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1.
Lancet Neurol ; 21(1): 31-41, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34942135

RESUMO

BACKGROUND: Down syndrome is a chromosomal disorder with considerable neurodevelopmental impact and neurodegenerative morbidity. In a pilot trial in young adults with Down syndrome, memantine (a drug approved for Alzheimer's disease) showed a significant effect on a secondary measure of episodic memory. We aimed to test whether memantine would improve episodic memory in adolescents and young adults with Down syndrome. METHODS: We did a randomised, double-blind, placebo-controlled phase 2 trial with a parallel design, stratified by age and sex. Participants (aged 15-32 years) with either trisomy 21 or complete unbalanced translocation of chromosome 21 and in general good health were recruited from the community at one site in Brazil and another in the USA. Participants were randomly assigned (1:1) to receive either memantine (20 mg/day orally) or placebo for 16 weeks. Computer-generated randomisation tables for both sites (allocating a placebo or drug label to each member of a unique pair of participants) were centrally produced by an independent statistician and were shared only with investigational pharmacists at participating sites until unblinding of the study. Participants and investigators were masked to treatment assignments. Neuropsychological assessments were done at baseline (T1) and week 16 (T2). The primary outcome measure was change from baseline to week 16 in the California Verbal Learning Test-second edition short-form (CVLT-II-sf) total free recall score, assessed in the per-protocol population (ie, participants who completed 16 weeks of treatment and had neuropsychological assessments at T1 and T2). Linear mixed effect models were fit to data from the per-protocol population. Safety and tolerability were monitored and analysed in all participants who started treatment. Steady-state concentrations in plasma of memantine were measured at the end of the trial. This study is registered at ClinicalTrials.gov, number NCT02304302. FINDINGS: From May 13, 2015, to July 22, 2020, 185 participants with Down syndrome were assessed for eligibility and 160 (86%) were randomly assigned either memantine (n=81) or placebo (n=79). All participants received their allocated treatment. Linear mixed effect models were fit to data from 149 (81%) participants, 73 in the memantine group and 76 in the placebo group, after 11 people (eight in the memantine group and three in the placebo group) discontinued due to COVID-19 restrictions, illness of their caregiver, adverse events, or low compliance. The primary outcome measure did not differ between groups (CVLT-II-sf total free recall score, change from baseline 0·34 points [95% CI -0·98 to 1·67], p=0·61). Memantine was well tolerated, with infrequent mild-to-moderate adverse events, the most common being viral upper respiratory infection (nine [11%] participants in the memantine group and 12 [15%] in the placebo group) and transient dizziness (eight [10%] in the memantine group and six [8%] in the placebo group). No serious adverse events were observed. Amounts of memantine in plasma were substantially lower than those considered therapeutic for Alzheimer's disease. INTERPRETATION: Memantine was well tolerated, but cognition-enhancing effects were not recorded with a 20 mg/day dose in adolescents and young adults with Down syndrome. Exploratory analyses point to a need for future work. FUNDING: Alana Foundation. TRANSLATION: For the Portuguese translation of the abstract see Supplementary Materials section.


Assuntos
Síndrome de Down/tratamento farmacológico , Memantina/uso terapêutico , Adolescente , Cognição/efeitos dos fármacos , Método Duplo-Cego , Síndrome de Down/psicologia , Feminino , Humanos , Masculino , Memantina/administração & dosagem , Memantina/farmacologia , Resultado do Tratamento , Adulto Jovem
2.
Viruses ; 13(10)2021 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-34696509

RESUMO

We report the in vitro efficacy of ion-channel inhibitors amantadine, memantine and rimantadine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In VeroE6 cells, rimantadine was most potent followed by memantine and amantadine (50% effective concentrations: 36, 80 and 116 µM, respectively). Rimantadine also showed the highest selectivity index, followed by amantadine and memantine (17.3, 12.2 and 7.6, respectively). Similar results were observed in human hepatoma Huh7.5 and lung carcinoma A549-hACE2 cells. Inhibitors interacted in a similar antagonistic manner with remdesivir and had a similar barrier to viral escape. Rimantadine acted mainly at the viral post-entry level and partially at the viral entry level. Based on these results, rimantadine showed the most promise for treatment of SARS-CoV-2.


Assuntos
Amantadina/farmacologia , Antivirais/farmacologia , COVID-19/tratamento farmacológico , Memantina/farmacologia , Rimantadina/farmacologia , SARS-CoV-2/efeitos dos fármacos , Células A549 , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/farmacologia , Alanina/análogos & derivados , Alanina/farmacologia , Animais , Linhagem Celular Tumoral , Chlorocebus aethiops , Dinamarca , Reposicionamento de Medicamentos , Humanos , Canais Iônicos/antagonistas & inibidores , Células Vero
3.
Neurocrit Care ; 35(Suppl 2): 135-145, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34657268

RESUMO

BACKGROUND: Spreading depolarization (SD) has been identified as a key mediator of secondary lesion progression after acute brain injuries, and clinical studies are beginning to pharmacologically target SDs. Although initial work has focused on the N-Methyl-D-aspartate receptor antagonist ketamine, there is also interest in alternatives that may be better tolerated. We recently showed that ketamine can inhibit mechanisms linked to deleterious consequences of SD in brain slices. The present study tested the hypothesis that memantine improves recovery of brain slices after SD and explored the effects of memantine in a clinical case targeting SD. METHODS: For mechanistic studies, electrophysiological and optical recordings were made from hippocampal area CA1 in acutely prepared brain slices from mice. SDs were initiated by localized microinjection of K+ in conditions of either normal or reduced metabolic substrate availability. Memantine effects were assessed from intrinsic optical signals and extracellular potential recordings. For the clinical report, a subdural strip electrode was used for continuous electrocorticographic recording after the surgical evacuation of a chronic subdural hematoma. RESULTS: In brain slice studies, memantine (10-300 µM) did not prevent the initiation of SD, but impaired SD propagation rate and recovery from SD. Memantine reduced direct current (DC) shift duration and improved recovery of synaptic potentials after SD. In brain slices with reduced metabolic substrate availability, memantine reduced the evidence of structural disruption after the passage of SD. In our clinical case, memantine did not noticeably immediately suppress SD; however, it was associated with a significant reduction of SD duration and a reduction in the electrocorticographic (ECoG) suppression that occurs after SD. SD was completely suppressed, with improvement in neurological examination with the addition of a brief course of ketamine. CONCLUSIONS: These data extend recent work showing that N-Methyl-D-aspartate receptor antagonists can improve recovery from SD. These results suggest that memantine could be considered for future clinical trials targeting SD, and in some cases as an adjunct or alternative to ketamine.


Assuntos
Ketamina , Memantina , Animais , Encéfalo , Antagonistas de Aminoácidos Excitatórios/farmacologia , Ketamina/farmacologia , Memantina/farmacologia , Camundongos , Receptores de N-Metil-D-Aspartato
4.
Molecules ; 26(18)2021 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-34576998

RESUMO

A new series of conjugates of aminoadamantane and γ-carboline, which are basic scaffolds of the known neuroactive agents, memantine and dimebon (Latrepirdine) was synthesized and characterized. Conjugates act simultaneously on several biological structures and processes involved in the pathogenesis of Alzheimer's disease and some other neurodegenerative disorders. In particular, these compounds inhibit enzymes of the cholinesterase family, exhibiting higher inhibitory activity against butyrylcholinesterase (BChE), but having almost no effect on the activity of carboxylesterase (anti-target). The compounds serve as NMDA-subtype glutamate receptor ligands, show mitoprotective properties by preventing opening of the mitochondrial permeability transition (MPT) pore, and act as microtubule stabilizers, stimulating the polymerization of tubulin and microtubule-associated proteins. Structure-activity relationships were studied, with particular attention to the effect of the spacer on biological activity. The synthesized conjugates showed new properties compared to their prototypes (memantine and dimebon), including the ability to bind to the ifenprodil-binding site of the NMDA receptor and to occupy the peripheral anionic site of acetylcholinesterase (AChE), which indicates that these compounds can act as blockers of AChE-induced ß-amyloid aggregation. These new attributes of the conjugates represent improvements to the pharmacological profiles of the separate components by conferring the potential to act as neuroprotectants and cognition enhancers with a multifunctional mode of action.


Assuntos
Amantadina/química , Amantadina/farmacologia , Carbolinas/química , Carbolinas/farmacologia , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Acetilcolinesterase/química , Amantadina/análogos & derivados , Animais , Butirilcolinesterase/química , Carboxilesterase/química , Domínio Catalítico , Linhagem Celular , Inibidores da Colinesterase/síntese química , Cavalos , Humanos , Cinética , Ligantes , Memantina/química , Memantina/farmacologia , Necrose Dirigida por Permeabilidade Transmembrânica da Mitocôndria/efeitos dos fármacos , Simulação de Acoplamento Molecular , Propídio/química , Ratos , Receptores de N-Metil-D-Aspartato/química , Receptores de N-Metil-D-Aspartato/metabolismo , Relação Estrutura-Atividade , Suínos , Tubulina (Proteína)/efeitos dos fármacos , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacologia
5.
Biomolecules ; 11(7)2021 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-34356631

RESUMO

Chronic sensitization to serotonin 1A and 7 receptors agonist 8-OH-DPAT induces compulsive checking and perseverative behavior. As such, it has been used to model obsessive-compulsive disorder (OCD)-like behavior in mice and rats. In this study, we tested spatial learning in the 8-OH-DPAT model of OCD and the effect of co-administration of memantine and riluzole-glutamate-modulating agents that have been shown to be effective in several clinical trials. Rats were tested in the active place avoidance task in the Carousel maze, where they learned to avoid the visually imperceptible shock sector. All rats were subcutaneously injected with 8-OH-DPAT (0.25 mg/kg) or saline (control group) during habituation. During acquisition, they were pretreated with riluzole (1 mg/kg), memantine (1 mg/kg), or saline solution 30 min before each session and injected with 8-OH-DPAT ("OH" groups) or saline ("saline" groups) right before the experiment. We found that repeated application of 8-OH-DPAT during both habituation and acquisition significantly increased locomotion, but it impaired the ability to avoid the shock sector. However, the application of 8-OH-DPAT in habituation had no impact on the learning process if discontinued in acquisition. Similarly, memantine and riluzole did not affect the measured parameters in the "saline" groups, but in the "OH" groups, they significantly increased locomotion. In addition, riluzole increased the number of entrances and decreased the maximum time avoided of the shock sector. We conclude that monotherapy with glutamate-modulating agents does not reduce but exacerbates cognitive symptoms in the animal model of OCD.


Assuntos
8-Hidroxi-2-(di-n-propilamino)tetralina/efeitos adversos , Comportamento Animal/efeitos dos fármacos , Memantina/farmacologia , Transtorno Obsessivo-Compulsivo , Riluzol/farmacologia , Aprendizagem Espacial/efeitos dos fármacos , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Animais , Modelos Animais de Doenças , Masculino , Memória/efeitos dos fármacos , Transtorno Obsessivo-Compulsivo/induzido quimicamente , Transtorno Obsessivo-Compulsivo/tratamento farmacológico , Transtorno Obsessivo-Compulsivo/fisiopatologia , Ratos , Ratos Long-Evans
6.
Psychopharmacology (Berl) ; 238(11): 3273-3281, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34387707

RESUMO

RATIONALE: There 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). OBJECTIVES: Here, we tested the hypothesis that cognitive enhancer effects of memantine can be potentiated through modulating alpha7 nAChRs in a scopolamine-induced amnesia model. METHODS: Monotreatments, 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. RESULTS: Low 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. CONCLUSION: Our 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.


Assuntos
Doença de Alzheimer , Nootrópicos , Doença de Alzheimer/tratamento farmacológico , Animais , Compostos Bicíclicos Heterocíclicos com Pontes , Memantina/farmacologia , Memantina/uso terapêutico , Teste do Labirinto Aquático de Morris , Nootrópicos/uso terapêutico , Quinuclidinas , Ratos , Receptor Nicotínico de Acetilcolina alfa7
7.
Int J Mol Sci ; 22(15)2021 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-34360588

RESUMO

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.


Assuntos
Dopaminérgicos/farmacologia , Memantina/farmacologia , Doenças Neurodegenerativas/prevenção & controle , Neuroglia/efeitos dos fármacos , Optogenética/efeitos adversos , Substâncias Protetoras/farmacologia , Células de Purkinje/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Camundongos , Doenças Neurodegenerativas/etiologia , Doenças Neurodegenerativas/patologia , Neuroglia/patologia , Células de Purkinje/patologia
8.
Int J Mol Sci ; 22(15)2021 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-34360704

RESUMO

The activation of the endocannabinoid system controls the release of many neurotransmitters involved in the brain reward pathways, including glutamate. Both endocannabinoid and glutamate systems are crucial for alcohol relapse. In the present study, we hypothesize that N-methyl-D-aspartate (NMDA) glutamate receptors regulate the ability of a priming dose of WIN 55,212-2 to cross-reinstate ethanol-induced conditioned place preference (CPP). To test this hypothesis, ethanol-induced (1.0 g/kg, 10% w/v, i.p.) CPP (unbiased method) was established using male adult Wistar rats. After CPP extinction, one group of animals received WIN 55,212-2 (1.0 and 2.0 mg/kg, i.p.), the cannabinoid receptor 1 (CB1) agonist, or ethanol, and the other group received memantine (3.0 or 10 mg/kg, i.p.), the NMDA antagonist and WIN 55,212-2 on the reinstatement day. Our results showed that a priming injection of WIN 55,212-2 (2.0 mg/kg, i.p.) reinstated (cross-reinstated) ethanol-induced CPP with similar efficacy to ethanol. Memantine (3.0 or 10 mg/kg, i.p.) pretreatment blocked this WIN 55,212-2 effect. Furthermore, our experiments indicated that ethanol withdrawal (7 days withdrawal after 10 days ethanol administration) down-regulated the CNR1 (encoding CB1), GRIN1/2A (encoding GluN1 and GluN2A subunit of the NMDA receptor) genes expression in the prefrontal cortex and dorsal striatum, but up-regulated these in the hippocampus, confirming the involvement of these receptors in ethanol rewarding effects. Thus, our results show that the endocannabinoid system is involved in the motivational properties of ethanol, and glutamate may control cannabinoid induced relapse into ethanol seeking behavior.


Assuntos
Benzoxazinas/farmacologia , Condicionamento Psicológico/efeitos dos fármacos , Etanol/farmacologia , Memantina/farmacologia , Morfolinas/farmacologia , Motivação/efeitos dos fármacos , Naftalenos/farmacologia , Animais , Masculino , Ratos , Ratos Wistar
9.
Biol Psychiatry ; 90(7): 458-472, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34274107

RESUMO

BACKGROUND: Major depressive disorder is a common, recurrent illness. Recent studies have implicated the NMDA receptor in the pathophysiology of major depressive disorder. (R,S)-ketamine, an NMDA receptor antagonist, is an effective antidepressant but has numerous side effects. Here, we characterized a novel NMDA receptor antagonist, fluoroethylnormemantine (FENM), to determine its effectiveness as a prophylactic and/or antidepressant against stress-induced maladaptive behavior. METHODS: Saline, memantine (10 mg/kg), (R,S)-ketamine (30 mg/kg), or FENM (10, 20, or 30 mg/kg) was administered before or after contextual fear conditioning in 129S6/SvEv mice. Drug efficacy was assayed using various behavioral tests. Protein expression in the hippocampus was quantified with immunohistochemistry or Western blotting. In vitro radioligand binding was used to assay drug binding affinity. Patch clamp electrophysiology was used to determine the effect of drug administration on glutamatergic activity in ventral hippocampal cornu ammonis 3 (vCA3) 1 week after injection. RESULTS: Given after stress, FENM decreased behavioral despair and reduced perseverative behavior. When administered after re-exposure, FENM facilitated extinction learning. As a prophylactic, FENM attenuated learned fear and decreased stress-induced behavioral despair. FENM was behaviorally effective in both male and female mice. (R,S)-ketamine, but not FENM, increased expression of c-fos in vCA3. Both (R,S)-ketamine and FENM attenuated large-amplitude AMPA receptor-mediated bursts in vCA3, indicating a common neurobiological mechanism for further study. CONCLUSIONS: Our results indicate that FENM is a novel drug that is efficacious when administered at various times before or after stress. Future work will further characterize FENM's mechanism of action with the goal of clinical development.


Assuntos
Transtorno Depressivo Maior , Ketamina , Memantina/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Animais , Feminino , Ketamina/farmacologia , Masculino , Memantina/análogos & derivados , Camundongos , Estresse Psicológico
10.
Sci Rep ; 11(1): 12613, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-34131204

RESUMO

Secondary injury following cortical stroke includes delayed gliosis and eventual neuronal loss in the thalamus. However, the effects of aging and the potential to ameliorate this gliosis with NMDA receptor (NMDAR) antagonism are not established. We used the permanent distal middle cerebral artery stroke model (pdMCAO) to examine secondary thalamic injury in young and aged mice. At 3 days post-stroke (PSD3), slight microgliosis (IBA-1) and astrogliosis (GFAP) was evident in thalamus, but no infarct. Gliosis increased dramatically through PSD14, at which point degenerating neurons were detected. Flow cytometry demonstrated a significant increase in CD11b+/CD45int microglia (MG) in the ipsilateral thalamus at PSD14. CCR2-RFP reporter mouse further demonstrated that influx of peripheral monocytes contributed to the MG/Mϕ population. Aged mice demonstrated reduced microgliosis and astrogliosis compared with young mice. Interestingly, astrogliosis demonstrated glial scar-like characteristics at two years post-stroke, but not by 6 weeks. Lastly, treatment with memantine (NMDAR antagonist) at 4 and 24 h after stroke significantly reduced gliosis at PSD14. These findings expand our understanding of gliosis in the thalamus following cortical stroke and demonstrate age-dependency of this secondary injury. Additionally, these findings indicate that delayed treatment with memantine (an FDA approved drug) provides significant reduction in thalamic gliosis.


Assuntos
Gliose/tratamento farmacológico , Infarto da Artéria Cerebral Média/tratamento farmacológico , Memantina/farmacologia , Acidente Vascular Cerebral/tratamento farmacológico , Envelhecimento/efeitos dos fármacos , Envelhecimento/patologia , Animais , Isquemia Encefálica/complicações , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/patologia , Modelos Animais de Doenças , Gliose/etiologia , Gliose/patologia , Humanos , Infarto da Artéria Cerebral Média/complicações , Infarto da Artéria Cerebral Média/patologia , Camundongos , Fármacos Neuroprotetores/farmacologia , Acidente Vascular Cerebral/complicações , Tálamo/efeitos dos fármacos , Tálamo/patologia
11.
Pharmacology ; 106(7-8): 390-399, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33979803

RESUMO

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.


Assuntos
Memantina/farmacologia , Fator de Crescimento Neural/farmacologia , Fármacos Neuroprotetores/farmacologia , Quinidina/farmacologia , Acetilcolina/metabolismo , Animais , Núcleo Basal de Meynert/efeitos dos fármacos , Núcleo Basal de Meynert/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Neurônios Colinérgicos , Camundongos , Camundongos Endogâmicos C57BL , Transportador 2 de Cátion Orgânico/antagonistas & inibidores , Técnicas de Cultura de Tecidos
12.
Chem Biol Interact ; 342: 109463, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33831382

RESUMO

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.


Assuntos
Inibidores da Colinesterase/farmacologia , Memantina/farmacologia , Soman/farmacologia , Animais , Bovinos , Inibidores da Colinesterase/química , Dopaminérgicos/farmacologia , Redução da Medicação , Memantina/química , Memantina/metabolismo , Estrutura Molecular , Fatores de Tempo
13.
Life Sci ; 273: 119310, 2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-33667517

RESUMO

AIMS: Alzheimer's disease (AD) is a leading health problem in which increased amyloid ß (Aß) accumulation may occur due to abnormal Aß precursor protein processing by ß-secretase 1 (BACE1) enzyme. Lately, neuro-inflammation was recognized as a significant contributor to its pathogenesis. Although the causes of AD are not yet well understood, much evidence has suggested that dyslipidemia has harmful effects on cognitive function and is inextricably involved in AD pathogenesis. Cholesterol is a vital molecule involved in neuronal development. Alteration in neuronal cholesterol levels affects Aß metabolism and results in neurodegeneration. Proprotein-convertase-subtilisin/kexin type-9 (PCSK9) was found to decrease neuronal cholesterol uptake by degradation of LDL-receptor related protein 1 (LRP-1) responsible for neuronal cholesterol uptake. Accordingly, this study was designed to evaluate the effect of PCSK9-inhibition by alirocumab (Aliro) in high-fat-cholesterol-diet (HFCD)-induced-AD-like condition. MAIN METHODS: Wistar Rats were divided into six groups; control; HFCD; HFCD and Memantine; HFCD and Aliro (4, 8 and 16 mg/kg/week) to test for ability of Aliro to modulate cognitive impairment, amyloidosis, brain cholesterol homeostasis and neuro-inflammation in HFCD-induced-AD-like condition. KEY FINDINGS: Our results demonstrated an association between PCSK9 inhibition by Aliro and amelioration of cognitive deficit, cholesterol hemostasis and reduction of neuro-inflammation. Aliro was able to alleviate hippocampal LRP-1expression levels and reduce brain cholesterol, hippocampal BACE1, Aß42, high-mobility-group-box-1 protein, receptor for advanced-glycation-end-products and toll like receptor-4 with subsequent decrease of different inflammatory mediators as nuclear-factor-kappa-B (NF-κB), tumor-necrosis-factor-alpha (TNF-α), interleukin-1beta (IL-1ß) and IL-6. SIGNIFICANCE: PCSK9-inhibition may represent a new therapeutic target in AD especially for HFCD-induced-AD-like condition.


Assuntos
Amiloidose/tratamento farmacológico , Anticorpos Monoclonais Humanizados/farmacologia , Colesterol/toxicidade , Disfunção Cognitiva/tratamento farmacológico , Dieta Hiperlipídica/efeitos adversos , Memantina/farmacologia , Amiloidose/etiologia , Amiloidose/metabolismo , Amiloidose/patologia , Animais , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Ácido Glutâmico/metabolismo , Proteína HMGB1/genética , Proteína HMGB1/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Masculino , Ratos , Ratos Wistar , Receptor para Produtos Finais de Glicação Avançada/genética , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo
14.
Pol Merkur Lekarski ; 49(289): 67-70, 2021 Feb 24.
Artigo em Polonês | MEDLINE | ID: mdl-33713098

RESUMO

Amantadine and memantine, apart from their action on cholinergic receptors and dopamine secretion, have a significant influence on the inflammatory process, including the so-called "cytokine storm" and reduction of apoptosis and oxidative stress. Amantadine also inhibits the induction of inflammatory factors such as RANTES, activates kinase p38 of mitogen-activated protein (MAP) and c-Jun-NH2-terminal kinases (JNK), which inhibit viral replication. It also significantly inhibits the entry of SARS-CoV-2 into the bronchial epithelial cell and blocks the viroporin proton channel of the virus. In addition, it has the ability to pass through the membrane of lysosomes into their interior and act as an alkalizing agent, which prevents the release of viral RNA into the cell, which may be a key element in therapeutic management. Memantine also reduces inflammation, mainly in the nervous system, but also acts as a lysosomotropic factor, inhibiting viral replication. However, it is important to bear in mind when undertaking amantadine or memantine therapy with side effects that may overlap with COVID- 19 symptoms, worsening the condition of patients. Currently, the effectiveness of amantadine and memantine in the treatment of patients with COVID-19 symptoms has been demonstrated in a few clinical trials, mainly in patients treated for neurodegenerative diseases. The obtained results are of considerable value, but require confirmation in further studies.


Assuntos
COVID-19 , Memantina , Amantadina/farmacologia , Amantadina/uso terapêutico , Anti-Inflamatórios , Humanos , Memantina/farmacologia , Memantina/uso terapêutico , SARS-CoV-2
15.
Sci Rep ; 11(1): 6151, 2021 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-33731780

RESUMO

The pathophysiology of Alzheimer's disease (AD) is related to neuroinflammatory responses mediated by microglia. Memantine, an antagonist of N-methyl-D-aspartate (NMDA) receptors used as an anti-Alzheimer's drug, protects from neuronal death accompanied by suppression of proliferation and activation of microglial cells in animal models of AD. However, it remains to be tested whether memantine can directly affect microglial cell function. In this study, we examined whether pretreatment with memantine affects intracellular NO and Ca2+ mobilization using DAF-2 and Fura-2 imaging, respectively, and tested the effects of memantine on phagocytic activity by human ß-Amyloid (1-42) phagocytosis assay in rodent microglial cells. Pretreatment with memantine did not affect production of NO or intracellular Ca2+ elevation induced by TNF in rodent microglial cells. Pretreatment with memantine also did not affect the mRNA expression of pro-inflammatory (TNF, IL-1ß, IL-6 and CD45) or anti-inflammatory (IL-10, TGF-ß and arginase) phenotypes in rodent microglial cells. In addition, pretreatment with memantine did not affect the amount of human ß-Amyloid (1-42) phagocytosed by rodent microglial cells. Moreover, we observed that pretreatment with memantine did not affect 11 major proteins, which mainly function in the phagocytosis and degradation of ß-Amyloid (1-42), including TREM2, DAP12 and neprilysin in rodent microglial cells. To the best of our knowledge, this is the first report to suggest that memantine does not directly modulate intracellular NO and Ca2+ mobilization or phagocytic activity in rodent microglial cells. Considering the neuroinflammation hypothesis of AD, the results might be important to understand the effect of memantine in the brain.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Antagonistas de Aminoácidos Excitatórios/farmacologia , Memantina/farmacologia , Microglia/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Animais , Camundongos Endogâmicos C57BL , Cultura Primária de Células
16.
J Alzheimers Dis ; 81(1): 375-388, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33780366

RESUMO

BACKGROUND: Vitamin D deficiency and altered body composition are common in Alzheimer's disease (AD). Memantine with vitamin D supplementation can protect cortical axons against amyloid-ß exposure and glutamate toxicity. OBJECTIVE: To study the effects of vitamin D deprivation and subsequent treatment with memantine and vitamin D enrichment on whole-body composition using a mouse model of AD. METHODS: Male APPswe/PS1dE9 mice were divided into four groups at 2.5 months of age: the control group (n = 14) was fed a standard diet throughout; the remaining mice were started on a vitamin D-deficient diet at month 6. The vitamin D-deficient group (n = 14) remained on the vitamin D-deficient diet for the rest of the study. Of the remaining two groups, one had memantine (n = 14), while the other had both memantine and 10 IU/g vitamin D (n = 14), added to their diet at month 9. Serum 25(OH)D levels measured at months 6, 9, 12, and 15 confirmed vitamin D levels were lower in mice on vitamin D-deficient diets and higher in the vitamin D-supplemented mice. Micro-computed tomography was performed at month 15 to determine whole-body composition. RESULTS: In mice deprived of vitamin D, memantine increased bone mineral content (8.7% increase, p < 0.01) and absolute skeletal tissue mass (9.3% increase, p < 0.05) and volume (9.2% increase, p < 0.05) relative to controls. This was not observed when memantine treatment was combined with vitamin D enrichment. CONCLUSION: Combination treatment of vitamin D and memantine had no negative effects on body composition. Future studies should clarify whether vitamin D status impacts the effects of memantine treatment on bone physiology in people with AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Composição Corporal/efeitos dos fármacos , Dopaminérgicos/uso terapêutico , Memantina/uso terapêutico , Deficiência de Vitamina D/tratamento farmacológico , Vitamina D/uso terapêutico , Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Animais , Suplementos Nutricionais , Modelos Animais de Doenças , Dopaminérgicos/farmacologia , Masculino , Memantina/farmacologia , Camundongos , Camundongos Transgênicos , Presenilina-1/genética , Vitamina D/farmacologia , Deficiência de Vitamina D/sangue , Deficiência de Vitamina D/genética
17.
Eur J Med Chem ; 217: 113338, 2021 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-33744690

RESUMO

Hurdled and marred by the notorious nature of glioblastomas (GBM) in terms of resistance to therapy and limited drug delivery into the brain, the anti-GBM drug pipeline is required to be loaded with mechanistically diverse agents. The consideration of HDAC inhibition as a prudent approach to circumvent the resistance issue in GBM spurred us to pragmatically design and synthesizes hydroxamic acids endowed with CNS penetrating ability. By virtue of the blood brain barrier permeability (BBB), memantine was envisioned as an appropriate CAP component for the construction of the HDAC inhibitors. Diverse linkers were stapled for the tetheration of the zinc binding motif with the CAP group to pinpoint an appropriate combination (CAP and linker) that could confer inhibitory preference to HDAC6 isoform (overexpressed in GBM). Resultantly, hydroxamic acid 16 was identified as a promising compound that elicited striking antiproliferative effects against Human U87MG GBM cells as well as TMZ-resistant GBM cells and P1S cells, a concurrent chemo radiotherapy (CCRT)-resistant/patient-derived glioma cell line mediated through preferential HDAC6 inhibition (IC50 = 5.42 nM). Furthermore, 16 exerted cell cycle arrest at G2 phase, induced apoptosis in GBM cells at high concentration and exhibited high BBB permeability. To add on, in-vivo study revealed that the administration of compound 16 prolonged the survival of TMZ-resistant U87MG inoculated orthotopic mice. Overall, the cumulative results indicate that 16 is a tractable CNS penetrant preferential HDAC6 inhibitor that might emerge as a potent weapon against GBM.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Desenho de Fármacos , Glioblastoma/tratamento farmacológico , Desacetilase 6 de Histona/antagonistas & inibidores , Inibidores de Histona Desacetilases/farmacologia , Memantina/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Glioblastoma/metabolismo , Glioblastoma/patologia , Desacetilase 6 de Histona/metabolismo , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Humanos , Masculino , Memantina/síntese química , Memantina/química , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Simulação de Acoplamento Molecular , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Relação Estrutura-Atividade , Células Tumorais Cultivadas
18.
Life Sci ; 270: 119012, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33422543

RESUMO

AIMS: Memantine is a non-competitive antagonist of glutamatergic NMDA receptor that is mainly used in the treatment of Alzheimer's disease. The excitatory toxicity mediated by glutamate via glutamatergic receptor signals is considered to be one of the mechanisms mediating neuronal injury and cognitive impairment after exposure to a hypoxic environment at a high altitude. Therefore, in this study, we hypothesized that inhibiting glutamate signaling using memantine could alleviate neuronal injury and cognitive impairment in rats exposed to chronic hypoxia. MAIN METHODS: we made animal models in the natural environment of the Qinghai-Tibet Plateau at an altitude of 4300 m, and used animal behavior, morphology, molecular biology and other methods to evaluate the impact of chronic hypoxia exposure on cognitive function and the neuroprotective effect of Memantine. KEY FINDINGS: Our results showed that the expression of NMDA receptors increased, while the expression of AMPA receptors decreased, after 4 weeks of chronic hypoxia exposure. Concomitantly, apoptotic neuronal cell death in the hippocampus and frontal cortex was significantly increased, along with levels of oxidative stress, whereas innate ability to inhibit free radicals decreased. Moreover, after 8 weeks of hypoxia exposure, learning, memory, and space exploration abilities were significantly decreased. Notably, after treatment with memantine, apoptotic neuronal cell death, oxidative stress, and free radical levels decreased, and the cognitive function of the animals improved. SIGNIFICANCE: Present study shows that chronic hypoxia can produce the excitatory toxicity leading to neural injury and cognitive impairment that can be suppressed with memantine treatment by inhibiting excitatory toxicity.


Assuntos
Doença da Altitude/metabolismo , Disfunção Cognitiva/tratamento farmacológico , Memantina/farmacologia , Altitude , Doença da Altitude/tratamento farmacológico , Doença de Alzheimer/tratamento farmacológico , Animais , Morte Celular/efeitos dos fármacos , Cognição/efeitos dos fármacos , Modelos Animais de Doenças , Antagonistas de Aminoácidos Excitatórios/farmacologia , Ácido Glutâmico/metabolismo , Hipocampo/metabolismo , Hipóxia/metabolismo , Masculino , Memantina/metabolismo , Memória/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Neurotoxinas/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/metabolismo
19.
Theranostics ; 11(5): 2247-2262, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33500723

RESUMO

RATIONALE: Although significant progress has been made in understanding the mechanisms of steatosis and insulin resistance, the physiological functions of regulators in these processes remain largely elusive. Evidence has suggested that the glutamate/N-methyl-D-aspartic acid receptor (NMDAR) axis contributes to acute lung injury, pulmonary arterial hypertension, and diabetes, but the specific metabolic contribution of the glutamate/NMDAR axis is not clear. Here we provide data at the animal, cellular, and molecular levels to support the role of the glutamate/NMDAR axis as a therapeutic target for metabolic syndrome in obesity. Methods: We examined the glutamate level in the obese mouse induced by a high-fat diet (HFD) for 12 weeks. To assess the role of NMDAR in insulin sensitivity and lipid metabolism, we tested the effects of Memantine (an NMDAR antagonist) and NMDA (an NMDAR agonist) on mice fed with HFD or standard chow diet. The in vitros NMDAR roles were analyzed in hepatocytes and potential mechanisms involved in regulating lipid metabolism were investigated. Results: Glutamate was increased in the serum of HFD-treated mice. The NMDAR blockade by Memantine decreased the susceptibility to insulin resistance and hepatic steatosis in obese mice. NMDA treatment for 6 months induced obesity in mice, characterized by hyperglycemia, hyperlipidemia, insulin resistance, and pathological changes in the liver. We provided in vitro evidence demonstrating that NMDAR activation facilitated metabolic syndrome in obesity through promoting lipid accumulation. NMDAR inhibition attenuated lipid accumulation induced by palmitic acid. Mechanistically, NMDAR activation impaired fatty acid oxidation by reducing PPARα phosphorylation and activity. The PPARα activity reduction induced by NMDAR activation was reversibly mediated by ERK1/2 signaling. Conclusion: These findings revealed that targeting NMDAR might be a promising therapeutic strategy for metabolic syndrome in obesity.


Assuntos
Fígado Gorduroso/prevenção & controle , Intolerância à Glucose/prevenção & controle , Resistência à Insulina , Metabolismo dos Lipídeos , Memantina/farmacologia , Obesidade/complicações , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Animais , Dieta Hiperlipídica , Fígado Gorduroso/etiologia , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Intolerância à Glucose/etiologia , Intolerância à Glucose/metabolismo , Intolerância à Glucose/patologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Hepatócitos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Fosforilação , Transdução de Sinais
20.
Int J Mol Sci ; 22(3)2021 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-33498392

RESUMO

Four drugs are currently approved for the treatment of Alzheimer's disease (AD) by the FDA. Three of these drugs-donepezil, rivastigmine, and galantamine-belong to the class of acetylcholine esterase inhibitors. Memantine, a NMDA receptor antagonist, represents the fourth and a combination of donepezil and memantine the fifth treatment option. Recently, the gut and its habitants, its microbiome, came into focus of AD research and added another important factor to therapeutic considerations. While the first data provide evidence that AD patients might carry an altered microbiome, the influence of administered drugs on gut properties and commensals have been largely ignored so far. However, the occurrence of digestive side effects with these drugs and the knowledge that cholinergic transmission is crucial for several gut functions enforces the question if, and how, this medication influences the gastrointestinal system and its microbial stocking. Here, we investigated aspects such as microbial viability, colonic propulsion, and properties of enteric neurons, affected by assumed intestinal concentration of the four drugs using the mouse as a model organism. All ex vivo administered drugs revealed no direct effect on fecal bacteria viability and only a high dosage of memantine resulted in reduced biofilm formation of E. coli. Memantine was additionally the only compound that elevated calcium influx in enteric neurons, while all acetylcholine esterase inhibitors significantly reduced esterase activity in colonic tissue specimen and prolonged propulsion time. Both, acetylcholine esterase inhibitors and memantine, had no effect on general viability and neurite outgrowth of enteric neurons. In sum, our findings indicate that all AD symptomatic drugs have the potential to affect distinct intestinal functions and with this-directly or indirectly-microbial commensals.


Assuntos
Inibidores da Colinesterase/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Memantina/farmacologia , Fármacos Neuroprotetores/farmacologia , Animais , Sinalização do Cálcio , Células Cultivadas , Colo/efeitos dos fármacos , Colo/metabolismo , Colo/microbiologia , Colo/fisiologia , Sistema Nervoso Entérico/efeitos dos fármacos , Sistema Nervoso Entérico/metabolismo , Sistema Nervoso Entérico/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Crescimento Neuronal
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