebellar ataxias are a family of fatal inherited diseases affecting the brain. Although specific mutated proteins are different, they may have a common pathogenetic mechanism, such as insufficient glutamate clearance. This function fails in reactive glia, leading to excitotoxicity and overactivation of NMDA receptors. Therefore, NMDA receptor blockers could be considered for the management of excitotoxicity. One such drug, memantine, currently used for the treatment of Alzheimer’s disease, could potentially be used for the treatment of other forms of neurodegeneration, for example, spinocerebellar ataxias (SCA). We previously demonstrated close parallels between optogenetically induced cerebellar degeneration and SCA1. Here we induced reactive transformation of cerebellar Bergmann glia (BG) using this novel optogenetic approach and tested whether memantine could counteract changes in BG and Purkinje cell (PC) morphology and expression of the main glial glutamate transporter—excitatory amino acid transporter 1 (EAAT1). Reactive BG induced by chronic optogenetic stimulation presented increased GFAP immunoreactivity, increased thickness and decreased length of its processes. Oral memantine (~90 mg/kg/day for 4 days) prevented thickening of the processes (1.57 to 1.81 vs. 1.62 μm) and strongly antagonized light-induced reduction in their average length (186.0 to 150.8 vs. 171.9 μm). Memantine also prevented the loss of the key glial glutamate transporter EAAT1 on BG. Finally, memantine reduced the loss of PC (4.2 ± 0.2 to 3.2 ± 0.2 vs. 4.1 ± 0.3 cells per 100 μm of the PC layer). These results identify memantine as potential neuroprotective therapeutics for cerebellar ataxias.

Antitumorigenic Effect of Memantine via Interfering Glutamate Metabolism in Mouse 4T1 Breast Tumor Model.

Repurposing drug is an efficient strategy as the drug discovery process is timeconsuming, laborious and costly. Memantine is already used in Alzheimer's disease to prevent neurons from excess glutamate toxicity. As cancer cells benefit from higher amounts of cellular energetics like glucose and glutamine, we used memantine to interfere with the glutamate metabolism in order to restrict cancer cells' glutamine as a source for their growth. To investigate the potential antitumor effect of memantine by reducing glutamate levels in 4T1 mouse breast cancer model. 24 Balb/c female mice were subcutaneously inoculated with 4T1 cells. When tumors were palpable, memantine treatment was initiated as 5 and 10 mg/kg daily intraperitoneal injection. Tumor growth was recorded every 2-3 days. Tumor volumes, serum glutamate levels, spleen IL-6 levels, genome-wide DNA methylation levels and GSK3B. pGSK3B protein expressions were measured to enlighten the anticancer mechanism of action for memantine. We found that both two doses (5 and 10mg/kg) decreased tumor growth rates and serum glutamate levels significantly (p<0.05). 10mg/kg treatment increased spleen IL-6 levels (p<0.05) and decreased genomewide DNA methylation levels. Memantine treatment decreased GSK3B protein expression levels in tumor tissue samples. To the best of our knowledge, this is the first study that investigates the antitumor activity of memantine in a breast cancer tumor model. Our results suggest a potent anticancer mechanism of the action for memantine. Memantine decreased genome wide methylation and serum glutamate levels that are associated with a poor prognosis. Therefore, Memantine might be used for targeting glutamine metabolism in cancer treatment.

The effects of memantine on the serum concentrations of matrix metalloproteinases and neurologic function of patients with ischemic stroke

Memantine was suggested as a promising treatment for stroke due to its neuroprotective property and efficacy in reducing ischemic brain injury and improving post-ischemic neurological recovery. This pilot, open-label, randomized clinical trial was conducted to investigate the impact of memantine on serum concentrations of matrix metalloproteinases (MMP)-2 and MMP-9, as neuronal damage biomarkers, and neurologic function evaluated by the National Institute of Health Stroke Scale(NIHSS) and Barthelindex(BI) in patients with ischemic stroke. Admitted patients with mild to moderate ischemic stroke were assessed for eligibility, and eligible patients were randomized to the intervention or control group. Enrolled patients in the intervention group received 20 mg memantine every 8 h for five days and then 20 mg daily for three months. Both groups managed with the standard treatments. From 77 randomized patients, 29 participants in the control group and 24 patients in the intervention group completed the study. Data showed that the increase in the serum concentrations of MMP-9 within the first 5 days of the study was significantly lower in the intervention group (P = 0.005). This effect of memantine on the MMP-2 was not significant (P = 0.448). memantine also could significantly improve the neurologic function of the patients according to NIHSS (P < 0.0001) and BI (P = 0.002) during hospitalization and after that. In conclusion, memantine could be considered as a neuroprotective agent in patients with mild to moderate ischemic stroke, based on its significant effects on reducing brain damage and improving neurologic function of the patients.

Insight into Glutamatergic Involvement in Rewarding Effects of Mephedrone in Rats: In Vivo and Ex Vivo Study

Mephedrone is a widely used drug of abuse, exerting its effects by interacting with monoamine transporters. Although this mechanism has been widely studied heretofore, little is known about the involvement of glutamatergic transmission in mephedrone effects. In this study, we comprehensively evaluated glutamatergic involvement in rewarding effects of mephedrone using an interdisciplinary approach including (1) behavioural study on effects of memantine (non-selective NMDA antagonist) on expression of mephedrone-induced conditioned place preference (CPP) in rats; (2) evaluation of glutamate concentrations in the hippocampus of rats following 6 days of mephedrone administration, using in vivo magnetic resonance spectroscopy (MRS); and (3) determination of glutamate levels in the hippocampus of rats treated with mephedrone and subjected to MRS, using ion-exchange chromatography. In the presented research, we confirmed priorly reported mephedrone-induced rewarding effects in the CPP paradigm and showed that memantine (5 mg/kg) was able to reverse the expression of this effect. MRS study showed that subchronic mephedrone administration increased glutamate level in the hippocampus when measured in vivo 24 h (5 mg/kg, 10 mg/kg and 20 mg/kg) and 2 weeks (5 mg/kg and 20 mg/kg) after last injection. Ex vivo chromatographic analysis did not show significant changes in hippocampal glutamate concentrations; however, it showed similar results as obtained in the MRS study proving its validity. Taken together, the presented study provides new insight into glutamatergic involvement in rewarding properties of mephedrone.

Possible Antidepressant Effects of Memantine-Systematic Review with a Case Study.

The treatment of bipolar depression is hampered by the inadequate efficacy of antidepressants, moderate effect of mood stabilizers, and the side effects of some second-generation antipsychotics. There is limited evidence to date regarding the antidepressant effects of memantine in bipolar depression. The aim of the article was to provide a short review of preclinical and clinical studies on the antidepressant effect of memantine, and to present the case of a bipolar depression patient successfully treated with memantine. The described patient with bipolar disorder was unsuccessfully treated with two mood stabilizers. The addition of memantine at a dose of 20 mg/d to the treatment with lamotrigine and valproic acid resulted in a reduction in the severity of depression measured on the HDRS-17 scale by 35%, and by 47.1% after 7 weeks. The discussion presents experimental evidence for the antidepressant effect of memantine, as well as data from clinical trials in recurrent and bipolar depression. The presented case is the second report in the medical literature showing the antidepressant effect of memantine as an add-on treatment for bipolar depression. The described case and literature analysis indicate that memantine may be an effective and safe method of augmentation of mood stabilizing therapy in bipolar depression.

The Organic Cation Transporter 2 Inhibitor Quinidine Modulates the Neuroprotective Effect of Nerve Growth Factor and Memantine on Cholinergic Neurons of the Basal Nucleus of Meynert in Organotypic Brain Slices

Introduction: Alzheimer’s disease (AD) is a severe neurodegenerative disorder of the brain characterized by degeneration of cholinergic neurons which is directly linked to cognitive decline. Nerve growth factor (NGF) is the most potent protective factor for cholinergic neurons, additionally the NMDA antagonist memantine blocks glutamate-mediated excitotoxic activity. Quinidine is an inhibitor of organic cation transporter 2 (OCT2). OCT2 is located on cholinergic neurons and plays a role in presynaptic reuptake and recycling of acetylcholine in the brain. We hypothesize that quinidine can modulate the protective effects of NGF and memantine on cholinergic neurons in organotypic brain slices of the nucleus basalis of Meynert (nBM). Methods: Organotypic brain slices of nBM were incubated with 100 ng/mL NGF, 10 µM memantine, 10 µM quinidine, and combinations of these treatments for 2 weeks. Cholinergic neurons were immunohistochemically stained for choline acetyltransferase (ChAT). Results: Our data show that NGF as well as memantine counteracted the cell death of cholinergic nBM neurons. Quinidine alone had no toxic effect on cholinergic neurons but inhibited the protective effect of NGF and memantine when applied simultaneously. Discussion/Conclusion: Our data provide evidence that quinidine modulates the survival of cholinergic nBM neurons via OCT2.

Effects of Akatinol Memantine on Gait Disturbances at the Developed Stages of Parkinson’s Disease

Effects of Akatinol Memantine on Gait Disturbances at the Developed Stages of Parkinson’s Disease

The Efficacy of Memantine for the Treatment of Migraine: A Meta-Analysis of Randomized Controlled Studies.

The efficacy of memantine for migraine remains controversial. We conduct a systematic review and meta-analysis to explore the influence of memantine versus placebo on treatment in migraine patients. We search PubMed, EMbase, Web of science, EBSCO, and Cochrane library databases through February 2020 for randomized controlled trials assessing the effect of memantine versus placebo on treatment efficacy in migraine patients. This meta-analysis is performed using the random-effect model. Three randomized controlled trials are included in the meta-analysis. Overall, compared with control group in migraine patients, memantine treatment is associated with substantially reduced monthly attack frequency (mean difference [MD], -2.14; 95% confidence interval [CI], -2.83 to -1.46; P < 0.00001), number of migraine days (MD, -4.17; 95% CI, -6.40 to -1.93; P = 0.0003) and Migraine Disability Assessment (MD, -5.63; 95% CI, -6.46 to -4.79; P < 0.00001), but demonstrates no obvious influence on acute pain medications (MD, -1.23; 95% CI, -4.63 to 2.17; P = 0.48). Memantine treatment may benefit to the control of migraine.

Beneficial effects of memantine on ischemia/reperfusion injury following torsion/detorsion induced testicular damage in rats: Improvement in histological and biochemical parameters

Testicular torsion is a common urologic emergency and one of the causes of infertility in males. Hence, prompt diagnosis and treatment are important to prevent testicular damages. It has been reported that memantine, a drug for Alzheimer's disease has anti-oxidative role against cerebral ischemic stroke and cardiac ischemia reperfusion. In this experimental study, the effects of memantine on a testicular torsion injury in adolescent rat testis after ischemia/reperfusion (I/R) were evaluated. Thirty-six adolescent rats were divided into three groups with 12 rats per group including sham-operated, T/D (torsion/detorsion)+vehicle, and T/D+memantine (10mg/kg). Testicular torsion was induced for 2h by rotating right testis 7200 in the clockwise direction. In treated group 30min before detorsion, a single intraperitoneal dose of memantine was administered. After 4h of reperfusion, orchiectomy was conducted and Histopathological and biochemical evaluations of testicular tissue samples were performed. The malondialdehyde level in the T/D group was significantly greater than in the sham operated group. Moreover, the testicular malondialdehyde values in the T/D+memantine group were significantly lower than in the T/D group. Also, significant decreases occurred in catalase and superoxide dismutase activities in the T/D group compared with sham operated group. These values were significantly greater in the memantine group than in the T/D group. Furthermore, after induction of T/D, histopathological evaluations also revealed severe testicular damages which were improved by memantine administration. Memantine prevented increases in oxidative stress markers and reductions of antioxidants during I/R injury in the current study. Subsequently the histologic injury was reduced in rats treated with memantine. The antioxidant characteristics of memantine and its protective effects have been shown in our study. These results suggest that administration of memantine before detorsion prevents I/R cellular damage in testicular torsion. This drug probably acts through reduction of reactive oxygen species and support antioxidant enzyme systems.

An Updated Review on Memantine Efficacy in Reducing Cognitive Dysfunction of Whole-brain Irradiation for Adult Patients with Brain metastasis

Context: Increased survival of patients with cancer raises the need to pay attention to long-term side effects. Patients with brain metastasis experienced cognition failure after whole-brain radiotherapy. This review aimed at concluding the efficacy of Memantine in preserving cognitive function by reducing the brain toxicity of whole-brain radiotherapy for metastatic brain cancers. Evidence Acquisition: Published studies evaluating memantine protective effects during brain metastasis radiotherapy were searched for in scientific databases (e.g., Embase, PubMed, Cochrane database, Google Scholar, Scopus) using keywords including whole-brain radiotherapy and Memantine. Results: A total of 4 prospective clinical trials were included in the review. Effects of Memantine on cognition tests were evaluated in these trials. A significantly better Hopkins Verbal Learning Test-Revised (HVLT-R) delayed recognition at months 6 was achieved in RTOG 0614 and NRG CC001. Longer time to cognitive decline was found in the memantine arm of the RTOG trial and was statistically significant. Memantine effects were not statistically significant before 2 months. Conclusions: It seems reasonable to consider Memantine during radiation to prevent long-term cognitive failure in patients with brain metastasis due to the current results. Memantine improves cognition function during whole-brain radiotherapy (WBRT) without adding irreparable complications.

Effect of memantine on calcium signaling in hippocampal neurons cultured with β-amyloid

Alzheimer’s disease (AD) is the most common type of dementia and is characterized by accumulating amyloid (Aβ) plaques and neurofibrillary tangles in the brain. Excessive stimulation of glutamate receptors, mainly NMDA-type, causes intense entry of calcium ions into cells and is a key early step in glutamateinduced excitotoxicity, resulting in many neurological diseases, including AD. Memantine, an NMDA receptor antagonist, blocks NMDA receptors and reduce the influx of calcium ions into neuron. In our experiments, we have modeled AD on cultured rat hippocampal neurons to test the effects of memantine on calcium signaling in neurons. Our results show that the neuroprotective effect of memantine could be provided not only through the inhibition of NMDA receptor current but also through the suppression of voltage-dependent Ca2+ channels, most likely L-type. This study suggests that NMDA receptor antagonist memantine can protect hippocampal neurons from calcium overloading induced by Aβ1–42 amyloid exposure via blocking Ca2+ channels

Effects of memantine and its metabolite Mrz 2/373 on soman-induced inhibition of acetylcholinesterase in vitro

Memantine is the non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist, used in the treatment of Alzheimer's disease. It is also known that memantine pretreatment assured protection of skeletal muscles from poisoning with nerve agents and an interaction between memantine and AChE was proposed. In the study presented we examined interactions of memantine and its main metabolite (1-amino-3-hydroxymethyl-5-methyl adamantine, Mrz 2/373) with AChE in vitro as well as their effect on kinetics of the soman-induced AChE inhibition and aging. The results have shown that memantine and Mrz 2/373 exerted concentration-dependent inhibition of AChE, with Mrz 2/373 being a more potent inhibitor than the parent compound. Addition of soman 7.5 nmol/l induced gradual AChE inhibition that became almost complete after 20 min. Memantine (0.1, 0.5 and 1 mmol/l) and Mrz 2/373 (0.1, 0.5 and 1 mmol/l) concentration-dependently slowed down the AChE inhibition. After 30 min of incubation of AChE with soman, 5 min of aging and 20 min of reactivation by asoxime (HI-6 dichloride), AChE activity was 8.1% in control medium, 30.7% and 41.9% after addition of 1 and 10 mmol/l memantine, and 16.1% after addition of 1 mmol/l Mrz 2/373. It was concluded that it is possible that memantine and Mrz 2/373 can prevent AChE from inhibition by soman, which could, along with known memantine's neuroprotective activity, explain its potent antidotal effect in soman poisoning. The potential effect on aging of the soman-AChE complex warrants further studies.

Novel Mechanism for Memantine in Attenuating Diabetic Neuropathic Pain in Mice via Downregulating the Spinal HMGB1/TRL4/NF-kB Inflammatory Axis.

Diabetic neuropathic pain (DNP) is a common diabetic complication that currently lacks an efficient therapy. The aim of the current work was to uncover the anti-allodynic and neuroprotective effects of memantine in a model of mouse diabetic neuropathy and its ameliorative effect on the high-mobility group box-1 (HMGB1)/toll-like receptor 4 (TLR4)/nuclear factor-k B (NF-kB) inflammatory axis. Diabetes was prompted by an alloxan injection (180 mg/kg) to albino mice. On the ninth week after diabetes induction, DNP was confirmed. Diabetic mice were randomly allocated to two groups (six mice each); a diabetes mellitus (DM) group and DM+memantine group (10 mg/kg, daily) for five weeks. DNP-related behaviors were assessed in terms of thermal hyperalgesia and mechanical allodynia by hot-plate and von Frey filaments. Enzyme-linked immunosorbent assay (ELISA) kits were used to measure the spinal glutamate, interleukin-1 beta (IL-1β), and tumor necrosis factor-α (TNF-α). The spinal levels of N-methyl-D-aspartate type 1 receptor (NMDAR1), HMGB1, TLR4, and phosphorylated NF-kB were assessed using Western blotting. Histopathological investigation of the spinal cord and sciatic nerves, together with the spinal cord ultrastructure, was employed for assessment of the neuroprotective effect. Memantine alleviated pain indicators in diabetic mice and suppressed excessive NMDAR1 activation, glutamate, and pro-inflammatory cytokine release in the spinal cord. The current study validated the ability of memantine to combat the HMGB1/TLR4/NF-kB axis and modulate overactive glutamate spinal transmission, corroborating memantine as an appealing therapeutic target in DNP.

Effect of Memantine on QT/QTc Interval in a Healthy Korean Population.

Studies on the effects of memantine on QT prolongation have yielded conflicting results. For a long time, memantine was reported to be a safe drug without QT prolongation; however, several case studies have reported memantine-induced QT prolongation in Alzheimer's patients. This study evaluated the relationship between memantine blood levels, and QT interval changes. Over a 2-week period, we orally administered 20 mg of memantine daily to achieve a steady state in 57 healthy Korean subjects. We measured and analyzed the QT interval and blood memantine concentrations simultaneously before and after treatment, as well as 2 weeks after the last dosing. Correlation analysis was done between blood memantine level and QT interval. No serious adverse events occurred during the study period. Repeated dosing of memantine did not show clinically significant QT interval changes after treatment. Regression analysis was performed based on the results; there was no statistical association between memantine blood level and QT prolongation. In conclusion, the results of the present study demonstrated no clinically significant changes in the QT interval with therapeutic blood levels of memantine.