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1.
Molecules ; 26(12)2021 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-34204308

RESUMO

Globally, Alzheimer's disease (AD) is one of the most prevalent age-related neurodegenerative disorders associated with cognitive decline and memory deficits due to beta-amyloid deposition (Aß) and tau protein hyperphosphorylation. To date, approximately 47 million people worldwide have AD. This figure will rise to an estimated 75.6 million by 2030 and 135.5 million by 2050. According to the literature, the efficacy of conventional medications for AD is statistically substantial, but clinical relevance is restricted to disease slowing rather than reversal. Withaferin A (WA) is a steroidal lactone glycowithanolides, a secondary metabolite with comprehensive biological effects. Biosynthetically, it is derived from Withania somnifera (Ashwagandha) and Acnistus breviflorus (Gallinero) through the mevalonate and non-mevalonate pathways. Mounting evidence shows that WA possesses inhibitory activities against developing a pathological marker of Alzheimer's diseases. Several cellular and animal models' particulates to AD have been conducted to assess the underlying protective effect of WA. In AD, the neuroprotective potential of WA is mediated by reduction of beta-amyloid plaque aggregation, tau protein accumulation, regulation of heat shock proteins, and inhibition of oxidative and inflammatory constituents. Despite the various preclinical studies on WA's therapeutic potentiality, less is known regarding its definite efficacy in humans for AD. Accordingly, the present study focuses on the biosynthesis of WA, the epidemiology and pathophysiology of AD, and finally the therapeutic potential of WA for the treatment and prevention of AD, highlighting the research and augmentation of new therapeutic approaches. Further clinical trials are necessary for evaluating the safety profile and confirming WA's neuroprotective potency against AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Vitanolídeos/uso terapêutico , Peptídeos beta-Amiloides/metabolismo , Animais , Disfunção Cognitiva/tratamento farmacológico , Humanos , Fármacos Neuroprotetores/farmacologia , Fragmentos de Peptídeos/uso terapêutico , Placa Amiloide/tratamento farmacológico , Solanaceae/metabolismo , Withania/metabolismo , Vitanolídeos/metabolismo , Proteínas tau/metabolismo
2.
Int J Mol Sci ; 22(12)2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34208092

RESUMO

Vascular dementia (VaD) is a progressive cognitive impairment caused by a reduced blood supply to the brain. Chronic cerebral hypoperfusion (CCH) is one cause of VaD; it induces oxidative stress, neuroinflammation, and blood-brain barrier (BBB) disruption, damaging several brain regions. Vitamin C plays a vital role in preventing oxidative stress-related diseases induced by reactive oxygen species, but it is easily oxidized and loses its antioxidant activity. To overcome this weakness, we have developed a vitamin C/DNA aptamer complex (NXP031) that increases vitamin C's antioxidant efficacy. Aptamers are short single-stranded nucleic acid polymers (DNA or RNA) that can interact with their corresponding target with high affinity. We established an animal model of VaD by permanent bilateral common carotid artery occlusion (BCCAO) in 12 week old Wistar rats. Twelve weeks after BCCAO, we injected NXP031 into the rats intraperitoneally for two weeks at moderate (200 mg/4 mg/kg) and high concentrations (200 mg/20 mg/kg). NXP031 administration alleviates cognitive impairment, microglial activity, and oxidative stress after CCH. NXP031 increased the expression of basal lamina (laminin), endothelial cell (RECA-1, PECAM-1), and pericyte (PDGFRß); these markers maintain the BBB integrity. We found that NXP031 administration activated the Nrf2-ARE pathway and increased the expression of SOD-1 and GSTO1/2. These results suggest that this new aptamer complex, NXP031, could be a therapeutic intervention in CCH-induced VaD.


Assuntos
Encéfalo/patologia , Disfunção Cognitiva/complicações , Disfunção Cognitiva/tratamento farmacológico , Demência Vascular/complicações , Fator 2 Relacionado a NF-E2/metabolismo , Transdução de Sinais , Aldeídos/metabolismo , Animais , Barreira Hematoencefálica/patologia , Doença Crônica , Modelos Animais de Doenças , Hipocampo/patologia , Masculino , Microglia/patologia , Microvasos/patologia , Ratos Wistar , Regulação para Cima
3.
Molecules ; 26(10)2021 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-34070220

RESUMO

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases leading to dementia. Despite research efforts, currently there are no effective pharmacotherapeutic options for the prevention and treatment of AD. Recently, numerous studies highlighted the beneficial effects of curcumin (CUR), a natural polyphenol, in the neuroprotection. Especially, its dual antioxidant and anti-inflammatory properties attracted the interest of researchers. In fact, besides its antioxidant and anti-inflammatory properties, this biomolecule is not degraded in the intestinal tract. Additionally, CUR is able to cross the blood-brain barrier and could therefore to be used to treat neurodegenerative pathologies associated with oxidative stress, inflammation and apoptosis. The present study aimed to assess the ability of CUR to induce neuronal protective and/or recovery effects on a rat model of neurotoxicity induced by aluminum chloride (AlCl3), which mimics the sporadic form of Alzheimer's disease. Our results showed that treatment with CUR enhances pro-oxidant levels, antioxidant enzymes activities and anti-inflammatory cytokine production and decreases apoptotic cells in AlCl3-exposed hippocampus rats. Additionally, histopathological analysis of hippocampus revealed the potential of CUR in decreasing the hallmarks in the AlCl3-induced AD. We also showed that CUR post-treatment significantly improved the behavioral, oxidative stress and inflammation in AlCl3-exposed rats. Taken together, our data presented CUR as a nutraceutical potential through its protective effects that are more interesting than recovery ones in sporadic model of AD.


Assuntos
Doença de Alzheimer/complicações , Doença de Alzheimer/tratamento farmacológico , Curcumina/uso terapêutico , Síndromes Neurotóxicas/complicações , Síndromes Neurotóxicas/tratamento farmacológico , Acetilcolinesterase/metabolismo , Cloreto de Alumínio/administração & dosagem , Animais , Ansiedade/complicações , Ansiedade/tratamento farmacológico , Apoptose/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Disfunção Cognitiva/complicações , Disfunção Cognitiva/tratamento farmacológico , Curcumina/farmacologia , Citocinas/metabolismo , Modelos Animais de Doenças , Hipocampo/patologia , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Masculino , Degeneração Neural/patologia , Fármacos Neuroprotetores/farmacologia , Tamanho do Órgão/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar
4.
BMC Geriatr ; 21(1): 367, 2021 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-34134667

RESUMO

BACKGROUND: The irreversibility of cognitive impairment of Alzheimer's disease (AD) prompts that preventing or delaying the onset of AD should be a public health priority. Vitamin B supplements can lower the serum homocysteine (Hcy) level, but whether it can prevent cognitive decline or not remains unclear. We aimed to evaluate the preventive efficacy of vitamin B supplements on the cognitive decline of elderly adults. METHODS: We searched PubMed, Embase, The Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, Scopus, Science Direct, PsycINFO from inception to December 1, 2019, and then updated the retrieved results on June 1, 2020. The randomized controlled trials (RCTs) which evaluated the efficacy of vitamin B in mild cognitive impairment (MCI) patients or elderly adults without cognitive impairment were selected. Standardized mean difference (SMD) or mean difference (MD) as well as their 95 % confidence interval (CI) were calculated by performing random effects models or fixed effects models. RESULTS: A total of 21 RCTs involving 7571 participants were included for meta-analysis. The forest plots showed that there is significant effect in global cognitive function (15 RCTs, SMD: 0.36; 95 % CI: 0.18 to 0.54, P < 0.01) and Hcy (11 RCTs, MD: -4.59; 95 %CI: -5.51 to -3.67, P < 0.01), but there is no effect in information processing speed (10 RCTs, SMD: 0.06; 95 % CI: -0.12 to 0.25, P = 0.49), episodic memory (15 RCTs, SMD: 0.10; 95 % CI: -0.04 to 0.25, P = 0.16), executive function (11 RCTs, SMD: -0.21; 95 % CI: -0.49 to 0.06, P = 0.13). The value of effect size and heterogeneity did not vary apparently when excluding the low-quality studies, so we could believe that the results of meta-analysis were robust. CONCLUSIONS: Vitamin B supplements might delay or maintain the cognitive decline of elderly adults. We can recommend that the vitamin B supplements should be considered as a preventive medication to MCI patients or elderly adults without cognitive impairment. More well-designed RCTs with large sample sizes were required to clarify the preventive efficacy in the future.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Idoso , Cognição , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/prevenção & controle , Suplementos Nutricionais , Humanos , Vitaminas
5.
Artigo em Russo | MEDLINE | ID: mdl-34184475

RESUMO

OBJECTIVE: To assess the efficacy and safety of prospecta in the treatment of moderate cognitive impairment in the early recovery period of ischemic stroke. MATERIAL AND METHODS: The study included 275 patients (mean age 64.0±8.1 years) with a history of single ischemic stroke from 3 to 6 months, with moderate cognitive impairment, and moderate activity in everyday life, who were randomized in two groups. During the screening phase, the severity of cognitive impairment was assessed with the Mini-Mental State Examination and Montreal Cognitive Assessment scales; the level of activity in everyday life was evaluated with the Barthel Scale; and quality of life was assessed with the Stroke Specific Quality of Life Scale. Patients took 2 tablets of prospecta or placebo 2 times a day for 24 weeks. The follow-up period was 4 weeks. The primary endpoint of the study was the proportion of patients with improvement in cognitive function (+1 or more on the MoCA test) after 24 weeks of treatment. The occurrence and type of adverse events (AEs), their severity, relationship to the drug, outcome, changes in vital signs, and the proportion of patients with clinically significant abnormality in laboratory tests were analyzed to assess the safety. RESULTS: A clinically significant improvement in cognitive function was obtained in 91.9% of patients in the prospecta group vs 82.,1% in the placebo group, (p=0.02). There were 57 AEs in 37 (27.4%) Prospecta group patients and 53 AEs in 39 (27.9%) Placebo group participants (p=1.00). No AEs were certainly associated with taking the medication. No clinically significant changes in vital signs or abnormal laboratory results were detected during the study. CONCLUSION: Prospecta is an effective and safe treatment option for patients with moderate cognitive impairment in the early recovery period of ischemic stroke.


Assuntos
Isquemia Encefálica , Disfunção Cognitiva , AVC Isquêmico , Acidente Vascular Cerebral , Idoso , Isquemia Encefálica/complicações , Isquemia Encefálica/tratamento farmacológico , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/etiologia , Humanos , Pessoa de Meia-Idade , Qualidade de Vida , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/tratamento farmacológico
6.
Artigo em Russo | MEDLINE | ID: mdl-34184478

RESUMO

OBJECTIVE: To evaluate the effectiveness of computer stimulating programs in rehabilitation of post-traumatic cognitive impairments in patients with concomitant aphasia. MATERIAL AND METHODS: The study included 32 young and middle-aged patients with moderate and severe cognitive impairment with concomitant and mild aphasia that occurred after traumatic brain injury. RESULTS: The advantageous restoration of cognitive functions in patients with concomitant aphasia was observed when computer stimulating programs of both types were used, while the improvement of verbal-mediated functions (auditory speech memory and speech activity) was observed when the author's method VerbalCOG was utilized. CONCLUSION: The methods of computerized cognitive training have proven their effectiveness in the recovery from post-traumatic cognitive impairment in patients with concomitant aphasia in comparison with the control group that received medications only. At the same time, the author's program VerbalCOG showed the best results in restoration of verbal-mediated functions in comparison with other presented methods of treatment.


Assuntos
Afasia , Disfunção Cognitiva , Acidente Vascular Cerebral , Afasia/etiologia , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/etiologia , Humanos , Pessoa de Meia-Idade , Fala , Fonoterapia
7.
J Int Med Res ; 49(5): 3000605211014294, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33983077

RESUMO

OBJECTIVE: Senile patients often experience neurocognitive disturbance after non-cardiac surgery. Several clinical trials have investigated if the perioperative intravenous use of dexmedetomidine has a positive effect on the prevention of neurocognitive dysfunction, but the results have been inconsistent. We performed a meta-analysis to investigate the effects of dexmedetomidine on neurocognitive disturbance after elective non-cardiac surgery in senile patients. METHODS: The PubMed, Cochrane Library, EMBASE and China National Knowledge Infrastructure databases were comprehensively searched for all randomized controlled trials published before 1 February 2020 that investigated the efficacy of dexmedetomidine in the prevention of postoperative delirium (POD) or postoperative cognitive dysfunction (POCD). RESULTS: Sixteen studies involving 4376 patients were included in this meta-analysis. Compared with the control (i.e., saline), the perioperative intravenous use of dexmedetomidine significantly reduced the incidence of POD and POCD. However, patients in the dexmedetomidine group were more likely to develop bradycardia and hypotension during the administration of dexmedetomidine than patients in the control group. There were no differences between the two groups in the incidence of nausea and vomiting or mortality rate. CONCLUSION: Dexmedetomidine has a positive effect on the prevention of neurocognitive disturbance in senile patients after elective non-cardiac surgery.


Assuntos
Disfunção Cognitiva , Delírio , Dexmedetomidina , Hipotensão , China , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/prevenção & controle , Dexmedetomidina/uso terapêutico , Humanos , Complicações Pós-Operatórias/prevenção & controle
8.
Exp Gerontol ; 151: 111400, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33974937

RESUMO

Shenqi Yizhi Granule (SYG), a modern preparation herbs based on the theory of traditional Chinese medicine, has been proved to be effective against Alzheimer's disease in clinical trials, APP/PS1 mice and 5XFAD transgenic mice. But the underlying mechanism remains ambiguous. Increasing evidence supports the crucial role of astrocyte reactivity in the pathogenesis of Alzheimer's disease (AD). In the present study, we attempt to explore the underlying mechanisms of SYG from astrocyte reactivity in Aß1-42-induced rat model of Alzheimer's disease. After SYG treatment, the impairment of learning and memory induced by Aß1-42 was significantly improved and the hippocampal neuron damages were alleviated. Additionally, the activity of glutamine synthetase and the concentration of glutamate, which might be involved in the cognitive dysfunctions, were outstandingly reduced. Meanwhile, the astrocyte reactivity was also remarkably inhibited. The expressions of JAK2 and STAT3, key proteins in the JAK2/STAT3 signaling pathway that is tightly associated with reactive astrocytes, were clearly attenuated, too. Collectively, our data demonstrate that SYG might exert protective effects on cognitive impairment induced by amyloid-ß oligomers via inhibition of astrocyte reactivity regulated by the JAK2/STAT3 signaling pathway. It may be a potential therapeutic for cognitive dysfunctions in many neurological and psychiatric disorders such as Alzheimer's disease.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Medicamentos de Ervas Chinesas , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/toxicidade , Animais , Astrócitos , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/tratamento farmacológico , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/farmacologia , Janus Quinase 2 , Camundongos , Camundongos Transgênicos , Ratos
9.
Nutrients ; 13(5)2021 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-33946356

RESUMO

Due to the global increase in lifespan, the proportion of people showing cognitive impairment is expected to grow exponentially. As target-specific drugs capable of tackling dementia are lagging behind, the focus of preclinical and clinical research has recently shifted towards natural products. Curcumin, one of the best investigated botanical constituents in the biomedical literature, has been receiving increased interest due to its unique molecular structure, which targets inflammatory and antioxidant pathways. These pathways have been shown to be critical for neurodegenerative disorders such as Alzheimer's disease and more in general for cognitive decline. Despite the substantial preclinical literature on the potential biomedical effects of curcumin, its relatively low bioavailability, poor water solubility and rapid metabolism/excretion have hampered clinical trials, resulting in mixed and inconclusive findings. In this review, we highlight current knowledge on the potential effects of this natural compound on cognition. Furthermore, we focus on new strategies to overcome current limitations in its use and improve its efficacy, with attention also on gender-driven differences.


Assuntos
Anti-Inflamatórios/farmacologia , Disfunção Cognitiva/tratamento farmacológico , Curcuma , Inflamação/tratamento farmacológico , Glucose/metabolismo , Homeostase/efeitos dos fármacos , Humanos
10.
Medicine (Baltimore) ; 100(21): e25886, 2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34032701

RESUMO

BACKGROUND: Vascular dementia (VaD) is the second most common type of dementia; it has a significant impact on patients and exerts a great social and economic burden. However, there has been no comprehensive systematic review assessing the efficacy and safety of Buyang Huanwu-Tang (Boyang Hwano-Tang, BHT) for VaD. Therefore, this protocol was developed to conduct a comprehensive systematic review and meta-analysis to evaluate the effectiveness and safety of BHT in the treatment of VaD. METHODS: We will perform a comprehensive electronic search including MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Allied and Complementary Medicine Database, Cumulative Index to Nursing and Allied Health Literature, PsycARTICLES, Oriental Medicine Advanced Searching Integrated System, Korean Studies Information Service System, Research Information Service System, Korean Medical Database, KMbase, National Digital Science Library, China National Knowledge Infrastructure, Wanfang database, VIP database, Citation Information by NII, and other sources from their inception to November 25, 2020. This systematic review will include only randomized controlled clinical trials of BHT for VaD. The main outcomes will include the Mini-Mental State Examination, Montreal Cognitive Assessment, and Revised Hasegawa's Dementia Scale. Two researchers will independently conduct study selection, data extraction, and appraise the quality and risk of bias of the included studies. A meta-analysis will be conducted using Review Manager version 5.4. The evidence quality of each outcome will be appraised according to the Grades of Recommendation, Assessment, Development, and Evaluation. RESULTS: This study will provide comprehensive understanding of the efficacy and safety of BHT for the treatment of VaD. CONCLUSIONS: The findings of this study will provide reliable evidence for clinical application and further study of BHT for VaD. ETHICS AND DISSEMINATION: Ethical approval is not required because individual patient data will not be included in this study. The study findings will be disseminated through conference presentations. OSF REGISTRATION DOI: 10.17605/OSF.IO/NDYGP.


Assuntos
Disfunção Cognitiva/tratamento farmacológico , Demência Vascular/tratamento farmacológico , Medicamentos de Ervas Chinesas/administração & dosagem , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/etiologia , Demência Vascular/complicações , Demência Vascular/diagnóstico , Medicamentos de Ervas Chinesas/efeitos adversos , Humanos , Testes de Estado Mental e Demência/estatística & dados numéricos , Metanálise como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Revisões Sistemáticas como Assunto , Resultado do Tratamento
11.
J Med Chem ; 64(10): 6856-6876, 2021 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-33973470

RESUMO

Butyrylcholinesterase (BChE) has been considered as a potential therapeutic target for Alzheimer's disease (AD) because of its compensation capacity to hydrolyze acetylcholine (ACh) and its close association with Aß deposit. Here, we identified S06-1011 (hBChE IC50 = 16 nM) and S06-1031 (hBChE IC50 = 25 nM) as highly effective and selective BChE inhibitors, which were proved to be safe and long-acting. Candidate compounds exhibited neuroprotective effects and the ability to improve cognition in scopolamine- and Aß1-42 peptide-induced cognitive deficit models. The best candidate S06-1011 increased the level of ghrelin, a substrate of BChE, which can function as improving the mental mood appetite. The weight gain of the S06-1011-treated group remarkably increased. Hence, BChE inhibition not only plays a protective role against dementia but also exerts a great effect on treating and nursing care.


Assuntos
Butirilcolinesterase/química , Inibidores da Colinesterase/química , Fármacos Neuroprotetores/química , Peptídeos beta-Amiloides/farmacologia , Animais , Sítios de Ligação , Butirilcolinesterase/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Inibidores da Colinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/uso terapêutico , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/patologia , Modelos Animais de Doenças , Desenho de Fármacos , Grelina/metabolismo , Meia-Vida , Humanos , Camundongos , Camundongos Endogâmicos ICR , Simulação de Dinâmica Molecular , Fármacos Neuroprotetores/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Fragmentos de Peptídeos/farmacologia , Quinolinas/química , Quinolinas/metabolismo , Quinolinas/farmacologia , Quinolinas/uso terapêutico , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Regulação para Cima/efeitos dos fármacos
12.
Am J Alzheimers Dis Other Demen ; 36: 15333175211016185, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34008421

RESUMO

PURPOSE: The aim of this study is to examine the potential effect of cilostazol and inflammation on cognitive impairment after stroke in an Asian population. METHODS: Forty-five patients with cognitive impairment after ischemic stroke using cilostazol were enrolled as the study group and 45 patients using aspirin or clopidogrel were enrolled as the control group. Neuropsychiatric assessments were administered at the start of the study and after 6 months. Multiple logistic regression analysis was used to estimate the association between the cognitive change and cilostazol use. Macrophage polarization were assessed using flow cytometry in 7 patients. RESULTS: There were a significantly higher number of patients with peripheral arterial occlusive disease in the cilostazol group. No significant differences were observed in the cognitive change between the cilostazol and control groups. M1 macrophage subset increment were observed in the patient having a declined cognitive change. CONCLUSION: Cilostazol did not make a significant difference in cognitive change after ischemic stroke. M1 macrophage subset increment may indicate post stroke cognitive decline. Due to limited number of subjects, these findings should be examined further in large-scale randomized clinical trials.


Assuntos
Isquemia Encefálica , Disfunção Cognitiva , AVC Isquêmico , Acidente Vascular Cerebral , Isquemia Encefálica/complicações , Isquemia Encefálica/tratamento farmacológico , Cilostazol , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/etiologia , Humanos , Inflamação , Acidente Vascular Cerebral/complicações , Resultado do Tratamento
13.
Alzheimers Res Ther ; 13(1): 96, 2021 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-33952306

RESUMO

BACKGROUND: The relationship between cancer and dementia is triggering growing research interest. Several preclinical studies have provided the biological rationale for the repurposing of specific anticancer agents in Alzheimer's disease (AD), and a growing number of research protocols are testing their efficacy and safety/tolerability in patients with AD. METHODS: The aim of the present systematic review was to provide an overview on the repurposing of approved anticancer drugs in clinical trials for AD by considering both ongoing and completed research protocols in all phases. In parallel, a systematic literature review was conducted on PubMed, ISI Web, and the Cochrane Library to identify published clinical studies on repurposed anticancer agents in AD. RESULTS: Based on a structured search on the ClinicalTrials.gov and the EudraCT databases, we identified 13 clinical trials testing 11 different approved anticancer agents (five tyrosine kinase inhibitors, two retinoid X receptor agonists, two immunomodulatory agents, one histone deacetylase inhibitor, and one monoclonal antibody) in the AD continuum. The systematic literature search led to the identification of five published studies (one phase I, three phase II, and one phase IIb/III) reporting the effects of antitumoral treatments in patients with mild cognitive impairment or AD dementia. The clinical findings and the methodological characteristics of these studies are described and discussed. CONCLUSION: Anticancer agents are triggering growing interest in the context of repurposed therapies in AD. Several clinical trials are underway, and data are expected to be available in the near future. To date, data emerging from published clinical studies are controversial. The promising results emerging from preclinical studies and identified research protocols should be confirmed and extended by larger, adequately designed, and high-quality clinical trials.


Assuntos
Doença de Alzheimer , Antineoplásicos , Disfunção Cognitiva , Doença de Alzheimer/tratamento farmacológico , Antineoplásicos/uso terapêutico , Disfunção Cognitiva/tratamento farmacológico , Humanos
14.
J Med Food ; 24(5): 505-516, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-34009025

RESUMO

We previously reported that mature Bombyx mori silkworm (SW) ameliorated scopolamine (Sco)-induced amnesia, and Angelica gigas (AG) prevented cognitive impairment. SW is known for its gastroprotective effects such as improving liver function and alleviating the effects of Parkinson's disease. AG is known for its neuroprotective effects and for lowering the effects of low-density lipoprotein cholesterol. However, the neuroprotective effect of combined SW and AG (SWA-1) treatment and the underlying molecular mechanism by which SWA-1 regulates neurodegenerative diseases remains unclear. We evaluated the neuroprotective effect of SWA-1 against Sco-induced mild cognitive impairment in mice and H2O2-induced cell death in HT22 mouse hippocampal neuronal cells and elucidated the underlying molecular mechanism. Morris water maze and Y-maze tests were performed to examine the learning and memory abilities of mice. The underlying molecular mechanism was investigated by using western blotting. We demonstrated that SWA-1 significantly protects against H2O2-induced cell death in HT22 mouse hippocampal neuronal cells. SWA-1 also significantly reversed Sco-induced spatial learning and memory impairment. Specifically, SWA-1 upregulates the protein levels of phosphorylated extracellular signal-related kinase (Erk1/2) and phosphorylated p38 MAP kinase (p38). SWA-1 remarkably decreased the apoptotic index Bax/Bcl2 expression in the hippocampus of Sco-treated mice. Our results suggest that SWA-1 may be administered as alternative therapy for cognitive impairment and neurodegenerative diseases and should be studied further in human trials.


Assuntos
Angelica , Bombyx , Disfunção Cognitiva , Fármacos Neuroprotetores , Animais , Morte Celular , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/tratamento farmacológico , Hipocampo , Peróxido de Hidrogênio/toxicidade , Aprendizagem em Labirinto , Camundongos , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Escopolamina/toxicidade
15.
J Psychiatr Res ; 138: 492-499, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33971483

RESUMO

BACKGROUND: Cognitive impairment is one of the core symptoms of schizophrenia patients. There are often various differences in the efficacy of different antipsychotics in the treatment of cognitive impairment by sex. The purpose of this study was to explore whether there are gender differences in the association between serum BDNF levels and cognitive performance in patients with schizophrenia taking different antipsychotics. METHODS: We used Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) to assess the cognitive function of three groups of schizophrenia patients (420 on clozapine, 183 on risperidone, 215 on typical antipsychotic drugs) and 467 healthy controls. Positive and Negative Syndrome Scale (PANSS) was used to assess schizophrenia symptoms of patients. Enzyme-Linked ImmunoSorbent Assay was used to measure serum brain-derived neurotrophic factor (BDNF) levels. RESULTS: Among the patients taking clozapine and typical antipsychotic drugs, the RBANS total score, immediate memory, attention, and delayed memory subscores in females were higher than those in males (all p < 0.05). The RBANS total score and the delayed memory subscores in female patients taking risperidone were higher than those in male patients (all p < 0.05). Significant correlation between BDNF and cognition only existed in male patients taking clozapine, male patients taking risperidone, and male and female patients taking typical antipsychotic drugs (all p < 0.05). CONCLUSION: Regardless of antipsychotic effect, the cognitive function of female patients is better compared to that of male patients. For male patients, the association between BDNF and cognitive performance exists in each medication group. For female patients, this significant association was only shown in the typical antipsychotic group, but not in the clozapine and risperidone groups.


Assuntos
Antipsicóticos , Disfunção Cognitiva , Esquizofrenia , Antipsicóticos/uso terapêutico , Fator Neurotrófico Derivado do Encéfalo , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/etiologia , Feminino , Humanos , Masculino , Esquizofrenia/tratamento farmacológico , Caracteres Sexuais
16.
Food Funct ; 12(8): 3586-3596, 2021 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-33900338

RESUMO

Myricetin is a flavonol highly prevalent in edible vegetables and fruits, with recognized hypoglycemic and anti-obesity effects, besides great antioxidant capacity. Thus, this study sought to investigate whether myricetin is able to improve metabolic and behavioral outcomes found in monosodium l-glutamate (MSG) obese mice, a model of metabolic syndrome characterized by early hyperinsulinemia associated to obesity, dyslipidemia, hepatic steatosis, anxiety and cognitive deficit. Newborn male mice received MSG (4 mg kg-1 day-1, s.c.) on alternate days during the first 10 days of life for obesity induction, while control pups received equimolar saline solution. From postnatal day 90 to 135, MSG mice were orally treated with myricetin (50 mg kg-1 day-1) or distilled water, while control animals received vehicle. During the last week of treatment, all groups were submitted to behavioral tests: open field maze, elevated plus maze and Morris water maze. At the end of treatment, animals were euthanized for collection of liver, serum and adipose tissue fat pads. Myricetin treatment reduced the elevated serum levels of glucose and triglycerides, typically found in MSG mice, as well as restored peripheral insulin sensitivity and liver steatosis. Moreover, myricetin ameliorated the lack of thigmotaxis and exploratory behavior, but did not improve the cognitive deficit presented by MSG mice. Therefore, this study contributes to the pharmacological validation of myricetin as an affordable and healthy therapeutic adjuvant for the treatment of metabolic syndrome and most of its comorbidities.


Assuntos
Disfunção Cognitiva/tratamento farmacológico , Flavonoides/uso terapêutico , Síndrome Metabólica/tratamento farmacológico , Síndrome Metabólica/fisiopatologia , Animais , Fármacos Antiobesidade , Disfunção Cognitiva/etiologia , Comportamento Exploratório/efeitos dos fármacos , Hipoglicemiantes , Masculino , Síndrome Metabólica/complicações , Camundongos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/etiologia , Obesidade/complicações , Obesidade/fisiopatologia
17.
ACS Chem Neurosci ; 12(8): 1343-1350, 2021 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-33818056

RESUMO

Many elderly individuals suffer from Alzheimer's disease (AD), which causes a growing concern. We investigated the mechanism underlying the effects of vitamin D (VD) as a prophylactic treatment. A mouse model of okadaic-acid-induced AD-like pathology was used in vivo and in vitro. Morris water maze and field trials were used to assess cognitive function. The expression levels of VDR, MTHFR, LCMT-1, PP2A, p-TAU (Thr396), and T-TAU and the methylation level of PP2A were measured by Western blotting, and a reversal of the increase in the levels of these proteins in an AD cell model was observed. We used MTHFR-knockdown SH-SY5Y cells to further test the effects of VD, treated these cells with cycloheximide and MG132, and used RT-PCR to explore the mechanism underlying MTHFR targeting. We found that the effects of VD on AD were impaired by MTHFR knockdown through a pretranscriptional mechanism. In addition, VD attenuated AD-induced cognitive impairment and significantly suppressed the expression of TAU. Our findings indicated that VD treatment alleviated TAU accumulation and rescued methylated PP2A by increasing the expression of LCMT-1 and MTHFR.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Idoso , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/tratamento farmacológico , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/tratamento farmacológico , Humanos , Ácido Okadáico/toxicidade , Fosforilação , Vitamina D , Proteínas tau/metabolismo
18.
ACS Chem Neurosci ; 12(9): 1648-1666, 2021 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-33852798

RESUMO

Cholinesterases are significant biological targets for the regulation of cholinergic neurotransmission, and their inhibitors are being exploited for the management of cognitive decline in various neurological conditions. The 1,4-benzoquinone scaffold possesses antioxidant potential along with AChE inhibition activity in various neurological disorders. To design novel and potent selective 1,4-benzoquinone analogues as cholinesterase inhibitors, a ligand-based drug design strategy was followed to develop a 3D quantitative structure-selectivity relationship (QSSR) model. On the basis of the best fit model, eight novel 1,4-benzoquinone derivatives were designed and synthesized implementing appropriate synthetic procedures and were characterized by various spectral and elemental techniques. All the synthesized compounds were evaluated for their selective in vitro acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory potential at different concentrations using mice brain homogenate as the source of the enzyme. Out of these compounds, the three most selective compounds were further evaluated for behavioral variations using step down passive avoidance and escape learning procedure at a dose of 0.5 mg/kg taking donepezil as the reference drug. Biochemical estimation of the markers of oxidative stress (lipid peroxidation, superoxide dismutase, glutathione, and catalase) has also been carried out to determine the role of the synthesized molecules on the scopolamine induced oxidative damage. Compound 2a displayed appreciable selectivity index values as predicted through the 3D-QSSR model. Further, docked complexes of compound 2a with AChE and BChE were subjected to molecular dynamic simulations for a period of 30 ns to study the orientations and stable conformations of the most active molecules in the catalytic domain of these enzymes. The results obtained from the 3D-QSSR analysis, docking, and molecular dynamic studies were found to be appreciable and provided a deep insight into the structural features required for the selectivity of AChE inhibitors over BChE. The outcome of this study may be used as a novel tool to design new highly selective and more potent molecules.


Assuntos
Acetilcolinesterase , Disfunção Cognitiva , Acetilcolinesterase/metabolismo , Animais , Benzoquinonas/farmacologia , Inibidores da Colinesterase/farmacologia , Disfunção Cognitiva/tratamento farmacológico , Simulação por Computador , Camundongos , Simulação de Acoplamento Molecular , Estudos Prospectivos , Relação Estrutura-Atividade
19.
Biofactors ; 47(2): 232-241, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: covidwho-1178977

RESUMO

COVID-19 leads to severe respiratory problems, but also to long-COVID syndrome associated primarily with cognitive dysfunction and fatigue. Long-COVID syndrome symptoms, especially brain fog, are similar to those experienced by patients undertaking or following chemotherapy for cancer (chemofog or chemobrain), as well in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) or mast cell activation syndrome (MCAS). The pathogenesis of brain fog in these illnesses is presently unknown but may involve neuroinflammation via mast cells stimulated by pathogenic and stress stimuli to release mediators that activate microglia and lead to inflammation in the hypothalamus. These processes could be mitigated by phytosomal formulation (in olive pomace oil) of the natural flavonoid luteolin.


Assuntos
COVID-19/tratamento farmacológico , Disfunção Cognitiva/tratamento farmacológico , Fadiga/tratamento farmacológico , Luteolina/uso terapêutico , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Encéfalo/virologia , COVID-19/complicações , COVID-19/fisiopatologia , COVID-19/virologia , Disfunção Cognitiva/complicações , Disfunção Cognitiva/fisiopatologia , Disfunção Cognitiva/virologia , Citocinas/genética , Fadiga/complicações , Fadiga/fisiopatologia , Fadiga/virologia , Humanos , Mastócitos/efeitos dos fármacos , Mastócitos/virologia , SARS-CoV-2/patogenicidade
20.
Biofactors ; 47(2): 232-241, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33847020

RESUMO

COVID-19 leads to severe respiratory problems, but also to long-COVID syndrome associated primarily with cognitive dysfunction and fatigue. Long-COVID syndrome symptoms, especially brain fog, are similar to those experienced by patients undertaking or following chemotherapy for cancer (chemofog or chemobrain), as well in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) or mast cell activation syndrome (MCAS). The pathogenesis of brain fog in these illnesses is presently unknown but may involve neuroinflammation via mast cells stimulated by pathogenic and stress stimuli to release mediators that activate microglia and lead to inflammation in the hypothalamus. These processes could be mitigated by phytosomal formulation (in olive pomace oil) of the natural flavonoid luteolin.


Assuntos
COVID-19/tratamento farmacológico , Disfunção Cognitiva/tratamento farmacológico , Fadiga/tratamento farmacológico , Luteolina/uso terapêutico , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Encéfalo/virologia , COVID-19/complicações , COVID-19/fisiopatologia , COVID-19/virologia , Disfunção Cognitiva/complicações , Disfunção Cognitiva/fisiopatologia , Disfunção Cognitiva/virologia , Citocinas/genética , Fadiga/complicações , Fadiga/fisiopatologia , Fadiga/virologia , Humanos , Mastócitos/efeitos dos fármacos , Mastócitos/virologia , SARS-CoV-2/patogenicidade
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