Effects Of Memantine Research Articles

RESOLUTION OF INAPPROPRIATE SEXUAL BEHAVIOR IN AN ELDERLY MALE WITH MAJOR NEUROCOGNITIVE DISORDER AND DEVELOPMENTAL DELAY WITH MEMANTINE

RESOLUTION OF INAPPROPRIATE SEXUAL BEHAVIOR IN AN ELDERLY MALE WITH MAJOR NEUROCOGNITIVE DISORDER AND DEVELOPMENTAL DELAY WITH MEMANTINE

Memantine treatment prevents okadaic acid induced neurotoxicity at the systemic and molecular levels

The present study was designed to investigate the effects of okadaic acid intracerebroventricular (ICV) injection on memory function and expression level of α7 subunit of nicotinic acetylcholine receptor (nAChR) and NR2B subunit of NMDA glutamate receptors in the hippocampus, as well as effect of the antidementic drug memantine on okadaic acid induced changes at systemic and molecular levels in rats. Okadaic acid was dissolved in artificial cerebrospinal fluid (aCSF) and injected ICV 200 ng/10 μl. Vehicle control received 10 μl of aCSF ICV bilaterally. Control and okadaic acid injected rats were divided into two subgroups: treated i.p. with saline or memantine (5 mg/kg daily for 13 days starting from the day of okadaic acid injection). Rats were trained in the dual-solution plus-maze task that can be solved by using place or response strategies. The Western immunoblotting was used to determine relative amount of hippocampal receptors protein levels. Obtained data revealed that okadaic acid ICV injected rats were severely impaired at acquiring the place version of the maze accompanied by significant decline in hippocampal α7 subunit of nACh receptors protein levels. Memantine treatment can prevent okadaic acid induced impairment of hippocampal-dependent spatial memory and accompanied by modulation of the expression level of α7 subunit of nACh and NR2B subunit of NMDA receptors in the hippocampus. Thus, our results support the presumption that α7 nACh receptors may play an important role in the cognitive enhancer effects of memantine and emphasize the role of cholinergic-glutamatergic interactions in memory.

Memantine Effects on Electroencephalographic Measures of Putative Excitatory/Inhibitory Balance in Schizophrenia

BackgroundAbnormalities in cortical excitation and inhibition (E/I) balance are thought to underlie sensory and information processing deficits in schizophrenia. Deficits in early auditory information processing mediate both neurocognitive and functional impairment and appear to be normalized by acute pharmacologic challenge with the NMDA antagonist memantine (MEM). MethodsThirty-six subjects with a diagnosis of schizophrenia and 31 healthy control subjects underwent electroencephalographic recordings. Subjects ingested either placebo or MEM (10 or 20 mg) in a double-blind, within-subject, crossover, randomized design. The aperiodic, 1/f-like scaling property of the neural power spectra, which is thought to index relative E/I balance, was estimated using a robust linear regression algorithm. ResultsPatients with schizophrenia had greater aperiodic components compared with healthy control subjects (p < .01, d = 0.64), which was normalized after 20 mg MEM. Analysis revealed a significant dose × diagnosis interaction (p < .0001, d = 0.82). Furthermore, the MEM effect (change in aperiodic component in MEM vs. placebo conditions) was associated with baseline attention and vigilance (r = .54, p < .05) and MEM-induced enhancements in gamma power (r = −.60, p < .01). ConclusionsFindings confirmed E/I balance abnormalities in schizophrenia that were normalized with acute MEM administration and suggest that neurocognitive profiles may predict treatment response based on E/I sensitivity. These data provide proof-of-concept evidence for the utility of E/I balance indices as metrics of acute pharmacologic sensitivity for central nervous system therapeutics.

Randomized trial to assess safety/feasibility of memantine administration during residential treatment for alcohol use disorder: a pilot study

The N-methyl-D-aspartate receptor (NMDAr) system is critically involved in the pathogenesis and neurobehavioral sequelae of alcohol use disorder (AUD), and constitutes a potential pharmacotherapeutic target. Memantine (Namenda) is an FDA-approved NMDAr antagonist with suggested utility in AUD, however its safety and tolerability during long-term administration among recently-detoxified patients remains uncharacterized. This pilot study assessed safety, feasibility, and several secondary measures of interest, during a 4-week period of residential AUD treatment. Participants (N = 18) met diagnostic criteria for AUD. A double-blind, placebo-controlled, escalating-dose design was utilized. Assessments of medication side-effects were conducted weekly. At intake, week 2, and study completion, participants completed a battery assessing affective symptomatology, craving, and neurocognitive function. Medication groups reported equivalent side effects and severity. Medication compliance was high, and did not differ by group. No memantine effects were observed in secondary outcome measures. Memantine maintains a profile of high tolerability and low side-effects during post-detoxification AUD treatment. These data suggest a more aggressive dosing/escalation schedule may be used safely in future trials designed to ascertain improvements in neurocognitive function, affect, and/or craving as primary measures.

Alzheimer's drug Memantine inhibits metastasis and p-Erk protein expression on 4T1 breast cancer cells.

Drug repurposing studies enable shorter routes to the clinic by skipping the steps like in vitro in vivo screening, chemical optimization and toxicological studies. In our study, we investigated the potent anti-cancer effect of Alzheimer's drug Memantine on 4T1 breast cancer cells. Memantine's effect on proliferation of 4T1 cells was evaluated by using the MTT assay. Memantine inhibited 4T1 cell proliferation in a concentration- dependent manner at 24 and 48 hours. We investigated the drug's effect on the protein expressions of Bax, Bcl-2, Casp-3, Casp-9, E-Cad, Vimentin, B-Cat, GSK3B, p-ERK, ERK, p-GS, GS that are involved in apoptosis, metastasis and cell survival. Memantine altered the Bcl-2, Bax, Casp3, Casp-9 apoptotic protein expression levels. We found that memantine inhibited p-Erk expression and that result suggested a plausible mechanism of action for memantine's antineoplastic effect. Memantine also inhibited wound closure at 24 h, significantly (p = 0.0055). Memantine inhibited 4T1 breast cancer cell proliferation at significantly lower doses than mostly studied re-purposed drug Metformin. Therefore, we believe that memantine might hold a great promise as a new repositioned drug in cancer treatment and it is our further interest to investigate its effects in vivo (Fig. 3, Ref. 22).

Effect of Artesunate vs Memantine in Aluminum Chloride Induced Model of Neurotoxicity in Rats

Alzheimer disease is one of the commonest neurological diseases which is characterized by amyloid plaques accumulation in multiple brain regions. This study investigated the potential neuroprotective effect of artesunate on aluminum induced neurotoxicity vs memantine in rats. 40 male albino Wistar rats were divided randomly into 4 groups as follow: Group 1 negative control, group 2 positive control group induced by ammonium chloride, group 3 rats treated by NH4Cl + artesunate solution, group 4 rats treated by NH4Cl + memantine S.C. spatial Memory and Learning were evaluated using Morris Water Maze (MWM) test. Malondialdehyde (MDA) and reduced glutathione (GSH) levels were measured in cerebral cortex tissue homogenate. Tumor necrosis factor-α (TNFα) and interleukin-1 beta (IL-1β) concentrations were measured in rat cerebral cortex tissue homogenate using rat enzyme linked immunosorbent assay (ELISA) kits. Real-time quantitative reverse transcription-polymerase chain reaction (Real-time qRT-PCR) for Caspase-3, Bcl-2 and iNOS gene expression was measured in rat cerebral cortex. Slices from cerebral cortex were studied by histopathological examination. Artesunate significantly decreased MDA level and inhibited iNOS, caspase and upregulated Bcl-2 gene expression in cerebral cortex. ART increased significantly antioxidant level GSH, and decreased significantly TNF-alpha and IL-B levels. It reduced significantly 1ry retention latency, 2ry retention latency and initial acquisition latency. It also improved brain histopathology and decreased amyloid plaque deposition. ART exerted neuroprotective effect through oxidative stress correction and enhancement of antiapoptotic markers in neuronal cells of the cerebral cortex.

Repurposing of Adamantanes with Transmitter Receptor Antagonist Properties for the Prevention/Treatment of COVID-19

Members of the adamantane family of agents in general and two such members, amantadine and memantine, in particular, have established beneficial actions across a wide range of infectious diseases including those caused by coronaviruses. Increasing evidence suggests that the protective effects of these agents is the result of actions on neurotransmitter systems namely the NMDA receptor subclass of the glutamatergic system and by the α7-nACh subclass of nicotinic cholinergic receptor. The potent NMDA receptor antagonist, memantine, prevents motor disabilities and reduces replication of the neuroinvasive/neurotropic human respiratory virus HCoV-OC43 dose-dependently. Moreover, the lysosomotrophic adamantanes amantadine and memantine also limit viral replication. Known lysomotrophic agents such as ammonium chloride inhibit cellular entry of SARS-CoV-2 on laboratory testing. Inhibiting clathrinmediated endocytosis (cellular entry) of the SARS-CoV-2/ACE2 complex by amantadine or rimantadine may block viral entry into vulnerable cellular populations, and also reduce platelet activating factor-priming of Polymorphonuclear [PMN] cells, potentially lessening PMN cell-mediated tissue damage and excess Neutrophil Extracellular Traps [NETs] seen in advanced cases of COVID-19. Rimantadine has inhibitory effects of SARS-CoV-1, a closely-related virus to SARS-CoV-2, which may indicate the need for further evaluation as a treatment for COVID-19. Amantadine increases Dopamine [DA] release and blocks its reuptake, increasing its action on DA receptors on T cells thus activating resting effector T cells and suppressing regulator T cells, which may have a beneficial immunomodulating function in infectious diseases. Proposed adverse effects of smoking on COVID-19 outcomes are attributed to the effects of nicotine via the α7-nACh receptor located on bronchial and alveolar epithelial cells. As an antagonist of this receptor, memantine has the potential to prevent the entry of SARSCoV- 2 into these cells. Independent case reports provide evidence of protective effects of amantadine and/or memantine against COVID-19. Additional epidemiologic studies however indicate a lower incidence of smoking in hospitalized patients, stimulating investigations of nicotine-related aspects, and amino acid sequence analysis indicate homologous sequences with those of neurotoxins seen in snake venoms blocking the α7-nAChR suggesting that COVID-19 may be a disease of the nicotinic cholinergic system; α7-nAChR is involved in the cholinergic anti-inflammatory pathway or reflex. COVID-19 is a biphasic disease, the initial aspect involved with the initial infection and viral replication which stimulates a prominent innate immune response. This then transitions to the adaptive immune response with suppression of infection and recovery, while the innate response is suppressed via the cholinergic anti-inflammatory pathway. Severe disease may occur when the initial innate immune response continues, the cholinergic anti-inflammatory pathway being arrested by the neurotoxin inherent in the viral amino acid sequence, causing a runaway innate immune response. Memantine, being an inhibitor of α7-nACHR, could possibly make COVID-19 worse should it be α7-nACHR inhibitor. Tilorone, a lysosomotrophic agent and α7-nACHR agonist could also have potential as a treatment for COVID-19. Further studies are necessary to determine whether repurposing of adamantanes is beneficial in COVID-19, and for further investigations of pharmacological and pathophysiological properties of SARS-CoV-2.

Effect of donepezil and memantine on improvement of cognitive function in patients with temporal lobe epilepsy

Background:Cognitive impairment is a common complication of patients with temporal lobe epilepsy (TLE). Therefore, the aim of this study was to compare the effects of donepezil and memantine on improving the cognitive function of patients with TLE.Materials and Methods:In a clinical trial study, 70 patients with TLE were divided into two groups of 35 each: 10 mg doses of donepezil (first group) and memantine (second group) were applied for 16 weeks. The level of cognitive function of patients in both groups before and after treatment was determined using Montreal Cognitive Assessment (MoCA) test.Results:The mean score of MoCA before and after intervention was 23.55 ± 3.67 and 26.09 ± 2.5, respectively, in the group treated with memantine, and the mean score of intervention was significantly improved (P < 0.001). In the group treated with donepezil, the score before and after the operation was 23.87 ± 3.18 and 24.35 ± 2.17, respectively, and no significant difference was observed in this group (P = 0.38).Conclusion:Hence, memantine was better than donepezil in the improvement of cognitive impairment in patients with TLE.

Targeting Cancer Cell Metabolism with Metformin, Dichloroacetate and Memantine in Glioblastoma (GBM).

To investigate the effects of metformin, dichloroacetate (DCA), and memantine on T98G and U87-MG human glioblastoma (GBM) cells to target tumor cell metabolism in a multi-directional manner. IC50 levels for metformin, DCA, metformin+DCA and memantine were determined by MTT assay in T98G and U87-MG cells in vitro. Casp3, Bcl-2, Bax, c-Myc and GSK-3B protein expressions were investigated post treatments. Fifteen GBM+ tumor tissues were assessed for Casp-3, Bcl-2, Bad, Bax for apoptotic protein expression patterns. Cancer cell metabolism targeting drugs metformin, DCA, metformin+DCA and memantine induced cytotoxicity in a dose-dependent manner in T98G and U87-MG cells. IC50 for memantine is found as 0.5 mM (p < 0.01) which is nearly 10 times lower concentration than that of metformin. Fifteen GBM+ tumor tissues had differential apoptotic protein expressions. Memantine exerted anti-cancer mechanism of action in T98G and U87-MG cells, however, such a mechanism requires deeper investigation for GBM treatment.

Gamma radiation preparation of chitosan nanoparticles for controlled delivery of memantine.

The purpose of the current study is to prepare chitosan nanoparticles by gamma radiation as a new brain delivery system for memantine to improve its therapeutic efficiency. Fourier-transform infrared analysis of chitosan nanoparticles showed the characteristic peaks of chitosan and the reduction of particle size induced by irradiation at doses 10, 20 and 30 kGy. The solubility of chitosan nanoparticles was tested using different solvents and exhibited good solubility in both water and 1% acetic acid than other tested solvents at 80°C. Different formulations containing memantine -loaded chitosan nanoparticles were evaluated for brain targeting on aluminum-induced Alzheimer’s disease in rats. Memory deficit was evaluated using the Morris water maze test. The levels of amyloid-β peptide, tumour necrosis factor alpha, interleukin-1β and interleukin-6 in brain tissues as well as the serum level of brain-derived neurotrophic factor were assayed. Data demonstrated that memantine -loaded chitosan nanoparticles 1:1 transported memantine effectively into the brain compared to free memantine as evidenced by better behaviour performance and biochemical amelioration and confirmed by histopathological examination in Alzheimer’s disease rats. Interestingly, the therapeutic effect of memantine -loaded chitosan nanoparticles 1:1 was superior to memantine -loaded chitosan nanoparticles 1:2 and memantine -loaded chitosan nanoparticles 2:1. Based on these findings, it is reasonable to suggest that memantine -loaded chitosan nanoparticles 1:1 could be a promising approach for Alzheimer’s disease.

Memantine Mitigates Oligodendrocyte Damage after Repetitive Mild Traumatic Brain Injury

Repetitive mild traumatic brain injury (rmTBI; e.g., sports concussions) is common and results in significant cognitive impairment, white matter injury and increased risk of neurodegeneration. Targeted therapies for rmTBI are lacking, though evidence from other injury models indicates that targeting N-methyl-d-aspartate (NMDA) receptor (NMDAR)-mediated glutamatergic toxicity might mitigate rmTBI-induced injury. We have previously shown that the NMDAR antagonist memantine lessens axonal injury and restores long term potentiation after rmTBI. Here, we evaluated whether the protective effects of memantine include oligodendrocyte specific mechanisms, as prior studies suggest that oligodendrocytes are particularly vulnerable to glutamatergic toxicity. Mice were subjected to rmTBI injury (5 injuries in 5 days) and randomized to treatment with memantine or with vehicle (n = 32/group). At the molecular level, oligodendrocyte counts and function (myelin basic protein, MBP) were assessed by immunohistochemistry and western blot at days 3, 7 and 28 days after the last injury. Axon integrity was assessed by neurofilament light chain (NF-l) expression and axonal ultrastructure was evaluated by electron microscopy. Compared to vehicle-treated mice, memantine-treated mice were protected against oligodendrocyte loss and decreased MBP expression at subacute time points after injury. Memantine treatment also protected against axon damage assessed by NF-l expression. These data suggest that the therapeutic effects of post-concussive NMDAR antagonism may in part work through oligodendrocyte specific mechanisms, which may have implications for long term neurodegenerative sequelae after multiple concussions.

Adjunctive memantine for opioid use disorder treatment: A systematic review

Memantine is commonly used for the treatment of moderate-to-severe Alzheimer's disease. Due to its antagonism of the N-methyl-d-aspartate (NMDA) receptor, which has been shown to block rewarding and reinforcing effects of morphine, memantine has been investigated for potential utilization in opioid use disorder (OUD). The objective of this systematic review is to assess the evidence available to determine the safety and efficacy of memantine as treatment for OUD. Pubmed (1946-August 2019) and Embase (1947-August 2019) were queried using the following search terms: opioid-related disorders, opioids, substance withdrawal syndrome, withdrawal syndrome, opiate addiction, opiate, opiate dependence, opiate substitution treatment, managed opioid withdrawal, or drug withdrawal and memantine. After assessing studies appropriate for the objective, one single-blind and five double-blind, placebo-controlled trials were included. Of the included studies, four demonstrated beneficial effects of memantine either as monotherapy or adjunct to methadone or buprenorphine on reducing opioid cravings and methadone dose, increasing retention rates, and improving cognitive performance in patients with OUD. Two studies did not show benefit on patient retention rates with memantine adjunct to naltrexone. Study durations ranged from 3 to 13 weeks, and memantine dosing ranged from 5 to 60 mg/day. Memantine was well tolerated with similar rates of adverse effects between treatment groups. Based on the reviewed literature, memantine appears most beneficial as an adjunctive treatment for OUD when combined with methadone or buprenorphine, but not naltrexone. Larger studies with longer periods of treatment and follow-up are needed to support the use of memantine in the management of OUD.

The effect of memantine, an antagonist of the NMDA glutamate receptor, in in vitro and in vivo infections by Trypanosoma cruzi.

Chagas disease, caused by Trypanosoma cruzi, is a neglected tropical disease that affects 5–6 million people in endemic areas of the Americas. Presently, chemotherapy relies on two compounds that were proposed as trypanocidal drugs four decades ago: nifurtimox and benznidazole. Both drugs are able to eliminate parasitemia and to avoid seroconversion in infected people when used in the acute phase; however, their use in the chronic phase (the time when the majority of cases are diagnosed) is limited due to their serious side effects. Memantine is a glutamate receptor antagonist in the central nervous system of mammals that has been used for the treatment of Alzheimer’s disease. Our group previously reported memantine as a trypanocidal drug that is able to induce apoptosis-like death in T. cruzi. In the present work, we further investigated the effects of memantine on the infection of RAW 264.7 macrophages and in vivo (in BALB/c mice). Here, we showed that memantine is able to diminish NO and Ca2+ entry in both LPS-activated and non-activated cells. These results, together with the fact that memantine was also able to reduce the infection of macrophages, led us to propose that this drug is able to activate a pro-oxidant non-NO-dependent cell defense mechanism. Finally, infected mice that were treated with memantine had diminished parasitemia, cardiac parasitic load, and inflammatory infiltrates. In addition, the treated mice had an increased survival rate. Taken together, these results indicate memantine to be a candidate drug for the treatment of Chagas disease.

THE EFFECTIVENESS OF MEMANTINE ADMINISTRATON IN PATIENTS WITH NON-DEMENTIA COGNITIVE IMPAIRMENT. THE RESULTS OF A MULTICENTRE CLINICAL FOLLOW-UP STUDY

Memantine is a reversible N-methyl-D-a spartate (NMDA) receptor blocker. The paper reports the results of an investigation aimed at the assessment of memantine effectiveness, safety and tolerability in patients with non-dementia cognitive impairment. Two hundred and forty (240) patients were enrolled in this open-label, comparative, multicentre study. In these subjects cognitive disorders were less severe than dementia (MMSE score made up 22—27). Mean age was 69.2 + 5.7 years old. Among them 148 patients received acatinol memantine at a dosage of 20 mg daily within 6 months and 92 subjects comprised a comparison group. Memantine administration resulted in decreased severity of cognitive impairment, first of all due to the improvement of dysregulatory, mnestic and visual-spatial disorders. Besides, the treatment caused the alleviation of emotional disturbances. The degree of therapeutic effectiveness was independent from the presence or lack of cardiovascular diseases in the examined population. Further double-blind studies aimed at the assessment of memantine effectiveness in patients with non-dementia cognitive impairment are necessary.

Memantine Attenuates Salicylate-induced Tinnitus Possibly by Reducing NR2B Expression in Auditory Cortex of Rat.

Memantine, a noncompetitive antagonist of the N-methyl-d-aspartate (NMDA) receptor, suppresses the release of excessive levels of glutamate that may induce neuronal excitation. Here we investigated the effects of memantine on salicylate-induced tinnitus model. The expressions of the activity-regulated cytoskeleton-associated protein (ARC) and tumor necrosis factor-alpha (TNF α) genes; as well as the NMDA receptor subunit 2B (NR2B) gene and protein, were examined in the SH-SY5Y cells and the animal model. We also used gap-prepulse inhibition of the acoustic startle reflex (GPIAS) and noise burst prepulse inhibition of acoustic startle, and the auditory brainstem level (electrophysiological recordings of auditory brainstem responses, ABR) and NR2B expression level in the auditory cortex to evaluate whether memantine could reduce salicylate-mediated behavioral disturbances. NR2B was significantly upregulated in salicylate-treated cells, but downregulated after memantine treatment. Similarly, expression of the inflammatory cytokine genes TNFα and immediate-early gene ARC was significantly increased in the salicylate-treated cells, and decreased when the cells were treated with memantine. These results were confirmed by NR2B immunocytochemistry. GPIAS was attenuated to a significantly lesser extent in rats treated with a combination of salicylate and memantine than in those treated with salicylate only. The mean ABR threshold in both groups was not significant different before and 1 day after the end of treatment. Additionally, NR2B protein expression in the auditory cortex was markedly increased in the salicylate-treated group, whereas it was reduced in the memantine-treated group. These results indicate that memantine is useful for the treatment of salicylate-induced tinnitus.

Neuroprotective effects of memantine via enhancement of autophagy

IntroductionChemical intervention of autophagy has been investigated in clinical trials for various age-related conditions such as sarcopenia and neurodegeneration. However, at present, no autophagy inducer has been established as a disease-modifying agent against neurodegenerative diseases. MethodsWe screened a library consisting of 796 medicines clinically approved (in Japan) for autophagy enhancers as potential neurodegeneration therapeutics using HeLa cells stably expressing green fluorescent protein-microtubule-associated protein light chain 3 (GFP-LC3) followed by an analysis of the molecular mechanisms using various neuronal models. ResultsThe primary screening identified 152 hits in a static cellular state. A widely available Alzheimer's disease drug, memantine, which antagonizes N-Methyl-d-aspartate receptor (NMDAR), was one of the hits. Memantine increased the levels of LC3-II in a dose-dependent and time-dependent manner, and upregulated autophagic flux. In addition, the pharmacological effects of memantine on autophagy were independent of mTORC1 activity and NMDAR activation. Furthermore, a VPS34 inhibitor suppressed the memantine-induced LC3-II upregulation, suggesting that memantine may affect VPS34 complex activity. Notably, intracellular Huntington's disease-specific aggregates of elongated huntingtin, a well-established autophagy substrate, were significantly decreased by memantine. In addition, memantine enhanced elimination of degraded mitochondrial in neurons derived from induced pluripotent stem cells of PARK2 or PARK6 patients, who exhibited defective PINK1/parkin-mediated mitophagy, suggests that memantine accelerated the clearance of damaged mitochondria. ConclusionThese findings indicate that memantine may be beneficial for the treatment of neurodegeneration characterized by the abnormal accumulation of autophagy or mitophagy substrates.

Chronic memantine decreases nicotine self-administration in rats

Neurobehavioral bases of tobacco addiction and nicotine reinforcement are complex, involving more than only nicotinic cholinergic or dopaminergic systems. Memantine is an NMDA glutamate antagonist used to improve cognitive function in people with Alzheimer's disease. Glutamate may be an important component of the reinforcing effects of nicotine, so memantine was evaluated as a potential smoking cessation aid. Two studies were conducted with adult female rats, one testing acute effects of memantine over a range of doses for changing nicotine self-administration and the other testing the chronic effects of memantine to reduce nicotine self-administration. Acute memantine injections slightly, but significantly, increased nicotine self-administration in a dose-related manner. In contrast, chronic memantine treatment significantly reduced nicotine self-administration. During the first day of memantine administration in the chronic study, nicotine self-administration was significantly elevated replicating the acute study. Starting in the second week of treatment there was a significant reduction of nicotine self-administration relative to controls. This was seen because memantine treatment prevented the increase in nicotine self-administration shown by controls. There even continued to be a memantine-induced lowered nicotine self-administration during the week after the cessation of memantine treatment. Memantine or other drugs affecting NMDA glutamate receptors may be useful aids to smoking cessation. Full efficacy for reducing nicotine self-administration was seen as the NMDA drug treatment is given chronically. Importantly, the effect persisted even after treatment is ended, indicating the high potential for NMDA glutamate receptors to impact nicotine addiction.

Improvement of PTSD-like behavior by the forgetting effect of hippocampal neurogenesis enhancer memantine in a social defeat stress paradigm

Post-traumatic stress disorder (PTSD) is a psychiatric disorder associated with memories of traumatic experiences. Recent studies have shown that the forgetting of contextual fear memory is promoted via increased adult hippocampal neurogenesis induced by neurogenesis enhancers, such as memantine (MEM) and exercise, raising the possibility that neurogenesis enhancers improve PTSD by facilitating the forgetting of traumatic memory. On the other hand, repeated exposure to social defeat (SD) stress by aggressor mice induces social avoidance behavior to the aggressor and chronic anxiety-like behavior. In this study, we assumed this SD stress paradigm as a PTSD-like model and examined the effects of treatment with neurogenesis enhancer MEM on SD stress-induced PTSD-like behavior. Male C57BL/6 mice received SD stress for 10 consecutive days and were assessed for social avoidance memory to the aggressor (memory of aggressor mice) and anxiety-like behavior using social interaction and elevated zero maze tasks. Consistent with previous studies, SD mice formed social avoidance memory and exhibited increased anxiety-like behavior. Importantly, subsequent MEM treatment (once a week for 4 weeks) significantly reduced social avoidance behavior, suggesting that MEM-treated SD mice showed forgetting of social avoidance memory. Interestingly, MEM-treated SD mice showed comparable anxiety-like behavior with control mice that were not exposed to SD stress. Moreover, MEM-treated SD mice showed no reinstatement of social avoidance memory following single re-exposure to the aggressor. Our findings suggest that neurogenesis enhancer not only enhanced the forgetting of traumatic memory but also improved PTSD (anxiety)-like behavior.

Chronic memantine administration prevents ouabain-induced hyperactivity in mice via maintenance of Na+, K+-ATPase activity in the hippocampus

We have previously reported that mice received intracerebroventricular injection of ouabain, an inhibitor of Na+, K+-ATPase, exhibited hyperactivity via overactivation of glutamatergic neurons. Here we investigated the effects of memantine, a blocker of N-methyl-d-aspartate receptors, on ouabain-induced hyperactivity. In mice that received ouabain injection, chronic memantine administration prevented the hyperactivity and the decrease in the Na+, K+-ATPase activity in the hippocampus. Memantine also protected neurons without affecting glial activation in the hippocampus of these mice. Our results suggest that memantine improves hyperactivity via the maintenance of Na+, K+-ATPase activity and neurons in the hippocampus in this mouse model.

Acute and chronic effects of single dose memantine after controlled cortical impact injury in adult rats.

Altered glutamatergic neurotransmission after traumatic brain injury (TBI) contributes to excitotoxic cell damage and death. Prevention or suppression of such changes is a desirable goal for treatment of TBI. Memantine (3,5-dimethyl-1-adamantanamine), an uncompetitive NMDA receptor antagonist with voltage-dependent open channel blocking kinetics, was reported to be neuroprotective in preclinical models of excitotoxicity, brain ischemia, and in TBI when administered prophylactically, immediately, or within minutes after injury. The current study examined effects of memantine administered by single intraperitoneal injection to adult male rats at a more clinically relevant delay of one hour after moderate-severe controlled cortical impact (CCI) injury or sham surgery. Histopathology was assessed on days 1, 7, 21, and 90, vestibulomotor function (beam balance and beam walk) was assessed on days 1-5 and 71-75, and spatial memory (Morris water maze test, MWM) was assessed on days 14-21 and 83-90 after CCI injury or sham surgery. When administered at 10 mg/kg, but not 2.5 or 5 mg/kg, memantine preserved cortical tissue and reduced neuronal degeneration 1 day after injury, and attenuated loss of synaptophysin immunoreactivity in the hippocampus 7 days after injury. No effects of 10 mg/kg memantine were observed on histopathology at 21 and 90 days after CCI injury or sham surgery, or on vestibulomotor function and spatial memory acquisition assessed during any of the testing periods. However, 10 mg/kg memantine resulted in trends for improved search strategy in the MWM memory retention probe trial. Administration of memantine at a clinically-relevant delay after moderate-severe CCI injury has beneficial effects on acute outcomes, while more significant improvement on subacute and chronic outcomes may require repeated drug administration or its combination with another therapy.