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1.
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
2.
Medicine (Baltimore) ; 99(31): e20707, 2020 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-32756077

RESUMO

INTRODUCTION: There is a risk of cognitive impairment in diabetic patients. Some studies have shown that dipeptidyl peptidase-4 inhibitors (DPP-4) inhibitors can play a protective role in controlling blood glucose and blocking the DPP-4 to attach antibody glucagon-like peptide -1 degradation and prolong antibody glucagon-like peptide -1, promoting the growth of neurites and the formation of synapses. The purpose of this study is to explore the effect of the DPP-4 inhibitor on cognitive impairment in diabetic patients by meta-analysis. METHODS: The system review plan will strictly follow the Systematic Review and Meta-Analysis Protocols entry for reporting. PubMed, EMBASE, Cochrane Library, Clinicaltrials(clinicaltrials.gov), Web of Science, China National Knowledge Infrastructure, China Science and Technology Journal Database and Wanfang Databases will be systematically searched, and all randomized controlled trials comparing DPP-4 inhibitors with placebo or other hypoglycemic drugs to study cognitive impairment in type 2 diabetic patients will be included. The inclusion, evaluation and data extraction of the literature will be conducted by 2 persons independently, and the dispute will be resolved by a third person. All the meta-analysis of the included literature and the research progress of the existing research are analyzed as the main results. ETHICS AND DISSEMINATION: It is to evaluate and analyze the completed research, so there is no ethical problem. The research results will be published in a peer-reviewed journal. REGISTRATION: The protocol of this systematic review and meta-analysis was registered on International Platform of Registered Systematic Review and Meta-analysis Protocols (https://inplasy.com/) (number. 202040185).


Assuntos
Disfunção Cognitiva/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Hipoglicemiantes/uso terapêutico , Disfunção Cognitiva/etiologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Humanos
3.
Life Sci ; 259: 118159, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32763288

RESUMO

AIMS: Parkinson's disease dementia (PDD) is one of the most common non-motor symptoms of advanced Parkinson's disease (PD). This study aimed to determine whether intranasal insulin has protective effects on cognition in the rat PD model induced by 6-hydroxylase dopamine (6-OHDA) through the insulin signaling pathway. MATERIALS AND METHODS: The rats were given intranasal insulin administration for six weeks after unilateral medial forebrain bundle (MFB) injection of 6-OHDA. Then a series of cognitive-behavioral tests, immunofluorescence, and immunoblotting was performed on the rats. KEY FINDINGS: The results demonstrated that the injection of 6-OHDA in the unilateral MFB damaged working memory and long-term habituation of rats in the T-maze rewarded alternation test and hole-board test. Besides, rats with unilateral 6-OHDA injury performed poorly in terms of escape latency and average speed during the hidden platform training phase rather than in the probe trial of the Morris Water Maze (MWM) test. Immunofluorescence results showed that unilateral 6-OHDA injury in MFB led to the massive death of ipsilateral-substantia nigra (SN) tyrosine hydroxylase (TH)-positive neurons. Western blot results further indicated that 6-OHDA-induced necrosis of ipsilateral-SN dopaminergic neurons reduced the levels of p-Akt (Ser473) and p-GSK3ß (Ser9) in the ipsilateral-hippocampus. SIGNIFICANCE: These findings provide a solid evidence base for the relationship between PD cognitive impairment and insulin signaling pathways.


Assuntos
Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/etiologia , Glicogênio Sintase Quinase 3 beta/efeitos dos fármacos , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Proteína Oncogênica v-akt/efeitos dos fármacos , Doença de Parkinson/complicações , Transdução de Sinais/efeitos dos fármacos , Administração Intranasal , Animais , Encéfalo/patologia , Disfunção Cognitiva/psicologia , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/patologia , Glicogênio Sintase Quinase 3 beta/metabolismo , Hipoglicemiantes/administração & dosagem , Insulina/administração & dosagem , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Doença de Parkinson/psicologia , Ratos , Ratos Wistar
4.
Medicine (Baltimore) ; 99(27): e20789, 2020 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-32629662

RESUMO

BACKGROUND: Hypertension in the elderly with cognitive impairment has been one of the global health issues. Mild cognitive impairment (MCI) is the state of transition between the normal aging process and cognitive changes of unformed dementia. Diagnosis and treatment of MCI are the keys to prevent dementia, and hypertension is one of the important influencing factors of MCI. Our preclinical experiment found that Yizhi Qingxin Decoction (YQD) could effectively reduce the blood pressure of spontaneously hypertensive rats (SHR), improve their spatial learning and memory abilities in Morris water maze, and play a neuroprotective role. The objective is to estimate the safety and efficacy of YQD (capsules) in the treatment of hypertension in the elderly with MCI (deficiency of kidney essence syndrome) through this study. METHODS: According to the random number generated by the block random method, 100 participants will be randomly and equally divided into the treatment group (YQD) or the control group (Ginkgo biloba extract tablets). The conversion rate of dementia will be used as the main evaluating indicator by the CDR scale. The MoCA scale, MMSE scale, ADCS-MCI-ADL-24 scale, CGIC-KDS scale, and 24-h ambulatory blood pressure will be used as the secondary evaluating indicator. Safety will be evaluated based on specific manifestations of adverse reactions and the incidence of adverse events. OBJECTIVE: The objective is to estimate the curative effect of YQD (capsules) on hypertension in the elderly with MCI (deficiency of kidney essence syndrome), and to evaluate the safety of its clinical application. TRIAL REGISTRATION: Chinese Clinical Trial Registry (ICTRP member): ChiCTR2000030292.


Assuntos
Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/epidemiologia , Medicamentos de Ervas Chinesas/uso terapêutico , Hipertensão/tratamento farmacológico , Hipertensão/epidemiologia , Idoso , Monitorização Ambulatorial da Pressão Arterial , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/efeitos adversos , Feminino , Humanos , Masculino , Memória , Extratos Vegetais/uso terapêutico , Projetos de Pesquisa , Aprendizagem Espacial
5.
J Clin Psychiatry ; 81(4)2020 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-32726521

RESUMO

OBJECTIVE: To review the efficacy of antidepressants and other therapeutic agents for the treatment of cognitive impairment in adults with major depressive disorder (MDD). DATA SOURCES: We conducted a database search of MEDLINE, PsycINFO, and Embase through Ovid on May 7, 2019. The year of publication was not restricted. The search terms "Major Depressive Disorder," "depress*," "cognit*," and "therapeutics" were used. STUDY SELECTION: The studies included in this review were clinical trials of antidepressants and other therapeutic agents in MDD populations. Participants were aged between 18 and 65 years and had a DSM-III, -IV, or -5 diagnosis of MDD. In total, 2,045 research papers were screened, 53 full-text articles were assessed, and 26 articles were eligible to be included in this systematic review. DATA EXTRACTION: The data and quality of research papers were assessed and screened by 2 independent reviewers. Discrepancies were resolved through a third reviewer. RESULTS: Overall, studies demonstrated that tricyclic antidepressants do not have procognitive effects, while vortioxetine and bupropion have demonstrated procognitive effects in MDD populations relative to selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors. Several non-antidepressant agents, such as modafinil, amphetamines, and erythropoietin, have also demonstrated significant positive effects on cognition in depression. CONCLUSIONS: Present-day antidepressants and other agents have demonstrated procognitive effects in MDD, but the findings between various agents are mixed. Further research looking at objective measures of cognitive performance would be helpful to obtain more definitive results regarding the efficacy of therapeutics for cognitive impairment in MDD.


Assuntos
Antidepressivos/uso terapêutico , Disfunção Cognitiva/tratamento farmacológico , Transtorno Depressivo Maior/tratamento farmacológico , Psicotrópicos/uso terapêutico , Disfunção Cognitiva/complicações , Transtorno Depressivo Maior/complicações , Humanos
6.
Life Sci ; 257: 118049, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32634430

RESUMO

AIMS: Mild traumatic brain injury (mTBI) is an important risk factor for cognitive impairment. Despite intense efforts to develop efficient treatments, the current therapies are not often effective and far from satisfactory. Silymarin has been suggested as a therapeutic agent in the treatment of traumatic brain injury. This study aimed to determine whether silymarin can exert neuroprotective effects on memory impairment following mTBI in mice. MAIN METHODS: After mTBI induction, mice were treated with silymarin once daily for 20 consecutive days by oral gavage. To investigate cognitive functions, animals were subjected to Y-maze, novel-object recognition, and Morris-water maze. Levels of tumor necrosis factor (TNF)-α, glutamate, and brain derived neurotrophic factor (BDNF) were measured in the hippocampus. KEY FINDINGS: Our findings showed that mTBI resulted in a significant decline in memory in the Y-maze and Morris-water maze in both sexes, whereas only impaired cognitive function in males in the novel-object recognition. We found notable increases in TNF-α and glutamate levels in the hippocampus of both sexes, while there was only a significant decrease in hippocampal BDNF in mTBI-induced females. In addition, silymarin treatment improved cognitive impairments in mTBI-induced males but not in females. Silymarin significantly reduced TNF-α and glutamate levels, and increased BDNF levels in the hippocampus of mTBI-induced male but not in female mice. SIGNIFICANCE: This study demonstrates that silymarin treatment sex-dependently improves cognitive impairment in mTBI-induced mice, and suggests that silymarin may be a therapeutic agent for cognitive decline following mTBI in males. Further studies are needed to establish the validity of these findings in humans.


Assuntos
Concussão Encefálica/tratamento farmacológico , Cognição/efeitos dos fármacos , Silimarina/uso terapêutico , Animais , Animais não Endogâmicos , Concussão Encefálica/metabolismo , Lesões Encefálicas/tratamento farmacológico , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Cognição/fisiologia , Disfunção Cognitiva/tratamento farmacológico , Modelos Animais de Doenças , Feminino , Ácido Glutâmico/metabolismo , Hipocampo/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Camundongos , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Fatores Sexuais , Silimarina/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
7.
Life Sci ; 258: 118107, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32682919

RESUMO

Cognitive impairment has been widely recognized as a common symptom of chronic stress. Ginsenoside Rd (GRd), the major active compound in Panax ginseng, was previously reported in various neurological researches. However, little research is available regarding on the effect of GRd on cognitive improvement in mice subjected to chronic stress. In the present study, we investigated the neuroprotective effects of GRd in chronic restraint stress (CRS)-induced cognitive deficits and explored the potential mechanism in male C57BL/6J mice. Our results demonstrated that oral administration of GRd for 28 days markedly increased the spontaneous alternation in Y-maze and the relative discrimination index in novel object or location recognition tests following CRS. Additionally, GRd treatment considerably increased the antioxidant enzymes activities in the hippocampus. The expression levels of hippocampus and serum inflammation factors in the CRS groups were also counter-regulated by GRd treatment. Meanwhile, GRd treatment could reverse CRS-induced the decrease in phosphorylated phosphoinositide 3-kinase (PI3K), camp-reflecting element binding protein (CREB), brain-derived neurotrophic factor (BDNF) and tyrosine kinase B (TrkB) expression in the hippocampus. These findings provided evidences that GRd improves cognitive impairment in CRS mice by mitigating oxidative stress and inflammation, while upregulating the hippocampal BDNF-mediated CREB signaling pathway.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Ginsenosídeos/uso terapêutico , Restrição Física , Transdução de Sinais , Estresse Psicológico/tratamento farmacológico , Animais , Doença Crônica , Disfunção Cognitiva/sangue , Disfunção Cognitiva/fisiopatologia , Modelos Animais de Doenças , Ginsenosídeos/química , Ginsenosídeos/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/enzimologia , Hipocampo/patologia , Hipocampo/fisiopatologia , Inflamação/sangue , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Memória de Curto Prazo/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Modelos Biológicos , Atividade Motora/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Receptor trkB/metabolismo , Transdução de Sinais/efeitos dos fármacos , Estresse Psicológico/sangue , Estresse Psicológico/fisiopatologia
8.
PLoS One ; 15(7): e0236370, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32702709

RESUMO

INTRODUCTION: Measuring the impact of care complexity on health outcomes, based on psychosocial, biological and environmental circumstances, is important in order to detect predictors of early deterioration of inpatients. We aimed to identify care complexity individual factors associated with selected adverse events and in-hospital mortality. METHODS: A multicenter, case-control study was carried out at eight public hospitals in Catalonia, Spain, from January 1, 2016 to December 31, 2017. All adult patients admitted to a ward or a step-down unit were evaluated. Patients were divided into the following groups based on the presence or absence of three adverse events (pressure ulcers, falls or aspiration pneumonia) and in-hospital mortality. The 28 care complexity individual factors were classified in five domains (developmental, mental-cognitive, psycho-emotional, sociocultural and comorbidity/complications). Adverse events and complexity factors were retrospectively reviewed by consulting patients' electronic health records. Multivariate logistic analysis was performed to identify factors associated with an adverse event and in-hospital mortality. RESULTS: A total of 183,677 adult admissions were studied. Of these, 3,973 (2.2%) patients experienced an adverse event during hospitalization (1,673 [0.9%] pressure ulcers; 1,217 [0.7%] falls and 1,236 [0.7%] aspiration pneumonia). In-hospital mortality was recorded in 3,996 patients (2.2%). After adjustment for potential confounders, the risk factors independently associated with both adverse events and in-hospital mortality were: mental status impairments, impaired adaptation, lack of caregiver support, old age, major chronic disease, hemodynamic instability, communication disorders, urinary or fecal incontinence, vascular fragility, extreme weight, uncontrolled pain, male sex, length of stay and admission to a medical ward. High-tech hospital admission was associated with an increased risk of adverse events and a reduced risk of in-hospital mortality. The area under the ROC curve for both outcomes was > 0.75 (95% IC: 0.78-0.83). CONCLUSIONS: Several care complexity individual factors were associated with adverse events and in-hospital mortality. Prior identification of complexity factors may have an important effect on the early detection of acute deterioration and on the prevention of poor outcomes.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Mortalidade Hospitalar , Pneumonia Aspirativa/epidemiologia , Úlcera/epidemiologia , Idoso , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/epidemiologia , Cuidadores , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/epidemiologia , Disfunção Cognitiva/patologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/classificação , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Hospitais , Humanos , Masculino , Pessoa de Meia-Idade , Pneumonia/induzido quimicamente , Pneumonia/tratamento farmacológico , Pneumonia/epidemiologia , Pneumonia Aspirativa/patologia , Fatores de Risco , Espanha/epidemiologia , Úlcera/induzido quimicamente , Úlcera/tratamento farmacológico
9.
Mult Scler Relat Disord ; 42: 102163, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32388458

RESUMO

Facing the outbreak of coronavirus disease 2019 (COVID-19) pandemic, there is an urgent need to find protective or curable drugs to prevent or to stop the course of the coronavirus SARS-CoV-2 infection. Recent evidence accumulates that adamantanes, widely used in different neurological diseases, could be repurposed for COVID-19. We hereby report on a questionnaire-based study performed to assess severity of COVID-19 in patients suffering from multiple sclerosis (n=10), Parkinson's disease (n=5) or cognitive impairment (n=7). In all patients infection with SARS-CoV-2 was confirmed by rtPCR of nasopharyngeal swabs. They were receiving treatment with either amantadine (n=15) or memantine (n=7) in stable registered doses. All of them had two-week quarantine since documented exposure and none of them developed clinical manifestations of infectious disease. They also did not report any significant changes in neurological status in the course of primary nervous system disease. Above results warrant further studies on protective effects of adamantanes against COVID-19 manifestation, especially in subjects suffering from neurological disease.


Assuntos
Amantadina/uso terapêutico , Infecções Assintomáticas , Disfunção Cognitiva/tratamento farmacológico , Infecções por Coronavirus/fisiopatologia , Dopaminérgicos/uso terapêutico , Memantina/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Doença de Parkinson/tratamento farmacológico , Pneumonia Viral/fisiopatologia , Adamantano/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Betacoronavirus , Disfunção Cognitiva/complicações , Infecções por Coronavirus/complicações , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/complicações , Pandemias , Doença de Parkinson/complicações , Pneumonia Viral/complicações , Fatores de Proteção , Índice de Gravidade de Doença
10.
Neurology ; 94(22): e2373-e2383, 2020 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-32430312

RESUMO

OBJECTIVE: Disease-modifying treatments (DMTs) are the gold standard for slowing disability progression in multiple sclerosis (MS), but their effects on cognitive impairment, a key symptom of the disease, are mostly unknown. We conducted a systematic review and meta-analysis to evaluate the differential effects of DMTs on cognitive test performance in relapsing-remitting MS (RRMS). METHODS: PubMed, Scopus, and Cochrane Library were searched for studies reporting longitudinal cognitive performance data related to all major DMTs. The standardized mean difference (Hedges g) between baseline and follow-up cognitive assessment was used as the main effect size measure. RESULTS: Forty-four studies, including 55 distinct MS patient samples, were found eligible for the systematic review. Twenty-five studies were related to platform therapies (mainly ß-interferon [n = 17] and glatiramer acetate [n = 4]), whereas 22 studies were related to escalation therapies (mainly natalizumab [n = 14] and fingolimod [n = 6]). Reported data were mostly confined to the cognitive domain processing speed. A meta-analysis including 41 studies and 7,131 patients revealed a small to moderate positive effect on cognitive test performance of DMTs in general (g = 0.27, 95% confidence interval [CI] = [0.21-0.33]), but no statistically significant differences between platform (g = 0.27, 95% CI = [0.18-0.35]) and escalation therapies (g = 0.28, 95% CI = [0.19-0.37]) or between any single DMT and ß-interferon. CONCLUSIONS: DMTs are effective in improving cognitive test performance in RRMS, but a treatment escalation mainly to amend cognition is not supported by the current evidence. Given the multitude of DMTs and their widespread use, the available data regarding differential treatment effects on cognitive impairment are remarkably scant. Clinical drug trials that use more extensive cognitive outcome measures are urgently needed.


Assuntos
Cognição/efeitos dos fármacos , Disfunção Cognitiva/tratamento farmacológico , Imunossupressores/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Cognição/fisiologia , Disfunção Cognitiva/epidemiologia , Disfunção Cognitiva/psicologia , Cloridrato de Fingolimode/farmacologia , Cloridrato de Fingolimode/uso terapêutico , Acetato de Glatiramer/farmacologia , Acetato de Glatiramer/uso terapêutico , Humanos , Fatores Imunológicos/farmacologia , Fatores Imunológicos/uso terapêutico , Imunossupressores/farmacologia , Interferon beta/farmacologia , Interferon beta/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/epidemiologia , Esclerose Múltipla Recidivante-Remitente/psicologia , Natalizumab/farmacologia , Natalizumab/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos
11.
Adv Exp Med Biol ; 1195: 19, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32468453

RESUMO

Over 40 million people worldwide suffer from dementia. This number is projected to exceed 110 million by 2050 because of the aging of the worldwide population, especially in lower- and middle-income countries. The most common cause of dementia is believed to be Alzheimer's, a brain disease associated with deposition of beta-amyloid protein and hyperphosphorylation of intraneuronal tau protein leading to synaptic degradation, neuronal loss, brain circuit disruption, a range of symptoms, and eventually, if the person lives long enough, death. Over the last few decades, treatment development has focused on the deposition of beta-amyloid protein (A-beta 1-42) that is produced in the brain in huge quantities continuously and is thought to be toxic. Unfortunately, amyloid oriented therapies targeting individuals with dementia, or its prodrome mild cognitive impairment (MCI), have not been successful therapeutically even though they have been associated with reductions in amyloid. Currently, efforts are underway to deliver these therapies to individuals with very early symptoms or at risk for Alzheimer's dementia by virtue of genetics or a brain amyloid PET scan. Results from these studies are expected to begin to emerge by early 2020. In the meantime, since the amyloid hypothesis has been called into question, a number of different avenues are being pursued for treatment development. These are driven in part by new findings related to the polygenic nature of Alzheimer's as well as the interaction between this brain disease with factors such as brain vascular disease, insulin resistance, and/or brain inflammation. The expected future of AD treatment development is thought to be precision medicine.


Assuntos
Doença de Alzheimer/metabolismo , Doença de Alzheimer/terapia , Doença de Alzheimer/patologia , Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Disfunção Cognitiva/tratamento farmacológico , Humanos , Tomografia por Emissão de Pósitrons , Medicina de Precisão , Proteínas tau/metabolismo
12.
Am J Chin Med ; 48(3): 487-511, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32329645

RESUMO

Cognitive impairment (CI) refers to the dysfunction of memory, language, visual space, execution, calculation, understanding, and judgment in one or more aspects. With global aging, CI will become prevalent worldwide. At present, there is no effective cure for CI. However, Nobel laureate Tu Youyou's research on artemisinin has inspired Chinese researchers to focus on traditional Chinese herbs (TCHs) for the treatment of CI. Traditional Chinese Medicine (TCM) has led to a theory for an independent CI system. The pathogenesis of such impairment involves deficiency, phlegm, and stagnation and involves a range of organs, including the brain, kidneys, heart, liver, and spleen. Our current understanding of the etiology and pathogenesis of this condition has led to the realization that TCHs can improve cognitive dysfunction. Clinical research has shown that TCHs can improve the neuropsychological scale score of patients, the TCM symptom score, and the patient's quality of life. Research has also suggested that TCHs can retard Aß deposits and tauopathy, regulate the metabolism of cholinergic neurotransmitters, and so on. However, due to their complexity, little is known of the safety and efficacy of TCHs in patients with CI. It is likely that we will be able to identify the precise mechanisms associated with the action of TCHs in such patients due to the integration of multiple technologies. This paper summarizes the pharmacokinetics, curative effect, and mechanisms of action of traditional Chinese herbs in order to provide a scientific basis for the improvement of cognitive dysfunction by TCHs.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Disfunção Cognitiva/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Medicina Tradicional Chinesa , Fitoterapia , Doença de Alzheimer/etiologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Humanos , Qualidade de Vida , Proteínas tau/metabolismo
13.
Exp Anim ; 69(3): 363-373, 2020 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-32336744

RESUMO

Schisandrin, an active component extracted from Schisandra chinensis (Turcz.) Baill has been reported to alleviate the cognitive impairment in neurodegenerative disorder like Alzheimer's disease (AD). However, the mechanism by which schisandrin regulates the cognitive decline is still unclear. In our study, intracerebroventricular injection of streptozotocin (STZ) was employed to establish AD model in male Wistar rats, and indicated dose of schisandrin was further administered. The Morris water maze test was performed to evaluate the ability of learning and memory in rats with schisandrin treatment. The results indicated that schisandrin improved the capacity of cognition in STZ-induced rats. The contents of pro-inflammatory cytokines in brain tissue were determined by ELISA, and the expressions of these cytokines were assessed by western-blot and immunohistochemistry. The results showed that treatment of schisandrin significantly reduced the production of inflammation mediators including tumor necrosis factor-α, interleukin-1ß and interleukin-6. Further study suggested a remarkable decrease in the expressions of ER stress maker proteins like C/EBP-homologous protein, glucose-regulated protein 78 and cleaved caspase-12 in the presence of schisandrin, meanwhile the up-regulation of sirtuin 1 (SIRT1) was also observed in the same group. Additionally, the results of western-blot and EMSA demonstrated that schisandrin inhibited NF-κB signaling in the brain of STZ-induced rats. In conclusion, schisandrin ameliorated STZ-induced cognitive dysfunction, ER stress and neuroinflammation which may be associated with up-regulation of SIRT1. Our study provides novel mechanisms for the neuroprotective effect of schisandrin in AD treatment.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Cognição/efeitos dos fármacos , Disfunção Cognitiva/tratamento farmacológico , Ciclo-Octanos/farmacologia , Ciclo-Octanos/uso terapêutico , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Lignanas/farmacologia , Lignanas/uso terapêutico , Fitoterapia , Compostos Policíclicos/farmacologia , Compostos Policíclicos/uso terapêutico , Schisandra/química , Estreptozocina , Animais , Modelos Animais de Doenças , Masculino , Ratos Wistar , Sirtuína 1/metabolismo , Regulação para Cima/efeitos dos fármacos
14.
J Comput Assist Tomogr ; 44(2): 255-261, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32195805

RESUMO

OBJECTIVE: We aimed to determine the effects of recombinant human growth hormone (rhGH) replacement on cognitive function in subjects with poststroke cognitive impairment using resting-state functional magnetic resonance imaging. METHODS: We included 60 patients with a first-ever stroke for 3 months and a diagnosis of cognitive impairment who were randomized 1:1 to receive either rhGH subcutaneously or placebo injection for 6 months. All subjects were required to receive the same rehabilitative therapy program. Both groups were subjected to pretreatment and posttreatment neuropsychological assessment using the Montreal Cognitive Assessment, serum neurotrophic factors, biomarkers of glucose and lipid metabolism, and functional magnetic resonance imaging during 6 months of the study period. The pattern of brain activity was determined by examining the functional connectivity and amplitude of low-frequency fluctuations (ALFF) of blood oxygen level dependent signal. RESULTS: Forty-three (82.7%) completed the study. Treatment with rhGH reduced levels of triglycerides and low-density lipoprotein cholesterol but did not significantly altered plasma concentrations of glucose and glycated hemoglobin. We found a significant increase in serum insulin-like growth factor 1 levels (32.6%; P < 0.001) in the rhGH-treated group compared with that in the controls. After 6 months of rhGH treatment, mean Montreal Cognitive Assessment score improved from 16.31 (5.32) to 21.19 (6.54) (P < 0.001). The rhGH group showed significant increased area of activation with increased ALFF values in the regions of the frontal lobe, putamen, temporal lobe, and thalamus (P < 0.05), relative to the baseline conditions. The correlation analysis revealed that the ALFF and functional connectivity of default mode network was positively correlated with the ΔMoCA score and ΔIGF-1 levels; that is, the more the scale score increased, the higher the functional connection strength. No undesirable adverse effects were observed. CONCLUSIONS: The rhGH replacement has a significant impact on global and domain cognitive functions in poststroke cognitive impairment.


Assuntos
Disfunção Cognitiva/complicações , Disfunção Cognitiva/tratamento farmacológico , Hormônio do Crescimento Humano/uso terapêutico , Imagem por Ressonância Magnética/métodos , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/tratamento farmacológico , Encéfalo/diagnóstico por imagem , Encéfalo/efeitos dos fármacos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Resultado do Tratamento
15.
Phytother Res ; 34(4): 846-858, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32115816

RESUMO

Sleep deprivation has been widely reported to cause cognitive dysfunction, and elevation in oxidative stress and inflammation in the body, including the brain, have been suggested as the main factors. Genistein (GE) is an isoflavone widely present in leguminous plants, and it was found to exert a wide spectrum of biological activities, including antioxidant, anti-inflammatory, hepatoprotective, neuroprotective, and antimetastatic effects. In this study, the protective effect of GE on chronic sleep deprivation (CSD)-induced cognitive dysfunction was investigated. The mice were subjected to the sleep interruption apparatus and continuously sleep deprived for 25 days. GE was orally administrated (10, 20, and 40 mg/kg) during the sleep deprivation process totally for 25 days. Cognitive behavioral tests were conducted to study the learning and memory using the object location recognition (OLR) task, novel object recognition (NOR) test, and the Morris water maze (MWM) task. Additionally, the cortex and hippocampus were dissected to measure the oxidative stress markers and the antioxidant element nuclear erythroid-2-related factor 2 (Nrf2) and its downstream targets, including glutamate cysteine ligase catalytic, glutamate cysteine ligase modifier, heme oxygenase 1, and quinone oxidoreductase 1, as well as nuclear factor kappa B (NF-κB) p65, nitric oxide synthase (iNOS), and cyclooxygenase 2 (COX-2) protein expression. Moreover, the pro-inflammatory cytokines (TNF-α, interleukin [IL]-6, and IL-1ß) level was examined in the serum. The current results showed that GE could dose-dependently ameliorate the cognitive deficits of CSD-treated mice in the OLR, NOR, and MWM tasks. In addition, GE treatment significantly elevated the activities of total antioxidant capacity and superoxide dismutase and the level of glutathione and lowered the content of malondialdehyde in the cortex and hippocampus of CSD-treated mice. Furthermore, GE administration effectively activated the antioxidant element Nrf2 and its downstream targets in the cortex and hippocampus of CSD-treated mice. Moreover, GE treatment significantly suppressed CSD-induced NF-κB p65, iNOS, and COX-2 activation in the cortex and hippocampus, as well as inhibited CSD-induced pro-inflammatory cytokines (TNF-α, IL-6, and IL-1ß) release in the serum. Taken together, all these results suggested that GE has substantial potential as a therapeutic intervention for the alleviation of CSD-induced deleterious effects.


Assuntos
Disfunção Cognitiva/etiologia , Disfunção Cognitiva/prevenção & controle , Genisteína/farmacologia , Fármacos Neuroprotetores/farmacologia , Privação do Sono/complicações , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Doença Crônica , Disfunção Cognitiva/tratamento farmacológico , Genisteína/uso terapêutico , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos ICR , Fármacos Neuroprotetores/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Privação do Sono/tratamento farmacológico , Privação do Sono/psicologia
16.
Lancet Diabetes Endocrinol ; 8(4): 325-336, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32135131

RESUMO

Adults with type 2 diabetes are at an increased risk of developing certain brain or mental disorders, including stroke, dementia, and depression. Although these disorders are not usually considered classic microvascular complications of diabetes, evidence is growing that microvascular dysfunction is one of the key underlying mechanisms. Microvascular dysfunction is a widespread phenomenon in people with diabetes, including effects on the brain. Cerebral microvascular dysfunction is also apparent in adults with prediabetes, suggesting that cerebral microvascular disease processes start before the onset of diabetes. The microvasculature is involved in the regulation of many cerebral processes that when impaired predispose to lacunar and haemorrhagic stroke, cognitive dysfunction, and depression. Main drivers of diabetes-related cerebral microvascular dysfunction are hyperglycaemia, obesity and insulin resistance, and hypertension. Increasing amounts of data from observational studies suggest that diabetes-related microvascular dysfunction is associated with a higher risk of stroke, cognitive dysfunction, and depression. Cerebral outcomes in diabetes might be improved following treatments targeting the pathways through which diabetes damages the microcirculation. These treatments might include drugs that reduce dicarbonyl compounds, augment cerebral insulin signalling, or improve blood-brain barrier permeability and cerebral vasoreactivity.


Assuntos
Circulação Cerebrovascular/efeitos dos fármacos , Disfunção Cognitiva/etiologia , Depressão/etiologia , Diabetes Mellitus Tipo 2/complicações , Microcirculação/efeitos dos fármacos , Acidente Vascular Cerebral/etiologia , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/fisiopatologia , Depressão/tratamento farmacológico , Depressão/fisiopatologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/fisiopatologia , Humanos , Hipertensão/tratamento farmacológico , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/fisiopatologia
17.
Toxicol Appl Pharmacol ; 394: 114954, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32171570

RESUMO

Learning and memory deficits are obvious symptoms that develop over time in patients with poorly controlled diabetes. Hyperactivity of the renin-angiotensin system (RAS) is directly associated with ß-cell dysfunction and diabetic complications, including cognitive impairment. Here, we investigated the protective and molecular effects of two RAS modifiers, aliskiren; renin inhibitor and captopril; angiotensin converting enzyme inhibitor, on cognitive deficits in the rat hippocampus. Injection of low dose streptozotocin for 4 days resulted in type 1 diabetes. Then, poorly controlled diabetes was mimicked with ineffective daily doses of insulin for 4 weeks. The hyperglycaemia and pancreatic atrophy caused memory disturbance that were identifiable in behavioural tests, hippocampal neurodegeneration, and the following significant changes in the hippocampus, increases in the inflammatory marker interleukin 1ß, cholinesterase, the oxidative stress marker malondialdehyde and protein expression of phosphorylated extracellular-signal-regulated kinase and glycogen synthase kinase-3 beta versus decrease in the antioxidant reduced glutathione and protein expression of phosphorylated glycogen synthase kinase-3 beta. Blocking RAS with either drugs along with insulin amended all previously mentioned parameters. Aliskiren stabilized the blood glucose level and restored normal pancreatic integrity and hippocampal malondialdehyde level. Aliskiren showed superior protection against the hippocampal degeneration displayed in the earlier behavioural modification in the passive avoidance test, and the aliskiren group outperformed the control group in the novel object recognition test. We therefore conclude that aliskiren and captopril reversed the diabetic state and cognitive deficits in rats with poorly controlled STZ-induced diabetes through reducing oxidative stress and inflammation and modulating protein expression.


Assuntos
Amidas/uso terapêutico , Captopril/uso terapêutico , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/psicologia , Diabetes Mellitus Experimental/psicologia , Fumaratos/uso terapêutico , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Hipocampo/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Encéfalo/patologia , Colinesterases/metabolismo , Disfunção Cognitiva/etiologia , Diabetes Mellitus Experimental/patologia , Hipocampo/enzimologia , Hipocampo/patologia , Interleucina-1beta/biossíntese , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Pâncreas/patologia , Ratos , Ratos Sprague-Dawley , Reconhecimento Psicológico/efeitos dos fármacos
18.
Psychopharmacology (Berl) ; 237(6): 1827-1840, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32206827

RESUMO

RATIONALE: Alcoholism and obesity impart a deleterious impact on human health and affects the quality of life. Chronic consumption of alcohol and western diet has been reported to cause memory deficits. 7,8-dihydroxyflavone (7,8-DHF), a TrkB agonist, comprises antioxidant and anti-inflammatory properties in treating various neurological disorders. OBJECTIVES: The current study was aimed to determine the protective effect and molecular mechanism of 7,8-DHF against alcohol and high-fat diet (HFD)-induced memory deficits in rats. METHODS: The adult male Wistar rats were given alcohol (3-15%) and HFD ad libitum for 12 weeks in different experimental groups. 7,8-DHF (5 mg/kg) was intraperitoneally injected daily for the last 4 weeks (9th-12th week). RESULTS: The alcohol and HFD administration caused cognitive impairment as evaluated through the Morris water maze (MWM) test in alcohol, HFD, and alcohol + HFD-fed animals. The last 4-week treatment of 7,8-DHF (5 mg/kg; i.p.) attenuated alcohol and HFD-induced memory loss. 7,8-DHF treatment also restored the glutathione (GSH) level along with attenuation of nitrite, malondialdehyde content (markers of oxidative and nitrosative stress), and reduction of the acetylcholinesterase activity in the hippocampus of alcohol and HFD-fed animals. Furthermore, the administration of 7,8-DHF caused downregulation of NF-κB, iNOS, and caspase-3 and upregulation of Nrf2, HO-1, and BDNF mRNA level in rat hippocampus. CONCLUSION: 7,8-DHF administration conferred beneficial effects against alcohol and HFD-induced memory deficit via its unique antioxidant, anti-inflammatory, anti-apoptotic potential, along with the activation of TrkB/BDNF signaling pathway in the hippocampus.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Etanol/toxicidade , Flavonas/uso terapêutico , Transtornos da Memória/tratamento farmacológico , Estresse Nitrosativo/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Animais , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/metabolismo , Etanol/administração & dosagem , Flavonas/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Transtornos da Memória/etiologia , Transtornos da Memória/metabolismo , Estresse Nitrosativo/fisiologia , Estresse Oxidativo/fisiologia , Ratos , Ratos Wistar
19.
J Agric Food Chem ; 68(8): 2381-2392, 2020 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-32037817

RESUMO

Increasing level of inflammation and oxidative stress could lead to memory impairment. The purpose of this study was to determine the neuroprotective effects of walnut peptides against memory deficits induced by lipopolysaccharide (LPS) in mice and further to explore the underlying anti-inflammatory mechanisms against LPS-elicited inflammation in BV-2 cells. Results showed that walnut protein hydrolysate (WPH) and its low-molecular-weight fraction (WPHL) could ameliorate the memory deficits induced by LPS via normalizing the inflammatory response and oxidative stress in brain, especially WPHL. Furthermore, 18 peptides with anti-inflammatory activities on LPS-activated BV-2 cells were identified from WPHL and it was found that Trp, Gly, and Leu residues in peptides might contribute to the anti-inflammation. Meanwhile, the strong anti-inflammatory effects of LPF, GVYY, and APTLW might be related to their hydrophobic and aromatic amino acid residues as well. LPF, GVYY, and APTLW could reduce the content of proinflammatory mediators and cytokines by downregulating related enzyme expressions and mRNA expressions. Additionally, ROS and mitochondria homeostasis might also contribute to their anti-inflammatory effects.


Assuntos
Anti-Inflamatórios/administração & dosagem , Disfunção Cognitiva/tratamento farmacológico , Juglans/química , Estresse Oxidativo/efeitos dos fármacos , Peptídeos/administração & dosagem , Animais , Anti-Inflamatórios/química , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/imunologia , Disfunção Cognitiva/psicologia , Humanos , Lipopolissacarídeos/efeitos adversos , Aprendizagem em Labirinto , Camundongos , Peso Molecular , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/química , Nozes/química , Peptídeos/química
20.
PLoS One ; 15(2): e0227820, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32032361

RESUMO

Cognitive impairment is a common complication observed after a stroke. Currently there are no definitively proven pharmacologic therapies for recovery from post-stroke cognitive impairment and vascular dementia. In this meta-analysis, we evaluated the efficacy and safety of cholinesterase inhibitors in their improvement of cognition in patients with post-stroke cognitive impairment and vascular dementia. We conducted a meta-analysis using seven eligible studies from 305 published articles. We investigated the differences in Mini-Mental State Examination (MMSE) and Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) scores, before and after cholinergic augmentation in patients with post-stroke cognitive impairment and vascular dementia. MMSE and ADAS-cog scores were also compared during the subsequent follow-up periods. MMSE score of patients with post-stroke cognitive impairment was increased after cholinergic augmentation throughout the 24 weeks with mean differences [MD] of 3.000, 1.732, 1.578 1.516, and 1.222, at 4, 4-8, 8-12, 12-18, and 18-24 weeks, respectively. In addition, ADAS-cog scores decreased at 6, 12, 18, and 24 weeks by pharmaceutical augmentation, but not with placebo with mean differences [MD] of -2.333, -2.913, -2.767, -2.416, and -1.859, respectively. This meta-analysis shows that acetylcholinesterase inhibitors maintain a stable pattern of improved cognitive function in patients with post stroke cognitive impairment and vascular dementia without the increased risk of side effects.


Assuntos
Inibidores da Colinesterase/uso terapêutico , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/etiologia , Demência Vascular/tratamento farmacológico , Demência Vascular/etiologia , Acidente Vascular Cerebral/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico , Inibidores da Colinesterase/efeitos adversos , Inibidores da Colinesterase/farmacologia , Feminino , Humanos , Masculino , Testes de Estado Mental e Demência , Pessoa de Meia-Idade
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