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2.
Medicine (Baltimore) ; 99(33): e21745, 2020 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-32872063

RESUMO

BACKGROUND: Alzheimer disease (AD) is a leading progressive neurodegenerative disease worldwide, but treating it is challenging in clinical practice. This review is aimed at evaluating the efficacy and safety of herbal medicine for treating AD. METHODS AND ANALYSIS: We will search for randomized controlled trials related to the effect and safety of herbal medicine for AD in the following databases: PubMed, Cochrane Central Register of Controlled Trials, Excerpta Medica Database, China National Knowledge Infrastructure database, Oriental Medicine Advanced Searching Integrated system, Korean Traditional Knowledge Portal, and Citation Information by National Institute for Informatics. The risk of bias will be evaluated using the Cochrane risk-of-bias assessment tool. After screening the studies, a meta-analysis will be performed. The primary outcome will be the Mini-Mental State Examination score. Secondary outcomes will consist of other scales for cognitive function and other aspects, such as behavioral and psychological symptoms and plasma levels of amyloid-ß. RESULTS: This study will provide the current status of evidence for herbal medicine to treat AD. CONCLUSION: The results of this review will determine the efficacy and safety of herbal medicine for AD. ETHICS AND DISSEMINATION: Ethical approval is not required, as this study is based on a review of published research. This review will be published in a peer-reviewed journal and disseminated both electronically and in print. TRIAL REGISTRATION NUMBER: Research Registry reviewregistry933.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Fitoterapia , Extratos Vegetais/uso terapêutico , Medicina Herbária , Humanos , Metanálise como Assunto , Revisões Sistemáticas como Assunto
3.
Nat Commun ; 11(1): 4790, 2020 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-32963242

RESUMO

Preventing aggregation of amyloid beta (Aß) peptides is a promising strategy for the treatment of Alzheimer's disease (AD), and gold nanoparticles have previously been explored as a potential anti-Aß therapeutics. Here we design and prepare 3.3 nm L- and D-glutathione stabilized gold nanoparticles (denoted as L3.3 and D3.3, respectively). Both chiral nanoparticles are able to inhibit aggregation of Aß42 and cross the blood-brain barrier (BBB) following intravenous administration without noticeable toxicity. D3.3 possesses a larger binding affinity to Aß42 and higher brain biodistribution compared with its enantiomer L3.3, giving rise to stronger inhibition of Aß42 fibrillation and better rescue of behavioral impairments in AD model mice. This conjugation of a small nanoparticle with chiral recognition moiety provides a potential therapeutic approach for AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/efeitos dos fármacos , Ouro/farmacologia , Transtornos da Memória/tratamento farmacológico , Nanopartículas Metálicas/química , Fragmentos de Peptídeos/efeitos dos fármacos , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Masculino , Transtornos da Memória/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Fragmentos de Peptídeos/metabolismo , Estereoisomerismo
4.
Nat Commun ; 11(1): 4571, 2020 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-32917871

RESUMO

Early therapeutic interventions are essential to prevent Alzheimer Disease (AD). The association of several inflammation-related genetic markers with AD and the early activation of pro-inflammatory pathways in AD suggest inflammation as a plausible therapeutic target. Inflammatory Caspase-1 has a significant impact on AD-like pathophysiology and Caspase-1 inhibitor, VX-765, reverses cognitive deficits in AD mouse models. Here, a one-month pre-symptomatic treatment of Swedish/Indiana mutant amyloid precursor protein (APPSw/Ind) J20 and wild-type mice with VX-765 delays both APPSw/Ind- and age-induced episodic and spatial memory deficits. VX-765 delays inflammation without considerably affecting soluble and aggregated amyloid beta peptide (Aß) levels. Episodic memory scores correlate negatively with microglial activation. These results suggest that Caspase-1-mediated inflammation occurs early in the disease and raise hope that VX-765, a previously Food and Drug Administration-approved drug for human CNS clinical trials, may be a useful drug to prevent the onset of cognitive deficits and brain inflammation in AD.


Assuntos
Envelhecimento/metabolismo , Doença de Alzheimer/metabolismo , Disfunção Cognitiva/metabolismo , Serpinas/metabolismo , Proteínas Virais/metabolismo , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Animais , Comportamento Animal , Disfunção Cognitiva/tratamento farmacológico , Citocinas/metabolismo , Dipeptídeos/sangue , Dipeptídeos/farmacologia , Modelos Animais de Doenças , Encefalite/metabolismo , Encefalite/patologia , Feminino , Humanos , Inflamação/metabolismo , Masculino , Transtornos da Memória/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Serpinas/sangue , Serpinas/farmacologia , Memória Espacial/fisiologia , Proteínas Virais/sangue , Proteínas Virais/farmacologia , para-Aminobenzoatos/sangue , para-Aminobenzoatos/farmacologia
5.
Medicine (Baltimore) ; 99(38): e22370, 2020 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-32957414

RESUMO

BACKGROUND: Dementia among the Japanese aged 65 years or over population is estimated to approach about 700 million cases by 2025, and a corresponding rapid increase in Alzheimer disease (AD) can also be expected. The ballooning number of dementia patients, including AD, is creating major medical and social challenges. At present, only 3 drugs are recognized for the treatment of mild AD, and these are only used to alleviate symptoms. Although new therapies are needed to treat mild AD, insufficient development of disease-modifying drugs is being done. METHODS/DESIGN: The aim of this exploratory, open standard, treatment-controlled, randomized allocation, multicenter trial is to determine the efficacy of the traditional Japanese Kampo medicine hachimijiogan (HJG) on the cognitive dysfunction of mild AD.Eighty-six patients with AD diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 and as mild AD according to the Mini Mental State Examination (MMSE ≥21) will be included. All will already have been taking the same dose of Donepezil, Galantamine, or Rivastigmine for more than 3 months. The patients will be randomly assigned to receive additional treatment with HJG or to continue mild AD treatment without additional HJG. The primary endpoint is the change from baseline of the Alzheimer's Disease Assessment Scale-cognitive component- Japanese version (ADAS-Jcog). ADAS-Jcog is a useful index for detecting change over time that investigates memory and visuospatial cognition injury from the early stage. The secondary endpoints are the changes from baseline of the Instrumental Activity of Daily Life, Apathy scale, and Nueropsychiatric Inventory scores. In this protocol, we will examine the Geriatric depression scale and do Metabolome analysis as exploratory endpoints. The recruitment period will be from August 2019 to July 2021. DISCUSSION: This is the first trial of Kampo medicine designed to examine the efficacy of HJG for the cognitive dysfunction of patients with mild AD. TRIAL REGISTRATION: This trial was registered on the Japan Registry of Clinical trials on 2 August 2, 2019 (jRCTs 071190018).


Assuntos
Doença de Alzheimer/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Idoso , Cognição/efeitos dos fármacos , Feminino , Humanos , Masculino , Medicina Kampo/métodos , Estudos Multicêntricos como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto
6.
Medicine (Baltimore) ; 99(36): e21924, 2020 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-32899026

RESUMO

BACKGROUND: Alzheimer's disease (AD) is an age-related neurodegenerative disease that is slowly becoming a global problem. Salvia miltiorrhiza (SM) has a history of thousands of years of use in China. In recent years, SM has been reported to have the effect of improving Alzheimer's disease. However, there is no systematic review of its efficacy and safety yet. Therefore, we propose a systematic review to evaluate the efficacy and safety of SM for AD patients. METHODS: Six databases will be searched: China National Knowledge Infrastructure (CNKI), China Biological Medicine (CBM), China Scientific Journals Database (CSJD), Wanfang database, PubMed, and EMBASE. The information is searched from January 2010 to July 2020. Languages are limited to English and Chinese. The primary outcomes include changes in the Mini-Mental State Examination (MMSE), Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog) and Activities of Daily Living scale (ADL). Additional outcomes include clinical effective rate and adverse event rate. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system will be used to assess the strength of the evidence. RESULTS: This systematic review will evaluate the efficacy and safety of SM in the treatment of Alzheimer's disease. CONCLUSION: This systematic review provides evidence as to whether SM is effective and safe for Alzheimer's disease patients. SYSTEMATIC REVIEW REGISTRATION: INPLASY202070066.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Salvia miltiorrhiza , Humanos , Metanálise como Assunto , Revisões Sistemáticas como Assunto
7.
PLoS One ; 15(8): e0237153, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32791516

RESUMO

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease characterized by cognitive dysfunction and memory loss as the main symptoms. The deposition of amyloid beta (Aß) and tau hyperphosphorylation are hallmarks of AD and are major therapeutic targets. However, the exact etiology has not yet been fully elucidated; thus, no drug that cures the disease has been approved. JBPOS0101 is a phenyl carbamate compound that has been tested as a drug for epileptic diseases. In our previous study, we showed that JBPOS0101 attenuated the accumulation of Aß as well as the deficits in learning and memory in the 5xFAD mouse model. Here, we tested the dose effect (70 or 35 mg/kg) of JBPOS0101 on the memory defect and pathological markers and further investigated the underlying mechanisms in 5xFAD mice. In the behavior tests, JBPOS0101 treatment ameliorated deficits in learning and memory. Moreover, JBPOS0101 attenuated Aß accumulation and tau phosphorylation. The elevated phosphorylation levels of the active GSK3ß form (GSK3ß-y216) in 5xFAD, which are responsible for tau phosphorylation, decreased in the JBPOS0101-treated groups. Furthermore, the elevation of reactive astrocytes and microglia in 5xFAD mice was attenuated in JBPOS0101-treated groups. These data suggest that JBPOS0101 may be a new drug candidate to lessen amyloid- and tau-related pathology by regulating glial cells.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Microglia/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Proteínas tau/metabolismo , Animais , Feminino , Glicogênio Sintase Quinase 3 beta/metabolismo , Memória , Camundongos , Microglia/metabolismo , Fármacos Neuroprotetores/uso terapêutico
8.
Life Sci ; 259: 118287, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32814066

RESUMO

Alzheimer's disease (AD) is a fatal neurodegenerative disease that requires immediate attention. Oxidative stress that leads to the generation of reactive oxygen species is a contributing factor to the disease progression by promoting synthesis and deposition of amyloid-ß, the main hallmark protein in AD. It has been previously demonstrated that nanoyttria possesses antioxidant properties and can alleviate cellular oxidative injury in various toxicity and disease models. This review proposed that nanoyttria could be used for the treatment of AD. In this paper, the evidence on the antioxidant potential of nanoyttria is presented and its prospects on AD therapy are discussed.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Depuradores de Radicais Livres/farmacologia , Nanopartículas/administração & dosagem , Estresse Oxidativo/efeitos dos fármacos , Ítrio/uso terapêutico , Doença de Alzheimer/metabolismo , Animais , Humanos , Ratos , Ítrio/administração & dosagem
9.
Life Sci ; 257: 118037, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32622942

RESUMO

Palmitoylethanolamide (PEA) is an endogenous lipid mediator that, also by blunting astrocyte activation, demonstrated beneficial properties in several in vitro and in vivo models of Alzheimer's disease (AD). In the present study, we used astrocyte-neuron co-cultures from 3xTg-AD mouse (i.e. an animal model of AD) cerebral cortex to further investigate on the role of astrocytes in PEA-induced neuroprotection. To this aim, we evaluated the number of viable cells, apoptotic nuclei, microtubule-associated protein-2 (MAP2) positive cells and morphological parameters in cortical neurons co-cultured with cortical astrocytes pre-exposed, or not, to Aß42 (0.5 µM; 24 h) or PEA (0.1 µM; 24 h). Pre-exposure of astrocytes to Aß42 failed to affect the viability, the number of neuronal apoptotic nuclei, MAP2 positive cell number, neuritic aggregations/100 µm, dendritic branches per neuron, the neuron body area, the length of the longest dendrite and number of neurites/neuron in 3xTg-AD mouse astrocyte-neuron co-cultures. Compared to neurons from wild-type (non-Tg) mouse co-cultures, 3xTg-AD mouse neurons co-cultured with astrocytes from this mutant mice displayed higher number of apoptotic nuclei, lower MAP2 immunoreactivity and several morphological changes. These signs of neuronal suffering were significantly counteracted when the 3xTg-AD mouse cortical neurons were co-cultured with 3xTg-AD mouse astrocytes pre-exposed to PEA. The present data suggest that in astrocyte-neuron co-cultures from 3xTg-AD mice, astrocytes contribute to neuronal damage and PEA, by possibly counteracting reactive astrogliosis, improved neuronal survival. These findings further support the role of PEA as a possible new therapeutic opportunity in AD treatment.


Assuntos
Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Etanolaminas/farmacologia , Ácidos Palmíticos/farmacologia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Sobrevivência Celular/efeitos dos fármacos , Córtex Cerebral/metabolismo , Técnicas de Cocultura , Modelos Animais de Doenças , Etanolaminas/metabolismo , Gliose , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Proteínas Associadas aos Microtúbulos , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Ácidos Palmíticos/metabolismo , Proteínas tau/metabolismo
10.
Life Sci ; 257: 118020, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32603820

RESUMO

Alzheimer's disease (AD) is the most common form of dementia worldwide. ß-amyloid peptide (Aß) is currently assumed to be the main cause of synaptic dysfunction and cognitive impairments in AD, but the molecular signaling pathways underlying its neurotoxic consequences have not yet been completely explored. Additional investigations regarding these pathways will contribute to development of new therapeutic targets. In context, developing evidence suggest that Aß decreases brain-derived neurotrophic factor (BDNF) mostly by lowering phosphorylated cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) protein. In fact, it has been observed that brain or serum levels of BDNF appear to be beneficial markers for cognitive condition. In addition, the participation of transcription mediated by CREB has been widely analyzed in the memory process and AD development. Designing pharmacologic or genetic therapeutic approaches based on the targeting of CREB-BDNF signaling could be a promising treatment potential for AD. In this review, we summarize data demonstrating the role of CREB-BDNF signaling pathway in cognitive status and mediation of Aß toxicity in AD. Finally, we also focus on the developing intervention methods for improvement of cognitive decline in AD based on targeting of CREB-BDNF pathway.


Assuntos
Doença de Alzheimer/terapia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/fisiologia , Cognição/fisiologia , Transtornos Cognitivos/metabolismo , Disfunção Cognitiva/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/fisiologia , Modelos Animais de Doenças , Humanos , Memória/fisiologia , Neurônios/metabolismo , Fosforilação , Transdução de Sinais
11.
ACS Chem Neurosci ; 11(15): 2145-2148, 2020 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-32662982

RESUMO

Studies have shown that the calcium ion (Ca2+) plays important roles both in Alzheimer's dementia and SARS-CoV S-mediated fusion to host cell entry. An elevated level of intracellular calcium causes neuronal dysfunction, cell death, and apoptosis. Dysregulation of calcium has also been shown to increase the production of amyloid beta (Aß) protein, the hallmark of Alzheimer's dementia. Reversely, deposition of Aß is also responsible for calcium dysregulation. On the other hand, it has been well investigated that viruses can disturb host cell Ca2+ homeostasis as well as modulate signal transduction mechanisms. Viruses can also hijack the host cell calcium channels and pumps to release more intracellular Ca2+ to utilize for their life cycle. Even though evidence has not been reported on SARS-CoV-2 concerning Ca2+ regulation, however, it has been well established that Ca2+ is essential for viral entry, viral gene replication, and virion maturation and release. Recent reports suggest that SARS-CoV needs two Ca2+ ions to fuse with the host cell at the entry step. Furthermore, some calcium channel blockers (CCBs), such as nimodipine, memantine, etc., have been reported to be effective in the treatment of dementia in Alzheimer's disease (AD) as well as have shown inhibition in various virus infections.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Betacoronavirus , Bloqueadores dos Canais de Cálcio/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Doença de Alzheimer/metabolismo , Doença de Alzheimer/psicologia , Cálcio/metabolismo , Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio/metabolismo , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/psicologia , Humanos , Pandemias , Pneumonia Viral/metabolismo , Pneumonia Viral/psicologia , Resultado do Tratamento
12.
Nat Rev Drug Discov ; 19(7): 447-462, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32612262

RESUMO

A large number of mouse models have been engineered, characterized and used to advance biomedical research in Alzheimer disease (AD). Early models simply damaged the rodent brain through toxins or lesions. Later, the spread of genetic engineering technology enabled investigators to develop models of familial AD by overexpressing human genes such as those encoding amyloid precursor protein (APP) or presenilins (PSEN1 or PSEN2) carrying mutations linked to early-onset AD. Recently, more complex models have sought to explore the impact of multiple genetic risk factors in the context of different biological challenges. Although none of these models has proven to be a fully faithful reproduction of the human disease, models remain essential as tools to improve our understanding of AD biology, conduct thorough pharmacokinetic and pharmacodynamic analyses, discover translatable biomarkers and evaluate specific therapeutic approaches. To realize the full potential of animal models as new technologies and knowledge become available, it is critical to define an optimal strategy for their use. Here, we review progress and challenges in the use of AD mouse models, highlight emerging scientific innovations in model development, and introduce a conceptual framework for use of preclinical models for therapeutic development.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Modelos Animais de Doenças , Desenvolvimento de Medicamentos/métodos , Doença de Alzheimer/genética , Doença de Alzheimer/fisiopatologia , Animais , Biomarcadores/metabolismo , Avaliação Pré-Clínica de Medicamentos/métodos , Predisposição Genética para Doença , Humanos , Camundongos , Mutação , Fatores de Risco
13.
Travel Med Infect Dis ; 36: 101812, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32645478

RESUMO

BACKGROUND: Hydroxychloroquine (HCQ) is currently being examined for COVID-19. No previous meta-analysis has evaluated its side effects versus placebo. We conducted this meta-analysis to compare the safety of HCQ versus placebo. METHODS: Two authors independently searched PubMed and EMBASE databases for randomized controlled trials (RCTs) of adults comparing the adverse events (AEs) of HCQ versus placebo for any indication. Peto odds ratios (Peto ORs) and 95% confidence intervals (CIs) were calculated based on random-effects models. The heterogeneity (I2) was assessed using Cochran's Q test. RESULTS: Nine RCTs (eight were double-blind) with a total of 916 patients were included. HCQ caused significantly more skin pigmentation than placebo (Peto OR, 4.64; 95% CI, 1.13 to 19.00; P-value = 0.033; I2 = 0%). The increase in other AEs did not reach statistical significance: rash (Peto OR, 1.11; 95% CI, 0.3 to 3.77; P-value = 0.03; I2 = 0%); gastrointestinal AEs (Peto OR, 1.43; 95% CI, 0.55 to 3.72; P-value = 0.46; I2 = 15.17%); headache (Peto OR, 1.94; 95% CI, 0.65 to 5.78; P-value = 0.23; I2 = 9.99%); dizziness (Peto OR, 1.32; 95% CI, 0.49 to 3.52; P-value = 0.58; I2 = 0%); fatigue (Peto OR, 2.13; 95% CI, 0.76 to 5.98; P-value = 0.15; I2 = 0%); and visual AEs (Peto OR, 1.61; 95% CI, 0.76 to 3.41; P-value = 0.22; I2 = 0%). Cardiac toxicity was not reported. CONCLUSIONS: This meta-analysis of RCTs found a significantly higher risk of skin pigmentation in HCQ users versus placebo. More data are needed to evaluate HCQ in the context of COVID-19 treatment.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Antirreumáticos/efeitos adversos , Urticária Crônica/tratamento farmacológico , Glomerulonefrite por IGA/tratamento farmacológico , Infecções por HIV/tratamento farmacológico , Hidroxicloroquina/efeitos adversos , Hiperpigmentação/induzido quimicamente , Doenças Reumáticas/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Infecções Assintomáticas , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Tontura/induzido quimicamente , Exantema/induzido quimicamente , Fadiga/induzido quimicamente , Gastroenteropatias/induzido quimicamente , Cefaleia/induzido quimicamente , Humanos , Lúpus Eritematoso Cutâneo/tratamento farmacológico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Osteoartrite/tratamento farmacológico , Pandemias , Pneumonia Viral/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto
14.
PLoS One ; 15(7): e0236318, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32726319

RESUMO

Lately, Drosophila has been favored as a model in sleep and circadian rhythm research due to its conserved mechanism and easily manageable operation. These studies have revealed the sophisticated parameters in whole-day sleep profiles of Drosophila, drawing connections between Drosophila sleep and human sleep. In this study, we tested several sleep deprivation protocols (mechanical shakes and light interruptions) on Drosophila and delineated their influences on Drosophila sleep. We applied a daytime light-deprivation protocol (DD) mimicking jet-lag to screen drugs that alleviate sleep deprivation. Characteristically, classical sleep-aid compounds exhibited different forms of influence: phenobarbital and pentobarbital modified total sleep time, while melatonin only shortened the latency to sleep. Such results construct the basis for further research on sleep benefits in other treatments in Drosophila. We screened seven herb extracts, and found very diverse results regarding their effect on sleep regulation. For instance, Panax notoginseng and Withania somnifera extracts displayed potent influence on total sleep time, while Melissa officinalis increased the number of sleep episodes. By comparing these treatments, we were able to rank drug potency in different aspects of sleep regulation. Notably, we also confirmed the presence of sleep difficulties in a Drosophila Alzheimer's disease (AD) model with an overexpression of human Abeta, and recognized clear differences between the portfolios of drug screening effects in AD flies and in the control group. Overall, potential drug candidates and receipts for sleep problems can be identified separately for normal and AD Drosophila populations, outlining Drosophila's potential in drug screening tests in other populations if combined with the use of other genetic disease tools.


Assuntos
Extratos Vegetais/farmacologia , Privação do Sono/tratamento farmacológico , Transtornos do Sono-Vigília/tratamento farmacológico , Sono/fisiologia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/genética , Animais , Ritmo Circadiano/efeitos dos fármacos , Modelos Animais de Doenças , Drosophila melanogaster/efeitos dos fármacos , Drosophila melanogaster/genética , Drosophila melanogaster/fisiologia , Regulação da Expressão Gênica/genética , Humanos , Melatonina/farmacologia , Mutação , Panax notoginseng/química , Fenobarbital/farmacologia , Extratos Vegetais/química , Sono/efeitos dos fármacos , Sono/genética , Privação do Sono/genética , Privação do Sono/fisiopatologia , Transtornos do Sono-Vigília/genética , Transtornos do Sono-Vigília/fisiopatologia , Withania/química
15.
J Pharmacol Sci ; 143(4): 245-254, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32482409

RESUMO

The accumulation of insoluble amyloid ß (Aß) peptides is one of the pathological changes in Alzheimer's disease (AD), which induced synaptic plasticity impairment and excitatory amino acid toxicity associated with decreased memory function. Xingnaojing (XNJ), a well-known prescription in traditional Chinese medicine, has been used for the treatment of stroke for many years in China. In this study, we aim to investigate the therapeutic effects of XNJ in a hippocampus of Aß1-42 induced mouse model of AD which showed significant memory loss and impaired synaptic morphology and function. Treatment of XNJ could attenuate spatial and working memory dysfunction, increase dendritic spine density and improve long-term potential (LTP) induction. In addition, XNJ treatment significantly increased the level of N-methyl-d-aspartate receptors (NMDARs) and inhibit the NMDA/α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) ratio in AD mice. XNJ treatment also activated the AKT/mechanistic target of rapamycin (mTOR) pathway, while inhibition of the mTOR pathway by rapamycin could reverse the protective effects of XNJ treatment. In conclusion, XNJ protected against synaptic plasticity and memory impairment in AD mice via the activation of AKT/mTOR signaling pathway, suggesting XNJ as an alternative treatment for AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Transtornos da Memória/tratamento farmacológico , Plasticidade Neuronal/efeitos dos fármacos , Fragmentos de Peptídeos/metabolismo , Doença de Alzheimer/metabolismo , Animais , Modelos Animais de Doenças , Masculino , Camundongos Endogâmicos C57BL
16.
Value Health ; 23(6): 710-718, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32540228

RESUMO

OBJECTIVES: Decision-analytic models for Alzheimer's disease (AD) have been advanced to a discrete-event simulation (DES), in which individual-level modeling of disease progression across continuous severity spectra become feasible. This study aimed to apply DES to perform cost-effectiveness analysis of AD treatment in Thailand. METHODS: A data set of Thai AD patients, representing unique demographic and clinical characteristics, was bootstrapped to generate a baseline cohort of 50 000 patients. Each patient was cloned and assigned to donepezil, galantamine, rivastigmine, memantine, or no treatment. Correlated changes in cognitive and behavioral status over time were developed using patient-level data. Treatment effects were obtained from the most recent network meta-analysis. Treatment persistence; mortality; and predictive equations for functional status, costs (Thai baht in 2017), and quality-adjusted life-year (QALY) were derived from country-specific real-world data. RESULTS: From a societal perspective, only the prescription of donepezil to AD patients with all disease-severity levels was found to be cost-effective (incremental cost-effectiveness ratio): 138 524 Thai baht/QALY ($4062/QALY)]. Regardless of whether the treatment-stopping rule when the mini-mental state examination score <10 was introduced, providing early treatment with donepezil to mild AD patients further reduced the incremental cost-effectiveness ratio. Extensive sensitivity analyses indicated robust simulation findings. CONCLUSIONS: Discrete-event simulation greatly enhances the real-world representativeness of decision-analytic models for AD. Donepezil is the most cost-effective treatment option for AD in Thailand and is worth being considered for universal financial coverage. Application of DES in heath technology assessment should be encouraged, especially when the validity of the model is questionable with classical modeling methods.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Nootrópicos/uso terapêutico , Anos de Vida Ajustados por Qualidade de Vida , Avaliação da Tecnologia Biomédica , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/economia , Estudos de Coortes , Simulação por Computador , Análise Custo-Benefício , Técnicas de Apoio para a Decisão , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nootrópicos/economia , Estudos Retrospectivos , Tailândia , Resultado do Tratamento
17.
Life Sci ; 256: 117996, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32585249

RESUMO

Alzheimer's disease (AD) is a neurodegenerative disorder and is identified as the most common cause for dementia. Despite huge global economic burden and the impact on the close family of the patients, there is no definitive cure and thus, improved treatment methods are of need. While memory and cognition are severely affected in AD, exact etiology is yet unknown. The ß-Amyloid plaque formation and aggregation hypothesis is among the well-known hypotheses used to explain disease pathogenesis. Currently there are five Food and Drug Administration (FDA) approved drugs as treatment options. All these drugs are used for symptomatic treatment of AD. Thus, disease modifying therapies which can directly address the pathological changes in AD, are needed. Such therapies could be designed based on inhibiting key steps of pathogenesis. Currently there are novel AD drug candidates with various therapeutic mechanisms, undergoing different stages of drug development. Extensive research is being done globally to broaden understanding of the exact mechanisms involved in AD and to develop therapeutic agents that can successfully hinder the occurrence and progression of the disease. In this review, a comprehensive approach to understanding AD and suggestions to be considered in the development of therapeutics for it are presented.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Desenvolvimento de Medicamentos , Doença de Alzheimer/fisiopatologia , Animais , Progressão da Doença , Desenho de Fármacos , Humanos
18.
Am J Geriatr Psychiatry ; 28(9): 913-920, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32507686

RESUMO

Advances in treating and preventing Alzheimer disease and other neurocognitive disorders of aging arise from rigorous preclinical and clinical research, with randomized controlled treatment trials as the last and definitive test. The COVID-19 pandemic has greatly disrupted ongoing interventional studies and researchers are scrambling to find ways to safely continue this critical work amidst rapidly shifting guidelines from sponsors, institutions, and state and federal guidelines. Here the authors describe novel approaches and work-flow adaptations to study visits, drug delivery and interim and endpoint safety and outcomes assessments to avoid sacrificing years of preparation and substantial financial investments, to work in the best interest of participants and their caregivers, and to continue on the path toward discovering disease-modifying treatments for the millions of individuals impacted by major neurocognitive disorders.


Assuntos
Ensaios Clínicos como Assunto/métodos , Ensaios Clínicos como Assunto/normas , Infecções por Coronavirus/prevenção & controle , Transtornos Neurocognitivos/tratamento farmacológico , Transtornos Neurocognitivos/prevenção & controle , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Idoso , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/prevenção & controle , Betacoronavirus , Guias como Assunto , Humanos
19.
Adv Gerontol ; 33(2): 273-281, 2020.
Artigo em Russo | MEDLINE | ID: mdl-32593241

RESUMO

The analysis of experiments and clinical data about research of neurobiological effects of chinese herbal medicine, which is used by Alzheimer`s disease treatment, was presented in given overview. The rats with injection of Aß1-42 or Aß25-35 peptides, or ibotenic acid, or streptozotocin as well as the natural line of mice SAMP8 with the phenotype of accelerated aging and other were used as the experimental models of Alzheimer`s disease. Various neurobiological effects of various herbal decoctions in the cells of hippocampus were demonstrated - the inhibition of amyloid ß peptides aggregation, increasing of neurons quantity with normal morphology and decreasing of apoptotic cells, decreasing of inducible nitric oxide synthase (iNOS) production, decreasing of reactive expression level of RAGE and increasing reactive expression level of LRP-1, decreasing of tau protein phosphorylation at Thr231 and Ser422, inhibition of expression of GSK-3ß and CDK-5, decreasing of activation and inflammation of microglia, production of 15 types of N-glycans in the cerebral cortex layers, which are absent in experimental animals. The improvement of memorization and training abilities was established.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Hipocampo/efeitos dos fármacos , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Modelos Animais de Doenças , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Proteínas tau/metabolismo
20.
Life Sci ; 256: 117912, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32504755

RESUMO

Histone deacetylase enzymes were prominent chromatin remodeling drug that targets in the pathophysiology of Alzheimer's disease associated with transcriptional dysregulation. In vitro and in vivo models of AD have demonstrated overexpression of HDAC activity. Non-specificity and non-selectivity of HDAC are the major problems of existing HDAC inhibitors. Hence, we aim to set up a methodology describing the rational development of isoform-selective HDAC inhibitor targeting class, I and class IIb. A convenient multistage virtual screening followed by machine learning and IC50 screenings were used to classify the 5064 compounds into inhibitors and non-inhibitors classes retrieved from the ChEMBL database. ADMET analysis identified the pharmacokinetics and pharmacodynamics properties of selected compounds. Molecular docking, along with mutational analysis of eleven compounds, characterized the inhibiting potency. Herein, for the first time, we reported ChEMBL1834473 (2-[[5-(4-chlorophenyl)-1,3,4-thiadiazol-2-yl]amino]-N-hydroxypyrimidine-5-carboxamide) as the isoform-selective HDAC inhibitor, which interact central Zn2+ atom. The negative energy and interacting residue of the ChEMBL1834473 with six HDAC isoform has also been tabulated and mapped. Moreover, our findings concluded histidine, glycine, phenylalanine, and aspartic acid as key residues in protein-ligand interaction and classify 2347 compounds as HDAC inhibitors. Later, a protein-protein interaction network of six HDAC with the key proteins involved in the progression of an AD and signaling pathway, which describes the relationship between ChEMBL1834473 and AD, has been demonstrated using PPI network where the chosen inhibitor will work. Altogether, we conclude that the compound ChEMBL1834473 may be capable of inhibiting all isoforms of class I and class IIb HDAC based on computational analysis for AD therapeutics.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/uso terapêutico , Pirimidinas/química , Pirimidinas/uso terapêutico , Ácido Aspártico/metabolismo , Bases de Dados de Compostos Químicos , Avaliação Pré-Clínica de Medicamentos , Glicina/metabolismo , Histona Desacetilases/metabolismo , Humanos , Aprendizado de Máquina , Simulação de Acoplamento Molecular , Estrutura Molecular , Terapia de Alvo Molecular , Fenilalanina/metabolismo , Isoformas de Proteínas/química , Termodinâmica , Zinco/metabolismo
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