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1.
Rev. esp. geriatr. gerontol. (Ed. impr.) ; 59(2): [101446], Mar-Abr. 2024. tab, graf
Artigo em Espanhol | IBECS | ID: ibc-231163

RESUMO

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)


Assuntos
Humanos , Masculino , Feminino , Idoso , Antipsicóticos/administração & dosagem , Demência/tratamento farmacológico , Memantina/administração & dosagem , Inibidores da Colinesterase , Prescrições de Medicamentos , Espanha , Geriatria , Saúde do Idoso , Epidemiologia Descritiva , Estudos Retrospectivos , Estudos Transversais
2.
Artigo em Russo | MEDLINE | ID: mdl-38465812

RESUMO

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.


Assuntos
Doença de Alzheimer , Demência Vascular , Feminino , Humanos , Masculino , Atividades Cotidianas , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/psicologia , Cognição , Demência Vascular/tratamento farmacológico , Método Duplo-Cego , Memantina/efeitos adversos , Resultado do Tratamento , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais
3.
BMC Geriatr ; 24(1): 123, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38302876

RESUMO

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.


Assuntos
Doença de Alzheimer , Transtorno do Espectro Autista , Demência , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Hipertensão , Masculino , Humanos , Idoso , Idoso de 80 Anos ou mais , Memantina/efeitos adversos , Transtorno do Espectro Autista/induzido quimicamente , Transtorno do Espectro Autista/tratamento farmacológico , Ecolalia/induzido quimicamente , Ecolalia/tratamento farmacológico , Doença de Alzheimer/tratamento farmacológico , Demência/tratamento farmacológico , Hipertensão/induzido quimicamente , Hipertensão/tratamento farmacológico
4.
Int J Biol Macromol ; 262(Pt 2): 130090, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38342269

RESUMO

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.


Assuntos
Doença de Alzheimer , Humanos , Doença de Alzheimer/metabolismo , Memantina/farmacologia , Memantina/uso terapêutico , Proteínas Serina-Treonina Quinases/metabolismo , Ligação Proteica , Microtúbulos/metabolismo
5.
Int J Mol Sci ; 25(3)2024 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-38338656

RESUMO

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.


Assuntos
Estradiol , Potenciação de Longa Duração , Ratos , Animais , Estradiol/farmacologia , Estradiol/metabolismo , Peptídeos beta-Amiloides/metabolismo , Memantina/farmacologia , Hipocampo/metabolismo , Glutamatos/metabolismo
6.
Planta Med ; 90(4): 286-297, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38286405

RESUMO

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.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Metais Pesados , Animais , Ratos , Doença de Alzheimer/tratamento farmacológico , Memantina/farmacologia , Memantina/uso terapêutico , Ginkgo biloba , Acetilcolinesterase/uso terapêutico , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Disfunção Cognitiva/tratamento farmacológico , Metais Pesados/uso terapêutico , Derivados da Escopolamina/uso terapêutico
7.
Radiat Oncol ; 19(1): 16, 2024 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-38291439

RESUMO

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.


Assuntos
Glioblastoma , Radiossensibilizantes , Humanos , Xenônio/farmacologia , Xenônio/metabolismo , Antagonistas de Aminoácidos Excitatórios/farmacologia , Glioblastoma/radioterapia , Glioblastoma/metabolismo , Memantina , Células HeLa , Receptores de N-Metil-D-Aspartato , Radiossensibilizantes/farmacologia
8.
Pharmacol Biochem Behav ; 234: 173688, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38056696

RESUMO

There is accumulating evidence supporting the involvement of tissue-plasminogen activator (tPA) in the mechanisms underlying the effects of morphine and an enriched environment. This study was designed to investigate possible interactive roles of the glutamatergic and the dopaminergic systems regarding hippocampal tPA in the neurobiology of morphine dependence. For this purpose, Wistar albino rats, housed in either a standard- (SE) or an enriched environment (EE) were implanted subcutaneously with morphine (150 mg base) or placebo pellets. Behavioral and somatic signs of morphine abstinence precipitated by an opioid-receptor antagonist naloxone (1 mg/kg, i.p.) 72 h after the pellet implantation were observed individually for 15 min in all groups. Memantine (10 mg/kg i.p.), an antagonist of N-methyl-D-aspartic acid class of glutamatergic receptor-subtype decreased teeth-chattering, ptosis, diarrhea and the loss of body weight. SKF82958 (1 mg/kg, i.p.), a dopamine D1-receptor agonist decreased jumping and ptosis but increased rearing and loss of body weight. On the other hand, co-administration of SKF82958 with memantine prevented some of their effects that occur when administered alone at the same doses. Furthermore, the EE did not change the intensity of morphine abstinence. The level of hippocampal tPA mRNA was found to be lower in the SE morphine abstinence group than in the placebo group and close to the EE morphine abstinence group, whereas there was no significant alteration of its level in the memantine or SKF82958 groups. These findings suggest that the interaction between the glutamatergic and the dopaminergic systems may be an important component of the neurobiology of morphine dependence, and the role of tPA in this interaction should be further investigated.


Assuntos
Dependência de Morfina , Síndrome de Abstinência a Substâncias , Ratos , Animais , Morfina/farmacologia , Naloxona/farmacologia , Memantina/farmacologia , Dependência de Morfina/prevenção & controle , Ratos Wistar , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Peso Corporal
9.
Rev Esp Geriatr Gerontol ; 59(2): 101446, 2024.
Artigo em Espanhol | MEDLINE | ID: mdl-38029634

RESUMO

OBJECTIVE: We 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.


Assuntos
Antipsicóticos , Demência , Humanos , Antipsicóticos/uso terapêutico , Inibidores da Colinesterase , Acetilcolinesterase , Memantina/uso terapêutico , Espanha , Estudos Transversais , Estudos Retrospectivos , Prescrições , Demência/tratamento farmacológico
10.
Maturitas ; 180: 107888, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38006816

RESUMO

History of cancer has been associated with decreased risk of dementia, but it is unclear if this is due to the use of antineoplastic medications. Participants were 442,795 adults aged ≥60 years, of whom 235,841 (53.26 %) were women. Those dispensed antineoplastic medications during 2012-2013 had lower odds of being dispensed an anti-dementia drug between 2015 and 2021 (age/sex-adjusted OR = 0.60, 95%CI = 0.55-0.66). The dispensing of antineoplastic medications was associated with an adjusted hazard ratio of 0.72 (95%CI = 0.65-0.80) of subsequent dispensing of an anti-dementia drug. Understanding the mechanisms that support this association may contribute to the introduction of novel approaches to dementia prevention.


Assuntos
Doença de Alzheimer , Antineoplásicos , Demência , Humanos , Feminino , Masculino , Estudos de Coortes , Memantina/uso terapêutico , Inibidores da Colinesterase/uso terapêutico , Demência/tratamento farmacológico , Antineoplásicos/uso terapêutico , Doença de Alzheimer/tratamento farmacológico
12.
Pharmacol Biochem Behav ; 234: 173678, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37979731

RESUMO

Multiple interacting neural systems are involved in sustaining nicotine reinforcement. We and others have shown that dopamine D1 receptors and glutamate NMDA receptors both play important roles in nicotine reinforcement. Blockade of D1 receptors with the antagonist SCH-23390 (0.02 mg/kg) both acutely and chronically significantly decreased nicotine self-administration in rats. Blockade of NMDA receptors (10 mg/kg) acutely with memantine significantly increased nicotine self-administration, but chronic blockade of NMDA receptors with memantine significantly decreased nicotine self-administration. The current study examined the interactions of acute and chronic administration of SCH-23390 and memantine on nicotine self-administration in female rats. Replicating earlier studies, acute and chronic SCH-23390 significantly decreased nicotine self-administration and memantine had a biphasic effect with acute administration increasing nicotine self-administration and chronic memantine showed a non-significant trend toward decreasing it. However, chronic interaction study showed that memantine significantly attenuated the decrease in nicotine self-administration caused by chronic SCH-23390. These studies provide important information that memantine attenuates the efficacy of D1 antagonist SCH 23390 in reducing nicotine-self-administration. These two drugs do not appear to have mutually potentiating effects to aid tobacco cessation.


Assuntos
Antagonistas de Dopamina , Nicotina , Ratos , Feminino , Animais , Nicotina/farmacologia , Antagonistas de Dopamina/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Dopamina , N-Metilaspartato , Memantina/farmacologia , Receptores de N-Metil-D-Aspartato , Ratos Sprague-Dawley , Receptores de Dopamina D1/metabolismo , Benzazepinas/farmacologia
13.
J Trace Elem Med Biol ; 82: 127352, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38070385

RESUMO

BACKGROUND: One of the hypotheses that leads to an increased incidence of Alzheimer's disease (AD) is the accumulation of aluminum in the brain's frontal cortex. The present study aimed to evaluate the therapeutic role of a novel bithiophene derivative at two doses against AlCl3-induced AD in a rat model. METHODOLOGY: Adult male rats were divided into six groups, 18 rats each. Group 1: naïve animals, group 2: animals received a daily oral administration of bithiophene dissolved in DMSO (1 mg/kg) for 30 days every other day, groups 3-6: animals received a daily oral administration of AlCl3 (100 mg/kg/day) for 45 consecutive days. Groups 4 and 5 received an oral administration of low or high dose of the bithiophene (0.5 or 1 mg/kg, respectively). Group 6; Animals were treated with a daily oral dose of memantine (20 mg/kg) for 30 consecutive days. MAIN FINDINGS: Al disturbed the antioxidant milieu, elevated the lipid peroxidation, and depleted the antioxidants. It also disturbed the synaptic neurotransmission by elevating the activities of acetylcholine esterase and monoamine oxidase resulting in the depletion of dopamine and serotonin and accumulation of glutamate and norepinephrine. Al also deteriorated the expression of genes involved in apoptosis and the production of amyloid-ß plaques as well as phosphorylation of tau. The new bithiophene at the low dose reversed most of the previous deleterious effects of aluminum in the cerebral cortex and was in many instances superior to the reference drug; memantine. CONCLUSION: Taking together, the bithiophene modulated the AD etiology through antioxidant activity, prevention of neuronal and synaptic loss, and probably mitigating the formation of amyloid-ß plaques and phosphorylation of tau.


Assuntos
Doença de Alzheimer , Fármacos Neuroprotetores , Ratos , Masculino , Animais , Antioxidantes/metabolismo , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Alumínio/efeitos adversos , Cloreto de Alumínio/farmacologia , Memantina/efeitos adversos , Ratos Wistar , Peptídeos beta-Amiloides/metabolismo , Transmissão Sináptica , Modelos Animais de Doenças , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Estresse Oxidativo
14.
Neuropharmacology ; 244: 109737, 2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-37832633

RESUMO

The great potential for NMDA receptor modulators as druggable targets in neurodegenerative disorders has been met with limited success. Considered one of the rare exceptions, memantine has consistently demonstrated restorative and prophylactic properties in many AD models. In clinical trials memantine slows the decline in cognitive performance associated with AD. Here, we provide an overview of the basic properties including pharmacological targets, toxicology and cellular effects of memantine. Evidence demonstrating reductions in molecular, physiological and behavioural indices of AD-like impairments associated with memantine treatment are also discussed. This represents both an extension and homage to Dr. Chris Parson's considerable contributions to our fundamental understanding of a success story in the AD treatment landscape.


Assuntos
Doença de Alzheimer , Memantina , Humanos , Memantina/farmacologia , Memantina/uso terapêutico , Doença de Alzheimer/tratamento farmacológico , Receptores de N-Metil-D-Aspartato , Cognição
15.
Neurotoxicology ; 100: 35-46, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38070654

RESUMO

Perioperative neurocognitive disorders are a common surgical and postanesthesia complication. Necroptosis contributes to the emergence of various neurological disorders. We conjecture that cognitive impairment is associated with necroptosis of hippocampal neurons, which is mediated by NMDA receptors leading to cytoplasmic calcium imbalance. C57BL/6 J male mice ( 18 months) were randomly divided into the C ( control group), S ( sevoflurane group), S+M ( sevoflurane plus the NMDA receptor antagonist memantine group) and S+N ( sevoflurane plus necrostatin-1) group. We exposed the mice to 3% sevoflurane for 2 h a day for three consecutive days in the S, S+M and S+N groups. Memantine ( 20 mg/kg) or Nec-1 ( 10 mg/kg) was injected intraperitoneally 1 h before sevoflurane anesthesia in the S+M or S+N group. We used the animal behavior tests to evaluate the cognitive function. Pathological damage, the rate of necroptosis, [Ca2+]i, and the expression of necroptosis-related proteins were evaluated. The cognitive function tests, pathological damage, the rate of necroptosis, the expression of necroptosis-related proteins, NMDAR2A and NMDAR2B were significantly different in the S group ( P < 0.05). Alleviated pathological damage, decreased the rate of necroptosis and down-regulated the expression of necroptosis-related proteins occurred in the S+M and S+N group ( P < 0.05). The lower elevated [Ca2+]i, expression of NMDAR2A and NMDAR2B were found in the S+M group. Our findings highlighted sevoflurane-induced cognitive dysfunction is associated with an imbalance in cytoplasmic calcium homeostasis by activating NMDA receptors, which causes hippocampus neurons to undergo necroptosis and ultimately affects cognitive performance in aged mice.


Assuntos
Disfunção Cognitiva , Éteres Metílicos , Animais , Camundongos , Masculino , Sevoflurano/toxicidade , Receptores de N-Metil-D-Aspartato/metabolismo , Cálcio/metabolismo , Éteres Metílicos/metabolismo , Éteres Metílicos/farmacologia , Memantina , Necroptose , Camundongos Endogâmicos C57BL , Disfunção Cognitiva/metabolismo , Hipocampo
16.
Behav Brain Res ; 461: 114834, 2024 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-38142859

RESUMO

Memantine, an N-Methyl-D-Aspartate (NMDA) antagonist, has been examined as a potential treatment for Obsessive-Compulsive Disorder (OCD). Yet, there is limited knowledge regarding how it works to reduce compulsive behaviour and whether it has different effects on individuals based on their sex. Herein, we investigated if there are sex differences in the anticompulsive-like effect of memantine in adult Swiss mice. Additionally, we explored whether the nitric oxide (NO) pathway and α-amino-3-hydroxy-5-methyl-4-isoazolepropionic acid (AMPA) receptors play a role in memantine's effects. To start, we assessed the impact of a single intraperitoneal dose of memantine (at 3, 5, and 10 mg/kg) on behaviours exhibited in the open field test (OFT) and the marble-burying test (MBT), the latter being a predictive test for anticompulsive effects. All doses of memantine reduced marble-burying behaviour in both male and female mice without affecting their locomotor activity in the OFT. This anticompulsive-like effect was also confirmed in another predictive test, the nest-building test, with the highest memantine dose (10 mg/kg) reducing nest-building behaviour without significant differences between male and female mice. We observed that pre-treatment with L-arginine, a NO precursor, mitigated the anticompulsive-like effect of memantine in male mice but had no effect in female mice in the MBT. Finally, NBQX, an AMPA receptor antagonist, did not block the anticompulsive-like effect of memantine. In summary, our study suggests that the anticompulsive-like effect of memantine does not appear to be sex-specific, does not depend on AMPA receptors, and involves the NO pathway primarily in male mice.


Assuntos
Memantina , Receptores de AMPA , Feminino , Camundongos , Masculino , Animais , Memantina/farmacologia , Óxido Nítrico/metabolismo , Caracteres Sexuais , Atividade Motora , Carbonato de Cálcio/metabolismo , Carbonato de Cálcio/farmacologia , Receptores de N-Metil-D-Aspartato
17.
Neuropharmacology ; 242: 109733, 2024 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-37844867

RESUMO

Fluoroethylnormemantine (FENM) is a Memantine derivative with anti-amnesic and neuroprotective activities showed in the Aß25-35 pharmacological mouse model of Alzheimer's disease (AD). As AD is a complex multi-factorial neurodegenerative pathology, combination therapies relying on drugs acting through different pathways, have been suggested to more adequately address neuroprotection. As several agonists of the sigma-1 receptor (S1R), an intracellular chaperone, are presently in phase 2 or 3 clinical trials in neurodegenetrative diseases including AD, we examined the potentialities of S1R drug-based combinations with FENM, or Memantine. Aß25-35-treated mice were treated with S1R agonists (PRE-084, Igmesine, Cutamesine) and/or FENM, or Memantine, during 7 days after intracerebroventricular administration of oligomerized Aß25-35. Mice were then tested for spatial short-term memory on day 8 and non-spatial long-term memory on days 9-10, using the spontaneous alternation or passive avoidance tests, respectively. The FENM or Memantine combination with Donepezil, that non-selectively inhibits acetylcholinesterase and activates S1R, was also tested. The efficacy of combinations using maximal non-active or minimal active doses of S1R agonist or FENM was analyzed using calculations of the combination index, based on simple isobologram representation. Data showed that most of the FENM-based combinations led to synergistic protection against Aß25-35-induced learning deficits, for both long- and short-term memory responses, with a higher efficiency on the latter. Memantine led to synergistic combination in short-term memory but poorly in long-term memory responses, with either PRE-084 or Donepezil. These study showed that drug combinations based on FENM and S1R agonists may lead to highly effective and synergistic protection in AD, particularly on short-term memory.


Assuntos
Doença de Alzheimer , Fármacos Neuroprotetores , Receptores sigma , Camundongos , Animais , Memantina/farmacologia , Doença de Alzheimer/metabolismo , Donepezila/uso terapêutico , Acetilcolinesterase , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Receptores sigma/metabolismo
18.
Neurochem Res ; 49(3): 758-770, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38104040

RESUMO

Maple Syrup Urine Disease (MSUD) is a metabolic disease characterized by the accumulation of branched-chain amino acids (BCAA) in different tissues due to a deficit in the branched-chain alpha-ketoacid dehydrogenase complex. The most common symptoms are poor feeding, psychomotor delay, and neurological damage. However, dietary therapy is not effective. Studies have demonstrated that memantine improves neurological damage in neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases. Therefore, we hypothesize that memantine, an NMDA receptor antagonist can ameliorate the effects elicited by BCAA in an MSUD animal model. For this, we organized the rats into four groups: control group (1), MSUD group (2), memantine group (3), and MSUD + memantine group (4). Animals were exposed to the MSUD model by the administration of BCAA (15.8 µL/g) (groups 2 and 4) or saline solution (0.9%) (groups 1 and 3) and treated with water or memantine (5 mg/kg) (groups 3 and 4). Our results showed that BCAA administration induced memory alterations, and changes in the levels of acetylcholine in the cerebral cortex. Furthermore, induction of oxidative damage and alterations in antioxidant enzyme activities along with an increase in pro-inflammatory cytokines were verified in the cerebral cortex. Thus, memantine treatment prevented the alterations in memory, acetylcholinesterase activity, 2',7'-Dichlorofluorescein oxidation, thiobarbituric acid reactive substances levels, sulfhydryl content, and inflammation. These findings suggest that memantine can improve the pathomechanisms observed in the MSUD model, and may improve oxidative stress, inflammation, and behavior alterations.


Assuntos
Doença da Urina de Xarope de Bordo , Ratos , Animais , Doença da Urina de Xarope de Bordo/tratamento farmacológico , Doença da Urina de Xarope de Bordo/metabolismo , Memantina/farmacologia , Memantina/uso terapêutico , Acetilcolinesterase , Modelos Animais de Doenças , Aminoácidos de Cadeia Ramificada , Antioxidantes/farmacologia , Inflamação
19.
J Ethnopharmacol ; 323: 117609, 2024 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-38142875

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: In elderly people, Alzheimer's disease (AD) is the most common form of dementia. It has been shown that traditional Chinese medicine (TCM) based on phytomedicines enhances the therapeutic effects of modern medicine when taken in conjunction with them. Modern medicine N-methyl-D-aspartate receptor (NMDA) antagonist memantine (Mm) are mainly used in the clinical treatment of AD. TCM Cerebralcare Granule® (CG) has long been an effective treatment for headaches, dizziness, and other symptoms. In this study, we employ a blend of CG and Mm to address Alzheimer's disease-like symptoms and explore their impacts and underlying mechanisms. AIM OF THE STUDY: The objective of our study was to observe the effects of CG combined with Memantine (Mm) on learning and memory impairment of AD mice induced by D-galactose and to explore the mechanism at work. MATERIALS AND METHODS: CG and Mm were combined to target multiple pathological processes involved in AD. For a thorough analysis, we performed various experiments such as behavioral detection, pathological detection, proteomic detection, and other experimental methods of detection. RESULTS: It was found that the combination of CG and Mm was significantly effective for improving learning and memory in AD mice as well as brain pathology. The serum and hippocampal tissue of AD mice were significantly enhanced with catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) activities and malondialdehyde (MDA) levels were decreased with this treatment. In AD mice, a combination of Mm and CG (CG + Mm) significantly increased the levels of the anti-inflammatory factors IL-4 and IL-10, decreased the levels of pro-inflammatory factors (IL-6, IL-1ß) and tumor necrosis factor-alpha (TNF-α), improved synaptic plasticity by restoring synaptophysin (SYP) and postsynaptic density protein-95 (PSD-95) expression in the hippocampus, enhanced Aß phagocytosis of microglia in AD mice, and increased mitochondrial respiratory chain enzyme complexes I, II, III, and IV, lead to an increase in the number of functionally active NMDA receptors in the hippocampus. Proteomic analysis GO analysis showed that the positive regulation gene H3BIV5 of G protein coupled receptor signal pathway and synaptic transmission was up-regulated, while the transsynaptic signal of postsynaptic membrane potential and regulation-related gene Q5NCT9 were down-regulated. Most proteins showed significant enriched signal transduction pathway profiles after CG + Mm treatment, based on the KEGG pathway database. CONCLUSION: The data supported the idea that CG and Mm could be more effective in treating AD mice induced by D-galactose than Mm alone. We provided a basis for the clinical use of CG with Mm.


Assuntos
Doença de Alzheimer , Humanos , Camundongos , Animais , Idoso , Doença de Alzheimer/metabolismo , Memantina/efeitos adversos , Galactose , Proteômica , Hipocampo , Antioxidantes/farmacologia
20.
Neurol Res ; 46(3): 261-271, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38122814

RESUMO

INTRODUCTION: The neuroinflammatory response was seen to impact the formation of phosphorylated tau protein in Alzheimer's disease (AD). This study aims to investigate the molecular mechanism of minocycline in reducing phosphorylated tau protein formation in the hippocampus of lipopolysaccharide (LPS)-induced rats. METHODS: Fifty adult male Sprague Dawley (SD) rats were randomly allocated to 1 of 5 groups: control, LPS (5 mg/kg), LPS + minocycline (25 mg/kg), LPS + minocycline (50 mg/kg) and LPS + memantine (10 mg/kg). Minocycline and memantine were administered intraperitoneally (i.p) for two weeks, and LPS was injected i.p. once on day 5. ELISA was used to determine the level of phosphorylated tau protein in SD rats' hippocampal tissue. The density and expression of Toll-like receptor-4 (TLR-4), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-кß), tumour necrosis factor-alpha (TNF-α), and cyclooxygenase (COX)-2 were determined using Western blot and immunohistochemistry. RESULTS: Minocycline, like memantine, prevented LPS-induced increasein phosphorylated tau protein level suggested via reduced density and expression of TLR-4, NF-кß, TNF-αand COX-2 proteins in rat hippocampal tissue. Interestingly, higher doses were shown to be more neuroprotective than lower doses. CONCLUSION: This study suggests that minocycline suppresses the neuroinflammation signalling pathway and decreased phosphorylated tau protein formation induced by LPS in a dose-dependent manner. Minocycline can be used as a preventative and therapeutic drug for neuroinflammatory diseases such as AD.


Assuntos
Doença de Alzheimer , Minociclina , Ratos , Animais , Masculino , Minociclina/farmacologia , Minociclina/uso terapêutico , Proteínas tau/metabolismo , Doenças Neuroinflamatórias , Lipopolissacarídeos , Ratos Sprague-Dawley , Memantina/farmacologia , Memantina/metabolismo , Receptor 4 Toll-Like/metabolismo , Hipocampo/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , NF-kappa B/metabolismo
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