Spectrum of NMDA Receptor Variants in Neurodevelopmental Disorders and Epilepsy.

N-methyl-D-aspartate receptors (NMDAR) are ligand-gated ion channels mediating excitatory neurotransmission and are important for normal brain development, cognitive abilities, and motor functions. Pathogenic variants in the Glutamate receptor Ionotropic N-methyl-D-aspartate (GRIN) genes (GRIN1, GRIN2A-D) encoding NMDAR subunits have been associated with a wide spectrum of neurodevelopmental disorders and epilepsies ranging from treatable focal epilepsies to devastating early-onset developmental and epileptic encephalopathies. Genetic variants in NMDA receptor genes can cause a range of complex alterations to receptor properties resulting in various degrees of loss-of-function, gain-of-function, or mixtures thereof. Understanding how genetic variants affect the function of the receptors, therefore, represents an important first step in the ongoing development towards targeted therapies. Currently, targeted treatment options for GRIN-related diseases are limited. However, treatment with memantine has been reported to significantly reduce seizure frequency in a few individuals with developmental and epileptic encephalopathies harboring de novo gain-of-function GRIN2A missense variants, and supplementary treatment with L-serine has been associated with improved motor and cognitive performance as well as reduced seizure frequency in patients with GRIN2B loss-of-function missense variants as well as GRIN2A and GRIN2B null variants.

Cholinesterase inhibitors and memantine are associated with a reduced mortality in nursing home residents with dementia: a longitudinal observational study.

BACKGROUND: A large proportion of nursing home (NH) residents suffer from dementia and effects of conventional anti-dementia drugs on their health is poorly known. We aimed to investigate the associations between exposure to anti-dementia drugs and mortality among NH residents. METHODS: This retrospective longitudinal observational study involved 329 French NH and the residents admitted in these facilities since 2014 and having major neurocognitive disorder. From their electronic health records, we obtained their age, sex, level of dependency, Charlson comorbidity index, and Mini mental examination score at admission. Exposure to anti-dementia drugs was determined using their prescription into 4 categories: none, exposure to acetylcholinesterase inhibitors (AChEI) alone, exposure to memantine alone, exposure to AChEI and memantine. Survival until the end of 2019 was studied in the entire cohort by Cox proportional hazards. To alleviate bias related to prescription of anti-dementia drugs, we formed propensity-score matched cohorts for each type of anti-dementia drug exposure, and studied survival by the same method. RESULTS: We studied 25,358 NH residents with major neurocognitive disorder. Their age at admission was 87.1 + 7.1 years and 69.8% of them were women. Exposure to anti-dementia drugs occurred in 2,550 (10.1%) for AChEI alone, in 2,055 (8.1%) for memantine alone, in 460 (0.2%) for AChEI plus memantine, whereas 20,293 (80.0%) had no exposure to anti-dementia drugs. Adjusted hazard ratios for mortality were significantly reduced for these three groups exposed to anti-dementia drugs, as compared to reference group: HR: 0.826, 95%CI 0.769 to 0.888 for AChEI; 0.857, 95%CI 0.795 to 0.923 for memantine; 0.742, 95%CI 0.640 to 0.861 for AChEI plus memantine. Results were consistent in propensity-score matched cohorts. CONCLUSION: The use of conventional anti-dementia drugs is associated with a lower mortality in nursing home residents with dementia and should be widely used in this population.

Targeting the autophagy-NAD axis protects against cell death in Niemann-Pick type C1 disease models.

Impairment of autophagy leads to an accumulation of misfolded proteins and damaged organelles and has been implicated in plethora of human diseases. Loss of autophagy in actively respiring cells has also been shown to trigger metabolic collapse mediated by the depletion of nicotinamide adenine dinucleotide (NAD) pools, resulting in cell death. Here we found that the deficit in the autophagy-NAD axis underpins the loss of viability in cell models of a neurodegenerative lysosomal storage disorder, Niemann-Pick type C1 (NPC1) disease. Defective autophagic flux in NPC1 cells resulted in mitochondrial dysfunction due to impairment of mitophagy, leading to the depletion of both the reduced and oxidised forms of NAD as identified via metabolic profiling. Consequently, exhaustion of the NAD pools triggered mitochondrial depolarisation and apoptotic cell death. Our chemical screening identified two FDA-approved drugs, celecoxib and memantine, as autophagy activators which effectively restored autophagic flux, NAD levels, and cell viability of NPC1 cells. Of biomedical relevance, either pharmacological rescue of the autophagy deficiency or NAD precursor supplementation restored NAD levels and improved the viability of NPC1 patient fibroblasts and induced pluripotent stem cell (iPSC)-derived cortical neurons. Together, our findings identify the autophagy-NAD axis as a mechanism of cell death and a target for therapeutic interventions in NPC1 disease, with a potential relevance to other neurodegenerative disorders.

Evaluating the efficacy and safety of Alzheimer's disease drugs: A meta-analysis and systematic review.

BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder. Dementia severity was assessed mainly through cognitive function, psychobehavioral symptoms, and daily living ability. Currently, there are not many drugs that can be selected to treat mild to moderate AD, and the value of drugs remains controversial. OBJECTIVE: The aim of this study is to quantitatively evaluate the efficacy and safety of cholinesterase inhibitors (ChEIs), memantine, and sodium oligomannate (GV-971) in the treatment of patients with AD. Additionally, molecular docking analysis will be used to investigate the binding affinities of donepezil, galantamine, rivastigmine, and memantine with key receptor proteins associated with AD, including beta-amyloid (Abeta), microtubule-associated protein (MAP), apolipoprotein E4 (APOE4), and Mitofusin-2 (MFN2), to further validate the results of the meta-analysis. METHODS: We obtained clinical trials characterized by randomization, placebo control, and double-blinded methodologies concerning ChEIs, memantine, and GV-971. Statistical analysis was performed using Review Manager Version 5.4 software. Molecular docking was also conducted to evaluate the results. RESULTS: All drugs improved the cognitive function, with the effect value ranging from -1.23 (95% CI -2.17 to -0.30) for 20 mg memantine to -3.29 (95% CI -4.14 to -2.45) for 32 mg galantamine. Although 32 mg galanthamine and GV-971 did not improve the clinicians' Global Impression of Change scale, other drugs showed significant results compared with placebo. On NPI, only 10 mg of donepezil and 24 mg of galantamine had improvement effects. On ADCS/ADL, only 20 mg memantine and 900 mg GV-971 had no significant difference from the placebo. Donepezil 5 mg and GV-971 900 mg did not increase the drug withdrawal rates due to various reasons or adverse reactions when compared to the placebo. Donepezil demonstrated superior binding to the protein and exhibited greater efficacy compared to other drugs. CONCLUSION: ChEIs, memantine, and GV-971 all can slow the progression of AD but have different effects on respective assessments. Donepezil and GV-971 were relatively well tolerated.

γ-Oryzanol from Rice Bran Antagonizes Glutamate-Induced Excitotoxicity in an In Vitro Model of Differentiated HT-22 Cells.

The excessive activation of glutamate in the brain is a factor in the development of vascular dementia. γ-Oryzanol is a natural compound that has been shown to enhance brain function, but more research is needed to determine its potential as a treatment for vascular dementia. This study investigated if γ-oryzanol can delay or improve glutamate neurotoxicity in an in vitro model of differentiated HT-22 cells and explored its neuroprotective mechanisms. The differentiated HT-22 cells were treated with 0.1 mmol/L glutamate for 24 h then given γ-oryzanol at appropriate concentrations or memantine (10 µmol/L) for another 24 h. Glutamate produced reactive oxygen species and depleted glutathione in the cells, which reduced their viability. Mitochondrial dysfunction was also observed, including the inhibition of mitochondrial respiratory chain complex I activity, the collapse of mitochondrial transmembrane potential, and the reduction of intracellular ATP levels in the HT-22 cells. Calcium influx triggered by glutamate subsequently activated type II calcium/calmodulin-dependent protein kinase (CaMKII) in the HT-22 cells. The activation of CaMKII-ASK1-JNK MAP kinase cascade, decreased Bcl-2/Bax ratio, and increased Apaf-1-dependent caspase-9 activation were also observed due to glutamate induction, which were associated with increased DNA fragmentation. These events were attenuated when the cells were treated with γ-oryzanol (0.4 mmol/L) or the N-methyl-D-aspartate receptor antagonist memantine. The results suggest that γ-oryzanol has potent neuroprotective properties against glutamate excitotoxicity in differentiated HT-22 cells. Therefore, γ-oryzanol could be a promising candidate for the development of therapies for glutamate excitotoxicity-associated neurodegenerative diseases, including vascular dementia.

Detection and analysis of signals of adverse events of memantine based on the US food and drug administration adverse event reporting system.

BACKGROUND: Despite its widespread use, the adverse effects (AEs) of memantine have not been well documented, and there is a need to find new ways to analyze the AEs of memantine. RESEARCH DESIGN AND METHODS: AEs in which the primary suspected drug was memantine were retrieved from the FAERS database. The proportional report ratio (PRR), reporting odds ratio (ROR), Bayesian confidence propagation neural network (BCPNN), and empirical Bayesian geometric mean (EBGM) were used to detect potential positive signals between memantine and AEs. SAS, MySQL, EXCEL, and R language software were used for data processing and statistical analysis. RESULTS: This study gathered a total of 5808 reports of AEs associated with memantine. Of these reports, a greater proportion of female patients (51.17%) than male patients (36.33%) had AEs. The AEs reported by FAERS were mainly in psychiatric category (n = 2157, IC025 = 2.69), various neurologic disorders (n = 1608, IC025 = 2.04), systemic disorders and various site reactions (n = 842, IC025 = 1.29). Unexpected ocular adverse events have been reported, ophthalmic vein thrombosis (n = 4, IC025 = 3.47) and scleral discolouration (n = 7, IC025 = 3.1), which may worsen glaucoma. CONCLUSIONS: This study observed conceivable new AEs signals and may supply important assist for scientific monitoring and threat identification of memantine.

Memantine suppresses the excitotoxicity but fails to rescue the ataxic phenotype in SCA1 model mice.

Spinocerebellar ataxia type 1 (SCA1) is a debilitating neurodegenerative disorder of the cerebellum and brainstem. Memantine has been proposed as a potential treatment for SCA1. It blocks N-methyl-D-aspartate (NMDA) receptors on neurons, reduces excitotoxicity and decreases neurodegeneration in Alzheimer models. However, in cerebellar neurodegenerative diseases, the potential value of memantine is still unclear. We investigated the effects of memantine on motor performance and synaptic transmission in the cerebellum in a mouse model where mutant ataxin 1 is specifically targeted to glia. Lentiviral vectors (LVV) were used to express mutant ataxin 1 selectively in Bergmann glia (BG). In mice transduced with the mutant ataxin 1, chronic treatment with memantine improved motor activity during initial tests, presumably due to preserved BG and Purkinje cell (PC) morphology and numbers. However, mice were unable to improve their rota rod scores during next days of training. Memantine also compromised improvement in the rota rod scores in control mice upon repetitive training. These effects may be due to the effects of memantine on plasticity (LTD suppression) and NMDA receptor modulation. Some effects of chronically administered memantine persisted even after its wash-out from brain slices. Chronic memantine reduced morphological signs of neurodegeneration in the cerebellum of SCA1 model mice. This resulted in an apparent initial reduction of ataxic phenotype, but memantine also affected cerebellar plasticity and ultimately compromised motor learning. We speculate that that clinical application of memantine in SCA1 might be hampered by its ability to suppress NMDA-dependent plasticity in cerebellar cortex.

Impact of NMDA receptors block versus GABA-A receptors modulation on synaptic plasticity and brain electrical activity in metabolic syndrome.

PURPOSE: Metabolic syndrome (MetS) is a common disorder associated with disturbed neurotransmitter homeostasis. Memantine, an N-methyl-d-aspartate receptor (NMDAR) antagonist, was first used in Alzheimer's disease. Allopregnanolone (Allo), a potent positive allosteric modulator of the Gamma-Amino-Butyric Acid (GABA)-A receptors, decreases in neurodegenerative diseases. The study investigated the impact of Memantine versus Allo administration on the animal model of MetS to clarify whether the mechanism of abnormalities is related more to excitatory or inhibitory neurotransmitter dysfunction. MATERIALS AND METHODS: Fifty-six male rats were allocated into 7 groups: 4 control groups, 1 MetS group, and 2 treated MetS groups. They underwent assessment of cognition-related behavior by open field and forced swimming tests, electroencephalogram (EEG) recording, serum markers confirming the establishment of MetS model and hippocampal Glial Fibrillary Acidic Protein (GFAP) and Brain-Derived Neurotrophic Factor (BDNF). RESULTS: Allo improved anxiety-like behavior and decreased grooming frequency compared to Memantine. Both drugs increased GFAP and BDNF expression, improving synaptic plasticity and cognition-related behaviors. The therapeutic effect of Allo was more beneficial regarding lipid profile and anxiety. We reported progressive slowing of EEG waves in the MetS group with Memantine and Allo treatment with increased relative theta and decreased relative delta rhythms. CONCLUSIONS: Both Allo and Memantine boosted the outcome parameters in the animal model of MetS. Allo markedly improved the anxiety-like behavior in the form of significantly decreased grooming frequency compared to the Memantine-treated groups. Both drugs were associated with increased hippocampal GFAP and BDNF expression, indicating an improvement in synaptic plasticity and so, cognition-related behaviors.

Uso de antipsicóticos en los pacientes con demencia en España: comparación con la prescripción de los inhibidores de la acetilcolinesterasa y de la memantina, y análisis de las asociaciones / Use of antipsychotics in patients with dementia in Spain: Comparison with prescription of acetylcholinesterase inhibitors and memantine and analysis of associations

Objetivo: Se ha analizado la prevalencia de antipsicóticos, inhibidores de la acetilcolinesterasa (IACE) y memantina en pacientes con demencia en España y la influencia de estas asociaciones en su prescripción. Método: Estudio descriptivo, retrospectivo y transversal de la base BIFAP de 2017 en los mayores de 65 años con demencia. Se recogieron las prescripciones de antipsicóticos, los IACE y la memantina. Para los antipsicóticos también se recogieron, la duración del tratamiento y el tiempo desde el diagnóstico de demencia, al de prescripción. Resultados: Se recuperaron 1.327.792 sujetos, 89.464 (6,73%) con demencia. El 31,76% tuvieron prescritos antipsicóticos; los más frecuentes: quetiapina (58,47%), risperidona (21%) y haloperidol (19,34%). Las prescripciones de IACE y memantina fueron más frecuentes en los menores de 84 años y las de antipsicóticos en los mayores de 85 años (p<0,001). Los antipsicóticos se mantuvieron una media de 1.174,5 días. En el 26,4% de los casos se prescribieron aislados, OR: 0,61 (IC 95%: 0,59-0,62), en el 35,85% asociados a IACE, OR: 1,26 (IC 95%: 1,22-1,30) y en el 42,4% a memantina, OR: 1,69 (IC 95%: 1,62-1,78); p<0,000). Desde el diagnóstico de demencia transcurrieron de 461 días (±1.576,5) cuando se prescribieron aislados; 651 días (±1.574,25) asociados a IACE y 1.224 (±1.779) a memantina. Conclusiones: Una tercera parte de los pacientes con demencia tuvieron prescritos antipsicóticos, mayoritariamente atípicos, más frecuentemente en los mayores de 85 años y durante periodos prolongados. La prescripción de IACE y memantina se asoció al incremento del riesgo de uso de antipsicóticos, pero paradójicamente, a la prolongación del tiempo hasta su prescripción.(AU)

ObjectiveWe have analyzed the prevalence of antipsychotics in patients with dementia in Spain, their age distribution and the influence of treatment with IACEs and memantine on their prescription. Method: Descriptive, retrospective and cross-sectional study of the 2017 BIFAP database in over 65 years of age with dementia. Prescriptions of antipsychotics, IACEs and memantine were collected. For antipsychotics were also collected, the duration of treatment and time from dementia diagnosis to prescription. Results: A total of 1,327,792 subjects were retrieved, 89,464 (6.73%) with dementia. Antipsychotics were prescribed in 31.76%; by frequency: quetiapine (58.47%), risperidone (21%) and haloperidol (19.34%). Prescriptions of IACEs and memantine were clustered in those younger than 84 years and antipsychotics in those older than 85 (P<.001). Antipsychotics were maintained for a mean of 1174.5 days. In 26.4% of cases they were prescribed alone, OR 0.61 (95% CI: 0.59-0.62), in 35.85% associated with IACEs, OR 1.26 (95% CI: 1.22-1.30) and in 42.4% with memantine, OR 1.69 (95% CI: 1.62-1.78) (P<.000). From the diagnosis of dementia, 461 days (±1576.5) elapsed when isolated drugs were prescribed; 651 days (±1574.25) associated with IACEs and 1224 (±1779) with memantine. Conclusions: One third of patients with dementia were prescribed antipsychotics, mostly atypical, more frequently in those older than 85 years and for prolonged periods. IACEs and memantine were associated with the risk of antipsychotic prescription, but paradoxically, with prolonged time to onset.(AU)

[Multi-center open comparative randomized study of efficacy and safety of Akatinol Memantine 20 mg (single-doses) vs Akatinol Memantine 10 mg (double-doses) in patients with vascular dementia]. / Mnogotsentrovoe otkrytoe sravnitel'noe randomizirovannoe issledovanie effektivnosti i bezopasnosti primeneniya preparata Akatinol Memantin, 20 mg (odnokratnyi priem) v sravnenii s preparatom Akatinol Memantin, 10 mg (dvukratnyi priem) u patsientov s sosudistoi dementsiei.

OBJECTIVE: Evaluation of the efficacy and safety of the drug Acatinol Memantine, 20 mg (once daily) in comparison with the drug Acatinol Memantine, 10 mg (twice daily) in patients with moderate to moderate severe vascular dementia. MATERIAL AND METHODS: The study included 130 patients aged 50-85 years of both sexes with instrumentally and clinically confirmed vascular dementia. The patients were randomized into 2 groups. Group I consisted of 65 patients receiving Akatinol Memantine, 20 mg once daily, group II - 65 patients receiving Akatinol Memantine, 10 mg twice daily for 24 weeks. Clinical, parametric and statistical research methods were used. The Alzheimer's disease assessment scale, the cognitive subscale (ADAS-cog), the short mental Status Assessment Scale (MMSE) and the general clinical impression scale for patients condition and illness severity (CGI-C and CGI-S) and the Hamilton Depression Rating scale (HAM-D) were used. Adverse events were collected and analyzed. RESULTS: At week 24, both groups showed statistically significant positive change in ADAS-cog total score: in group I the total score was 27.2±8.76 points (absolute difference from baseline 3.5 points; p<0.01), and in group II - 26.1±7.86 points (absolute difference from baseline 2.5 points; p<0.01) with no statistically significant differences between groups. Evaluation of secondary efficacy criteria (change in ADAS-cog total score at week 12 and MMSE at weeks 4, 12, and 24) also revealed statistically significant benefit in both groups compared to baseline with no significant differences between groups. Statistically significant improvement was noticed on CGI-S and CGI-C scales in both groups. Akatinol Memantine was safe and well tolerated in both groups. CONCLUSION: The study showed no lesser efficacy and safety of Akatinol Memantine, 20 mg (once daily) compared to Akatinol Memantine, 10 mg (twice daily) in patients with moderate and moderately severe vascular dementia.

Dementia Prevention and Treatment: A Narrative Review.

Importance: Dementia affects 10% of those 65 years or older and 35% of those 90 years or older, often with profound cognitive, behavioral, and functional consequences. As the baby boomers and subsequent generations age, effective preventive and treatment strategies will assume increasing importance. Observations: Preventive measures are aimed at modifiable risk factors, many of which have been identified. To date, no randomized clinical trial data conclusively confirm that interventions of any kind can prevent dementia. Nevertheless, addressing risk factors may have other health benefits and should be considered. Alzheimer disease can be treated with cholinesterase inhibitors, memantine, and antiamyloid immunomodulators, with the last modestly slowing cognitive and functional decline in people with mild cognitive impairment or mild dementia due to Alzheimer disease. Cholinesterase inhibitors and memantine may benefit persons with other types of dementia, including dementia with Lewy bodies, Parkinson disease dementia, vascular dementia, and dementia due to traumatic brain injury. Behavioral and psychological symptoms of dementia are best treated with nonpharmacologic management, including identifying and mitigating the underlying causes and individually tailored behavioral approaches. Psychotropic medications have minimal evidence of efficacy for treating these symptoms and are associated with increased mortality and clinically meaningful risks of falls and cognitive decline. Several emerging prevention and treatment strategies hold promise to improve dementia care in the future. Conclusions and Relevance: Although current prevention and treatment approaches to dementia have been less than optimally successful, substantial investments in dementia research will undoubtedly provide new answers to reducing the burden of dementia worldwide.

ATP1A2-related epileptic encephalopathy and movement disorder: Clinical features of three novel patients.

OBJECTIVE: Variants in the ATP1A2 gene exhibit a wide clinical spectrum, ranging from familial hemiplegic migraine to childhood epilepsies and early infantile developmental epileptic encephalopathy (EIDEE) with movement disorders. This study aims to describe the epileptology of three unpublished cases and summarize epilepsy features of the other 17 published cases with ATP1A2 variants and EIDEE. METHODS: Medical records of three novel patients with pathogenic ATP1A2 variants were retrospectively reviewed. Additionally, the PUBMED, EMBASE, and Cochrane databases were searched until December 2023 for articles on EIDEE with ATP1A2 variants, without language or publication year restrictions. RESULTS: Three female patients, aged 6 months-10 years, were investigated. Epilepsy onset occurred between 5 days and 2 years, accompanied by severe developmental delay, intellectual disability, drug-resistant epilepsy, severe movement disorder, and recurrent status epilepticus. All individuals had pathogenic variants of the ATP1A2 gene (ATP1A2 c.720_721del (p.Ile240MetfsTer9), ATP1A2c.3022C > T (p.Arg1008Trp), ATP1A2 c.1096G > T (p.Gly366Cys), according to ACMG criteria. Memantine was p) rescribed to three patients, one with a reduction in ictal frequency, one with improvement in gait pattern, coordination, and attention span, and another one in alertness without significant side effects. SIGNIFICANCE: This study reinforces the association between ATP1A2 variants and a severe phenotype. All patients had de novo variants, focal motor seizures with impaired awareness as the primary type of seizure; of the 11 EEGs recorded, 10 presented a slow background rhythm, 7 multifocal interictal epileptiform discharges (IED), predominantly temporal IEDs, followed by frontal IED, as well as ten ictal recordings, which showed ictal onset from the same regions mentioned above. Treatment with antiseizure medication was generally ineffective, but memantine showed moderate improvement. Prospective studies are needed to enlarge the phenotype and assess the efficacy of NMDA receptor antagonist therapies in reducing seizure frequency and improving quality of life.

Harnessing memantine in Alzheimer's disease therapy through inhibition of microtubule affinity-regulating kinase: Mechanistic insights.

Alzheimer's disease (AD) is one of the neurodegenerative disorder that primarily affects memory, thinking, and behavior, eventually leading to severe cognitive impairment. Therapeutic management of AD is urgently needed to improve the quality and lifestyle of patients. Tau phosphorylating kinases are considered attractive therapeutic targets. Microtubule affinity-regulating kinase 4 (MARK4) is directly linked with pathological phosphorylations of tau, highlighting its role in the therapeutic targeting of AD. The current manuscript shows the MARK4 inhibitory effect of Memantine (MEM), a drug used in treating AD. We have performed fluorescence based binding measurements, enzyme inhibition assay, docking and molecular dynamics (MD) simulations to understand the binding of of MARK4 and MEM and subsequent inhibition in the kinase activity. A 100 ns MD simulations provided a detailed analysis of MARK4-MEM complex and the role of potential critical residues in the binding. Finally, this study provides molecular insights into the therapeutic implication of MEM in AD therapeutics. We propose MEM effectively inhibits MARK4, it may be implicated in the development of targeted and efficient treatments for AD.

Case report: a unique presentation of memantine overdose causing echolalia and hypertension.

BACKGROUND: Since 2003 when memantine was first approved for use in the management of moderate-severe Alzheimer's dementia, its use has become more widespread and is being explored in other diseases like neuropathic pain, epilepsy, and mood disorders. Our case uniquely highlights two important adverse effects in a patient who overdosed on memantine. One is hypertension, which is easy to overlook as a medication side effect. The other is echolalia which is the repetition of words and phrases spoken by another person. It is commonly seen in children with autism spectrum disorder and has been reported in older adults with head injuries, delirium, and neurocognitive disorders. The aim of this patient story is to highlight the importance of medication reconciliation with caregivers and knowledge of adverse drug reactions in patient management. This case report has been presented previously in the form of an abstract at the American Geriatrics Society Presidential poster session in May 2023. CASE PRESENTATION: Our patient is an 86-year-old man with mild dementia and hypertension, who was brought to the emergency department (ED) due to abrupt onset of altered mental status and auditory hallucinations. Investigations including blood work, CT head and an electroencephalogram (EEG) did not reveal an etiology for this change in his condition. Due to elevated blood pressure on presentation, a nicardipine drip was started, and he was given IV midazolam to assist with obtaining imaging. While reviewing medications with his daughter, it was noted that sixty memantine pills were missing from the bottle. Poison control was contacted and they confirmed association of these features with memantine. With supportive care, his symptoms resolved in less than 100 h, consistent with the half-life of memantine. Notably, our patient was started on Memantine one month prior to this presentation. CONCLUSIONS: Hypertensive urgency and echolalia were the most striking symptoms of our patient's presentation. Though hypertension is a known sign of memantine overdose, it can easily be contributed to medication non-compliance in patients with dementia, being treated for hypertension. According to our literature review, this the first case of memantine overdose presenting with echolalia, a sign that is not commonly associated with adverse reactions to medications. This highlights the importance of an early medication review, especially with caregivers of people with dementia.

Locally Synthetized 17-ß-Estradiol Reverses Amyloid-ß-42-Induced Hippocampal Long-Term Potentiation Deficits.

Amyloid beta 1-42 (Aß42) aggregates acutely impair hippocampal long-term potentiation (LTP) of synaptic transmission, and 17ß-estradiol is crucial for hippocampal LTP. We tested whether boosting the synthesis of neural-derived 17ß-estradiol (nE2) saves hippocampal LTP by the neurotoxic action of Aß42. Electrophysiological recordings were performed to measure dentate gyrus (DG) LTP in rat hippocampal slices. Using a pharmacological approach, we tested the ability of nE2 to counteract the LTP impairment caused by acute exposure to soluble Aß42 aggregates. nE2 was found to be required for LTP in DG under physiological conditions. Blockade of steroid 5α-reductase with finasteride, by increasing nE2 synthesis from testosterone (T), completely recovered LTP in slices treated with soluble Aß42 aggregates. Modulation of the glutamate N-methyl-D aspartate receptor (NMDAR) by memantine effectively rescued the LTP deficit observed in slices exposed to Aß42, and memantine prevented LTP reduction observed under the blocking of nE2 synthesis. nE2 is able to counteract Aß42-induced synaptic dysfunction. This effect depends on a rapid, non-genomic mechanism of action of nE2, which may share a common pathway with glutamate NMDAR signaling.

Combination strategy employing BACE1 inhibitor and memantine to boost cognitive benefits in Alzheimer's disease therapy.

RATIONALE: The ß-secretase BACE1 initiates amyloid-ß (Aß) generation and represents a long-standing prime therapeutic target for the treatment of Alzheimer's disease (AD). However, BACE1 inhibitors tested to date in clinical trials have yielded no beneficial outcomes. In fact, prior BACE1 inhibitor trials targeted at ~ 50-90% Aß reductions in symptomatic or prodromal AD stages have ended in the discontinuation due to futility and/or side effects, including cognitive worsening rather than expected improvement at the highest dose. OBJECTIVES: We tested whether a combination strategy with the selective BACE1 inhibitor GRL-8234 and the FDA-approved symptomatic drug memantine may provide synergistic cognitive benefits within their safe dose range. METHODS: The drug effects were evaluated in the advanced symptomatic stage of 5XFAD mice that developed extensive cerebral Aß deposition. RESULTS: Chronic combination treatment with 33.4-mg/kg GRL-8234 and 10-mg/kg memantine, but not either drug alone, rescued cognitive deficits in 5XFAD mice at 12 months of age (the endpoint after 60-day drug treatment), as assessed by the contextual fear conditioning, spontaneous alternation Y-maze and nest building tasks. Intact baseline performances of wild-type control mice on three cognitive paradigms demonstrated that combination treatment did not augment potential cognitive side effects of individual drugs. Biochemical and immunohistochemical examination showed that combination treatment did not synergistically reduce the ß-amyloidogenic processing of amyloid precursor protein or Aß levels in 5XFAD mouse brains. CONCLUSIONS: A combination strategy with BACE1 inhibitors and memantine may be able to increase the effectiveness of individual drugs within their safe dose range in AD therapy.

Memantine versus Ginkgo biloba Extract: A Comparative Study on Cognitive Dysfunction Treatment in a Novel Rat Model.

Extracellular senile plaques and intraneuronal neurofibrillary tangles are two devastating brain proteinopathies that are indicative of Alzheimer's disease, the most prevalent type of dementia. Currently, no effective medications are available to stop or reverse Alzheimer's disease. Ginkgo biloba extract, commonly referred to as EGb 761, is a natural product made from the leaves of the G. biloba tree. It has long been demonstrated to have therapeutic benefits in Alzheimer's disease. The current study assessed the beneficial effects of EGb 761 against Alzheimer's disease in comparison with memantine, a standard treatment for Alzheimer's disease. The scopolamine-heavy metals mixture rat Alzheimer's disease model is a newly created model to study the effects of EGb 761 oral therapy on cognitive performance and other Alzheimer's disease-like changes over a 28-day experimental period. This new Alzheimer's disease model provides better criteria for Alzheimer's disease hallmarks than the conventional scopolamine model. The EGb 761 reversed memory and learning deficits induced by the scopolamine-heavy metals mixture. These outcomes were linked to a more pronounced inhibitory effect on acetylcholinesterase, caspase-3, hippocampal amyloid-beta protein (Aß1 - 42), phosphorylated tau protein counts, and proinflammatory cytokines (tumor necrosis factor-α and interleukin-1ß) compared to the memantine-treated group. Furthermore, EGb 761 treatment considerably reduced lipid peroxidation (malondialdehyde) and improved reduced glutathione levels compared to memantine. Our results suggest EGb 761's potential in treating central nervous system disorders. It's a promising candidate for future Alzheimer's disease therapeutic exploration. This study also highlights the need for future research to focus on the positive benefits of herbal medicines.

Combining a noble gas with radiotherapy: glutamate receptor antagonist xenon may act as a radiosensitizer in glioblastoma.

BACKGROUND: Ionotropic glutamate receptors α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) and N-methyl-D-aspartate receptor (NMDAR) modulate proliferation, invasion and radioresistance in glioblastoma (GB). Pharmacological targeting is difficult as many in vitro-effective agents are not suitable for in patient applications. We aimed to develop a method to test the well tolerated AMPAR- and NMDAR-antagonist xenon gas as a radiosensitizer in GB. METHODS: We designed a diffusion-based system to perform the colony formation assay (CFA), the radiobiological gold standard, under xenon exposure. Stable and reproducible gas atmosphere was validated with oxygen and carbon dioxide as tracer gases. After checking for AMPAR and NMDAR expression via immunofluorescence staining we performed the CFA with the glioblastoma cell lines U87 and U251 as well as the non-glioblastoma derived cell line HeLa. Xenon was applied after irradiation and additionally tested in combination with NMDAR antagonist memantine. RESULTS: The gas exposure system proved compatible with the CFA and resulted in a stable atmosphere of 50% xenon. Indications for the presence of glutamate receptor subunits were present in glioblastoma-derived and HeLa cells. Significantly reduced clonogenic survival by xenon was shown in U87 and U251 at irradiation doses of 4-8 Gy and 2, 6 and 8 Gy, respectively (p < 0.05). Clonogenic survival was further reduced by the addition of memantine, showing a significant effect at 2-8 Gy for both glioblastoma cell lines (p < 0.05). Xenon did not significantly reduce the surviving fraction of HeLa cells until a radiation dose of 8 Gy. CONCLUSION: The developed system allows for testing of gaseous agents with CFA. As a proof of concept, we have, for the first time, unveiled indications of radiosensitizing properties of xenon gas in glioblastoma.