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1.
Nutrients ; 14(3)2022 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-35276898

RESUMO

A lower body mass is associated with the progression of Alzheimer's disease (AD) and the risk of mortality in patients with AD; however, evidence of genetic determinants of decreased body mass in cognitively impaired older adults is limited. We therefore investigated the genetic effect of APOE-ε4 on body composition in older adults with mild cognitive impairment (MCI) and early-to-moderate-stage AD. A total of 1631 outpatients (aged 65-89 years) with MCI and early-to-moderate-stage AD were evaluated for the association between body composition and APOE-ε4 status. After adjusting for covariates, including cognitive function evaluated with the Mini-Mental State Examination, the presence of the APOE-ε4 was associated with lower weight (ß = -1.116 ± 0.468 kg per presence, p = 0.017), fat mass (ß = -1.196 ± 0.401 kg per presence, p = 0.003), and percentage of body fat (ß = -1.700 ± 0.539% per presence, p = 0.002) in women but not in men. Additionally, the impact of APOE-ε4 on measures of body composition in women was more remarkable in MCI than in AD patients. The presence of the APOE-ε4 allele was associated with lower fat mass, particularly in women with MCI, independent of cognitive decline.


Assuntos
Doença de Alzheimer , Transtornos Cognitivos , Disfunção Cognitiva , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/genética , Doença de Alzheimer/psicologia , Apolipoproteína E4/genética , Cognição , Transtornos Cognitivos/metabolismo , Transtornos Cognitivos/psicologia , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/psicologia , Feminino , Humanos , Masculino
2.
Int J Mol Sci ; 23(4)2022 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-35216241

RESUMO

Treatment of negative symptoms and cognitive disorders in patients with schizophrenia is still a serious clinical problem. The aim of our study was to compare the efficacy of chronic administration of the atypical antipsychotic drug aripiprazole (7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl] butoxy}-3,4-dihydro-2(1H)-quinolinone; ARI) and the well-known antioxidant N-acetylcysteine (NAC) both in alleviating schizophrenia-like social and cognitive deficits and in reducing the decreases in the levels of the brain-derived neurotrophic factor (BDNF) in the prefrontal cortex (PFC) and hippocampus (HIP) of adult Sprague-Dawley rats, that have been induced by chronic administration of the model compound L-buthionine-(S, R)-sulfoximine (BSO) during the early postnatal development (p5-p16). ARI was administered at doses of 0.1 and 0.3 mg/kg while NAC at doses of 10 and 30 mg/kg, alone or in combination. Administration of higher doses of ARI or NAC alone, or co-treatment with lower, ineffective doses of these drugs significantly improved social and cognitive performance as assessed in behavioral tests. Both doses of NAC and 0.3 mg/kg of ARI increased the expression of BDNF mRNA in the PFC, while all doses of these drugs and their combinations enhanced the levels of BDNF protein in this brain structure. In the HIP, only 0,3 mg/kg ARI increased the levels of both BDNF mRNA and its protein. These data show that in the rat BSO-induced neurodevelopmental model of schizophrenia, ARI and NAC differently modulated BDNF levels in the PFC and HIP.


Assuntos
Acetilcisteína/farmacologia , Aripiprazol/farmacologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Cognição/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Esquizofrenia/tratamento farmacológico , Animais , Antipsicóticos/farmacologia , Comportamento Animal/efeitos dos fármacos , Transtornos Cognitivos/tratamento farmacológico , Transtornos Cognitivos/metabolismo , Modelos Animais de Doenças , Feminino , Hipocampo/metabolismo , Córtex Pré-Frontal/metabolismo , Gravidez , Quinolonas/farmacologia , Ratos , Ratos Sprague-Dawley , Esquizofrenia/metabolismo , Comportamento Social
3.
Anal Biochem ; 636: 114437, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34715068

RESUMO

Hepatic encephalopathy and depression share a number of clinical features, such as cognitive impairment and psychomotor retardation, and are highly prevalent in patients with chronic liver disease. Both conditions signify a poor prognosis, carry an increased mortality and are major determinants of reduced health related quality of life. The pathophysiology of hepatic encephalopathy is complex. Whilst cerebral accumulation of ammonia is well-recognised as being central to the development of hepatic encephalopathy, systemic inflammation, which acts in synergy with hyperammonaemia, is emerging as a key driver in its development. The pro-inflammatory state is also widely documented in depression, and peripheral to brain communication occurs resulting in central inflammation, behavioural changes and depressive symptoms. Gut dysbiosis, with a similar reduction in beneficial bacteria, increase in pathogens and decreased bacterial diversity, has been observed in both hepatic encephalopathy and depression, and it may be that the resultant increased bacterial translocation causes their shared inflammatory pathophysiology. Whilst the literature on a positive association between hepatic encephalopathy and depression in cirrhosis remains to be substantiated, there is evolving evidence that treatment with psychobiotics may be of dual benefit, improving cognition and mood in cirrhosis.


Assuntos
Transtornos Cognitivos , Depressão , Encefalopatia Hepática , Hiperamonemia , Cirrose Hepática , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Doença Crônica , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/metabolismo , Transtornos Cognitivos/fisiopatologia , Depressão/etiologia , Depressão/metabolismo , Depressão/fisiopatologia , Encefalopatia Hepática/etiologia , Encefalopatia Hepática/metabolismo , Encefalopatia Hepática/fisiopatologia , Humanos , Hiperamonemia/etiologia , Hiperamonemia/metabolismo , Hiperamonemia/fisiopatologia , Inflamação/metabolismo , Inflamação/fisiopatologia , Cirrose Hepática/complicações , Cirrose Hepática/metabolismo , Cirrose Hepática/fisiopatologia , Qualidade de Vida
4.
Int J Mol Sci ; 22(23)2021 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-34884506

RESUMO

Due to their potent antibacterial properties, silver nanoparticles (AgNPs) are widely used in industry and medicine. However, they can cross the brain-blood barrier, posing a risk to the brain and its functions. In our previous study, we demonstrated that oral administration of bovine serum albumin (BSA)-coated AgNPs caused an impairment in spatial memory in a dose-independent manner. In this study, we evaluated the effects of AgNPs coating material on cognition, spatial memory functioning, and neurotransmitter levels in rat hippocampus. AgNPs coated with BSA (AgNPs(BSA)), polyethylene glycol (AgNPs(PEG)), or citrate (AgNPs(Cit)) or silver ions (Ag+) were orally administered at a dose of 0.5 mg/kg b.w. to male Wistar rats for a period of 28 days, while the control (Ctrl) rats received 0.2 mL of water. The acquisition and maintenance of spatial memory related to place avoidance were assessed using the active allothetic place avoidance task, in which rats from AgNPs(BSA), AgNPs(PEG), and Ag+ groups performed worse than the Ctrl rats. In the retrieval test assessing long-term memory, only rats from AgNPs(Cit) and Ctrl groups showed memory maintenance. The analysis of neurotransmitter levels indicated that the ratio between serotonin and dopamine concentration was disturbed in the AgNPs(BSA) rats. Furthermore, treatment with AgNPs or Ag+ resulted in the induction of peripheral inflammation, which was reflected by the alterations in the levels of serum inflammatory mediators. In conclusion, depending on the coating material used for their stabilization, AgNPs induced changes in memory functioning and concentration of neurotransmitters.


Assuntos
Transtornos Cognitivos/patologia , Hipocampo/patologia , Nanopartículas Metálicas/toxicidade , Polietilenoglicóis/toxicidade , Soroalbumina Bovina/toxicidade , Prata/química , Animais , Citratos/química , Citratos/toxicidade , Transtornos Cognitivos/induzido quimicamente , Transtornos Cognitivos/metabolismo , Citocinas/metabolismo , Hipocampo/efeitos dos fármacos , Masculino , Nanopartículas Metálicas/química , Polietilenoglicóis/química , Ratos , Ratos Wistar , Soroalbumina Bovina/química
5.
BMC Neurosci ; 22(1): 78, 2021 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-34911449

RESUMO

BACKGROUND: Sepsis is considered to be a high-risk factor for cognitive impairment in the brain. The purpose of our study is to explore whether sepsis causes cognitive impairment and try to evaluate the underlying mechanisms and intervention measures. METHODS: Here, we used cecum ligation and puncture (CLP) to simulate sepsis. Open field, Novel Objective Recognition, and Morris Water Maze Test were used to detect cognitive function, long-term potentiation was used to assess of synaptic plasticity, and molecular biological technics were used to assess synaptic proteins, ELISA kits were used to detect inflammatory factors. Metformin was injected into the lateral ventricle of SD rats, and we evaluated whether metformin alleviated CLP-mediated cognitive impairment using behavioral, electrophysiological and molecular biological technology experiments. RESULTS: Here we report hippocampal-dependent cognitive deficits and synaptic dysfunction induced by the CLP, accompanied by a significant increase in inflammatory factors. At the same time, metformin was able to improve cognitive impairment induced by CLP in adult male rats. CONCLUSION: These findings highlight a novel pathogenic mechanism of sepsis-related cognitive impairment through activation of inflammatory factors, and these are blocked by metformin to attenuate sepsis-induced neuronal injury and cognitive impairment.


Assuntos
Cognição/efeitos dos fármacos , Disfunção Cognitiva/tratamento farmacológico , Metformina/farmacologia , Sepse/complicações , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Ceco/efeitos dos fármacos , Ceco/lesões , Ceco/metabolismo , Ceco/patologia , Cognição/fisiologia , Transtornos Cognitivos/tratamento farmacológico , Transtornos Cognitivos/metabolismo , Disfunção Cognitiva/complicações , Disfunção Cognitiva/fisiopatologia , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Ligadura/efeitos adversos , Masculino , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Ratos Sprague-Dawley , Sepse/tratamento farmacológico , Sepse/metabolismo
6.
Int J Mol Sci ; 22(21)2021 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-34769380

RESUMO

Despite the well-accepted role of the two main neuropathological markers (ß-amyloid and tau) in the progression of Alzheimer's disease, the interaction and specific contribution of each of them is not fully elucidated. To address this question, in the present study, an adeno-associated virus (AAV9) carrying the mutant P301L form of human tau, was injected into the dorsal hippocampi of APP/PS1 transgenic mice or wild type mice (WT). Three months after injections, memory tasks, biochemical and immunohistochemical analysis were performed. We found that the overexpression of hTauP301L accelerates memory deficits in APP/PS1 mice, but it did not affect memory function of WT mice. Likewise, biochemical assays showed that only in the case of APP/PS1-hTauP301L injected mice, an important accumulation of tau was observed in the insoluble urea fraction. Similarly, electron microscopy images revealed that numerous clusters of tau immunoparticles appear at the dendrites of APP/PS1 injected mice and not in WT animals, suggesting that the presence of amyloid is necessary to induce tau aggregation. Interestingly, these tau immunoparticles accumulate in dendritic mitochondria in the APP/PS1 mice, whereas most of mitochondria in WT injected mice remain free of tau immunoparticles. Taken together, it seems that amyloid induces tau aggregation and accumulation in the dendritic mitochondria and subsequently may alter synapse function, thus, contributing to accelerate cognitive decline in APP/PS1 mice.


Assuntos
Doença de Alzheimer/complicações , Peptídeos beta-Amiloides/efeitos adversos , Transtornos Cognitivos/patologia , Modelos Animais de Doenças , Mitocôndrias/patologia , Proteínas tau/metabolismo , Precursor de Proteína beta-Amiloide/fisiologia , Animais , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/metabolismo , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mitocôndrias/metabolismo , Fosforilação , Presenilina-1/fisiologia , Sinapses , Proteínas tau/genética
7.
Sci Rep ; 11(1): 20057, 2021 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-34625629

RESUMO

Brain-derived neurotrophic factor (BDNF) is reported to be involved in cognitive decline in patients with schizophrenia (SZ). Previous studies have found that cognitive deficits remain stable during the chronic disease phase in SZ, but the findings were inconsistent. The role of BDNF in cognitive deficits at different stage of illness remains unclear. This study aimed to examine the effect of BDNF polymorphisms on cognitive deficits in drug-naïve first-episode (DNFE) patients and chronic patients with SZ. 262 DNFE patients, 844 chronic patients, and 1043 healthy controls were recruited to compare 4 polymorphisms in BDNF gene and cognitive function. We found that there was no significant difference in genotype and allele frequencies between SZ patients and controls. However, they were closely related to cognitive functioning. BDNF rs2030324 polymorphism played a strong role in language performance only in DNFE patients with SZ. The language index of DNFE patients with rs2030324 TT and TC genotypes was worse than that of chronic patients, but there was no significant difference in CC genotypes between DNFE and chronic patients. Rs6265 had no significant effect on cognitive functioning in patients and controls. Our result suggests BDNF gene polymorphisms were related to different domains of cognitive function at the different stage of SZ, especially language in DNFE patients.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/genética , Transtornos Cognitivos/patologia , Polimorfismo Genético , Esquizofrenia/complicações , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/metabolismo , Feminino , Seguimentos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Preparações Farmacêuticas , Prognóstico , Adulto Jovem
8.
Mol Neurobiol ; 58(11): 5954-5970, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34435330

RESUMO

The influence of long-term tacrolimus treatment on cognitive function remains to be elucidated. Using a murine model of chronic tacrolimus neurotoxicity, we evaluated the effects of tacrolimus on cognitive function, synaptic balance, its regulating protein (Klotho), and oxidative stress in the hippocampus. Compared to vehicle-treated mice, tacrolimus-treated mice showed significantly decreased hippocampal-dependent spatial learning and memory function. Furthermore, tacrolimus caused synaptic imbalance, as demonstrated by decreased excitatory synapses and increased inhibitory synapses, and downregulated Klotho in a dose-dependent manner; the downregulation of Klotho was localized to excitatory hippocampal synapses. Moreover, tacrolimus increased oxidative stress and was associated with activation of the PI3K/AKT pathway in the hippocampus. These results indicate that tacrolimus impairs cognitive function via synaptic imbalance, and that these processes are associated with Klotho downregulation at synapses through tacrolimus-induced oxidative stress in the hippocampus.


Assuntos
Transtornos Cognitivos/induzido quimicamente , Hipocampo/fisiopatologia , Imunossupressores/toxicidade , Proteínas do Tecido Nervoso/fisiologia , Sinapses/efeitos dos fármacos , Tacrolimo/toxicidade , Animais , Transtornos Cognitivos/metabolismo , Dendritos/metabolismo , Regulação para Baixo/efeitos dos fármacos , Hipocampo/patologia , Imunossupressores/farmacologia , /genética , Masculino , Aprendizagem em Labirinto , Camundongos , Camundongos Endogâmicos BALB C , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/genética , Teste de Campo Aberto , Estresse Oxidativo/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/fisiologia , Proteínas Proto-Oncogênicas c-akt/fisiologia , Distribuição Aleatória , Transdução de Sinais , Aprendizagem Espacial , Memória Espacial , Sinapses/fisiologia , Tacrolimo/farmacologia
9.
Cells ; 10(7)2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34359999

RESUMO

Much progress has been made toward deciphering RHO GTPase functions, and many studies have convincingly demonstrated that altered signal transduction through RHO GTPases is a recurring theme in the progression of human malignancies. It seems that 20 canonical RHO GTPases are likely regulated by three GDIs, 85 GEFs, and 66 GAPs, and eventually interact with >70 downstream effectors. A recurring theme is the challenge in understanding the molecular determinants of the specificity of these four classes of interacting proteins that, irrespective of their functions, bind to common sites on the surface of RHO GTPases. Identified and structurally verified hotspots as functional determinants specific to RHO GTPase regulation by GDIs, GEFs, and GAPs as well as signaling through effectors are presented, and challenges and future perspectives are discussed.


Assuntos
Proteínas Ativadoras de GTPase/genética , Fatores de Troca de Nucleotídeo Guanina Rho/genética , Proteína cdc42 de Ligação ao GTP/genética , Proteínas rac1 de Ligação ao GTP/genética , Inibidor alfa de Dissociação do Nucleotídeo Guanina rho/genética , Proteína rhoA de Ligação ao GTP/genética , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/patologia , Transtornos Cognitivos/genética , Transtornos Cognitivos/metabolismo , Transtornos Cognitivos/patologia , Doenças Transmissíveis/genética , Doenças Transmissíveis/metabolismo , Doenças Transmissíveis/patologia , Proteínas Ativadoras de GTPase/metabolismo , Regulação da Expressão Gênica , Humanos , Família Multigênica , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Fatores de Troca de Nucleotídeo Guanina Rho/metabolismo , Transdução de Sinais , Proteína cdc42 de Ligação ao GTP/metabolismo , Proteínas rac1 de Ligação ao GTP/metabolismo , Inibidor alfa de Dissociação do Nucleotídeo Guanina rho/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismo
10.
Nat Metab ; 3(8): 1058-1070, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34417591

RESUMO

Identifying secreted mediators that drive the cognitive benefits of exercise holds great promise for the treatment of cognitive decline in ageing or Alzheimer's disease (AD). Here, we show that irisin, the cleaved and circulating form of the exercise-induced membrane protein FNDC5, is sufficient to confer the benefits of exercise on cognitive function. Genetic deletion of Fndc5/irisin (global Fndc5 knock-out (KO) mice; F5KO) impairs cognitive function in exercise, ageing and AD. Diminished pattern separation in F5KO mice can be rescued by delivering irisin directly into the dentate gyrus, suggesting that irisin is the active moiety. In F5KO mice, adult-born neurons in the dentate gyrus are morphologically, transcriptionally and functionally abnormal. Importantly, elevation of circulating irisin levels by peripheral delivery of irisin via adeno-associated viral overexpression in the liver results in enrichment of central irisin and is sufficient to improve both the cognitive deficit and neuropathology in AD mouse models. Irisin is a crucial regulator of the cognitive benefits of exercise and is a potential therapeutic agent for treating cognitive disorders including AD.


Assuntos
Cognição , Fibronectinas/metabolismo , Hormônios/metabolismo , Condicionamento Físico Animal , Animais , Comportamento Animal , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/metabolismo , Transtornos Cognitivos/psicologia , Modelos Animais de Doenças , Fibronectinas/genética , Deleção de Genes , Expressão Gênica , Camundongos , Camundongos Knockout , Fenótipo
11.
Aging Cell ; 20(8): e13437, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34291567

RESUMO

Synapse degeneration correlates strongly with cognitive impairments in Alzheimer's disease (AD) patients. Soluble Amyloid-beta (Aß) oligomers are thought as the major trigger of synaptic malfunctions. Our earlier studies have demonstrated that Aß oligomers interfere with synaptic function through N-methyl-D-aspartate receptors (NMDARs). Our recent in vitro study found the neuroprotective role of astrocytic GluN2A in the promotion of synapse survival and identified nerve growth factor (NGF) derived from astrocytes, as a likely mediator of astrocytic GluN2A buffering against Aß synaptotoxicity. Our present in vivo study focused on exploring the precise mechanism of astrocytic GluN2A influencing Aß synaptotoxicity through regulating NGF. We generated an adeno-associated virus (AAV) expressing an astrocytic promoter (GfaABC1D) shRNA targeted to Grin2a (the gene encoding GluN2A) to perform astrocyte-specific Grin2a knockdown in the hippocampal dentate gyrus, after 3 weeks of virus vector expression, Aß were bilaterally injected into the intracerebral ventricle. Our results showed that astrocyte-specific knockdown of Grin2a and Aß application both significantly impaired spatial memory and cognition, which associated with the reduced synaptic proteins PSD95, synaptophysin and compensatory increased NGF. The reduced astrocytic GluN2A can counteract Aß-induced compensatory protective increase of NGF through regulating pNF-κB, Furin and VAMP3, which modulating the synthesis, mature and secretion of NGF respectively. Our present data reveal, for the first time, a novel mechanism of astrocytic GluN2A in exerting protective effects on synapses at the early stage of Aß exposure, which may contribute to establish new targets for AD prevention and early therapy.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Astrócitos/metabolismo , Transtornos Cognitivos/metabolismo , Disfunção Cognitiva/metabolismo , Fator de Crescimento Neural/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Astrócitos/patologia , Transtornos Cognitivos/patologia , Disfunção Cognitiva/patologia , Masculino , Ratos , Ratos Wistar , Receptores de N-Metil-D-Aspartato/deficiência , Receptores de N-Metil-D-Aspartato/genética
12.
J Med Chem ; 64(15): 10641-10665, 2021 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-34251799

RESUMO

A series of oxadiazole derivatives were synthesized and evaluated as 5-hydroxytryptamine-4 receptor (5-HT4R) partial agonists for the treatment of cognitive deficits associated with Alzheimer's disease. Starting from a reported 5-HT4R antagonist, a systematic structure-activity relationship was conducted, which led to the discovery of potent and selective 5-HT4R partial agonist 1-isopropyl-3-{5-[1-(3-methoxypropyl) piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate (Usmarapride, 12l). It showed balanced physicochemical-pharmacokinetic properties with robust nonclinical efficacy in cognition models. It also showed disease-modifying potential, as it increased neuroprotective soluble amyloid precursor protein alpha levels, and dose-dependent target engagement and correlation of efficacy with oral exposures. Phase 1 clinical studies have been completed and projected efficacious concentration was achieved without any major safety concerns. Phase 2 enabling long-term safety studies have been completed with no concerns for further development.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Transtornos Cognitivos/tratamento farmacológico , Descoberta de Drogas , Fármacos Neuroprotetores/farmacologia , Receptores 5-HT4 de Serotonina/metabolismo , Agonistas do Receptor 5-HT4 de Serotonina/farmacologia , Doença de Alzheimer/metabolismo , Transtornos Cognitivos/metabolismo , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Agonistas do Receptor 5-HT4 de Serotonina/síntese química , Agonistas do Receptor 5-HT4 de Serotonina/química , Relação Estrutura-Atividade
13.
Int J Mol Sci ; 22(11)2021 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-34072743

RESUMO

Alzheimer's disease (AD) is a neurodegenerative disease with a high incidence rate. The main pathological features of AD are ß-amyloid plaques (APs), which are formed by ß-amyloid protein (Aß) deposition, and neurofibrillary tangles (NFTs), which are formed by the excessive phosphorylation of the tau protein. Although a series of studies have shown that the accumulation of metal ions, including calcium ions (Ca2+), can promote the formation of APs and NFTs, there is no systematic review of the mechanisms by which Ca2+ affects the development and progression of AD. In view of this, the current review summarizes the mechanisms by which Ca2+ is transported into and out of cells and organelles, such as the cell, endoplasmic reticulum, mitochondrial and lysosomal membranes to affect the balance of intracellular Ca2+ levels. In addition, dyshomeostasis of Ca2+ plays an important role in modulating the pathogenesis of AD by influencing the production and aggregation of Aß peptides and tau protein phosphorylation and the ways that disrupting the metabolic balance of Ca2+ can affect the learning ability and memory of people with AD. In addition, the effects of these mechanisms on the synaptic plasticity are also discussed. Finally, the molecular network through which Ca2+ regulates the pathogenesis of AD is introduced, providing a theoretical basis for improving the clinical treatment of AD.


Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Cálcio/metabolismo , Íons/metabolismo , Agregação Patológica de Proteínas/metabolismo , Proteínas tau/metabolismo , Doença de Alzheimer/etiologia , Doença de Alzheimer/patologia , Animais , Transporte Biológico , Membrana Celular/metabolismo , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/metabolismo , Transtornos Cognitivos/patologia , Modelos Animais de Doenças , Progressão da Doença , Suscetibilidade a Doenças , Retículo Endoplasmático/metabolismo , Humanos , Lisossomos/metabolismo , Memória , Mitocôndrias/metabolismo , Plasticidade Neuronal , Neurônios/metabolismo , Fosforilação
14.
Int J Mol Sci ; 22(10)2021 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-34069523

RESUMO

Cognitive dysfunction is one of the core symptoms in schizophrenia, and it is predictive of functional outcomes and therefore useful for treatment targets. Rather than improving cognitive deficits, currently available antipsychotics mainly focus on positive symptoms, targeting dopaminergic/serotoninergic neurons and receptors in the brain. Apart from investigating the neural mechanisms underlying schizophrenia, emerging evidence indicates the importance of glial cells in brain structure development and their involvement in cognitive functions. Although the etiopathology of astrocytes in schizophrenia remains unclear, accumulated evidence reveals that alterations in gene expression and astrocyte products have been reported in schizophrenic patients. To further investigate the role of astrocytes in schizophrenia, we highlighted recent progress in the investigation of the effect of astrocytes on abnormalities in glutamate transmission and impairments in the blood-brain barrier. Recent advances in animal models and behavioral methods were introduced to examine schizophrenia-related cognitive deficits and negative symptoms. We also highlighted several experimental tools that further elucidate the role of astrocytes. Instead of focusing on schizophrenia as a neuron-specific disorder, an additional astrocytic perspective provides novel and promising insight into its causal mechanisms and treatment. The involvement of astrocytes in the pathogenesis of schizophrenia and other brain disorders is worth further investigation.


Assuntos
Astrócitos/fisiologia , Disfunção Cognitiva/fisiopatologia , Esquizofrenia/fisiopatologia , Animais , Astrócitos/metabolismo , Encéfalo/metabolismo , Cognição , Transtornos Cognitivos/metabolismo , Disfunção Cognitiva/metabolismo , Modelos Animais de Doenças , Dopamina/metabolismo , Ácido Glutâmico/metabolismo , Humanos , Neuroglia/metabolismo , Neurônios/metabolismo , Esquizofrenia/metabolismo
15.
Int J Mol Sci ; 22(10)2021 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-34069531

RESUMO

BACKGROUND: Alzheimer's disease (AD) is the most common neurodegenerative disease, and it manifests as progressive memory loss and cognitive decline. However, there are no effective therapies for AD, which is an urgent problem to solve. Evodiamine, one of the main bioactive ingredients of Evodia rutaecarpa, has been reported to ameliorate blood-brain barrier (BBB) permeability and improve cognitive impairment in ischemia and AD mouse models. However, whether evodiamine alleviates tauopathy remains unclear. This study aimed to examine whether evodiamine ameliorates tau phosphorylation and cognitive deficits in AD models. METHODS: A protein phosphatase 2A inhibitor, okadaic acid (OA), was used to induce tau phosphorylation to mimic AD-like models in neuronal cells. Protein expression and cell apoptosis were detected using Western blotting and flow cytometry, respectively. Spatial memory/cognition was assessed using water maze, passive avoidance tests, and magnetic resonance imaging assay in OA-induced mice models, and brain slices were evaluated further by immunohistochemistry. RESULTS: The results showed that evodiamine significantly reduced the expression of phosphor-tau, and further decreased tau aggregation and neuronal cell death in response to OA treatment. This inhibition was found to be via the inhibition of glycogen synthase kinase 3ß, cyclin-dependent kinase 5, and mitogen-activated protein kinase pathways. In vivo results indicated that evodiamine treatment ameliorated learning and memory impairments in mice, whereas Western blotting and immunohistochemical analysis of the mouse brain also confirmed the neuroprotective effects of evodiamine. CONCLUSIONS: Evodiamine can decrease the neurotoxicity of tau aggregation and exhibit a neuroprotective effect. Our results demonstrate that evodiamine has a therapeutic potential for AD treatment.


Assuntos
Quinazolinas/farmacologia , Tauopatias/tratamento farmacológico , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/fisiopatologia , Animais , Apoptose/efeitos dos fármacos , Encéfalo/metabolismo , Linhagem Celular , Cognição/efeitos dos fármacos , Cognição/fisiologia , Transtornos Cognitivos/metabolismo , Modelos Animais de Doenças , Humanos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos ICR , Doenças Neurodegenerativas/metabolismo , Neurônios/metabolismo , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/metabolismo , Fármacos Neuroprotetores/farmacologia , Ácido Okadáico/efeitos adversos , Ácido Okadáico/farmacologia , Fosforilação , Quinazolinas/metabolismo , Memória Espacial/efeitos dos fármacos , Proteínas tau/efeitos dos fármacos , Proteínas tau/metabolismo
16.
Eur Rev Med Pharmacol Sci ; 25(10): 3807-3821, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-34109590

RESUMO

OBJECTIVE: To explore the effect of rehabilitation training on cognitive impairment after cerebrovascular accident and its potential mechanism. PATIENTS AND METHODS: 100 patients of cerebrovascular accident treated in our hospital from August 2018 to August 2019 were selected as the subjects, and 50 patients with physical examination were selected as healthy control group. The patients with cerebrovascular accident were randomly divided into control group (50 patients) and research group (50 patients). The patients in the control group were given routine medication, the patients in research group were given rehabilitation training on the basis of routine drug therapy. The blood samples were collected on admission and 6 months after admission to detect the molecular markers related to inflammation, nerve cell nutrition and function and apoptosis in the serum. The cognitive function was evaluated by scales. We established a rat cerebral ischemia model, compared the differences in the evasive latency, serum CRP, BNDF, Bcl-2, BAX, Glu, NE levels and BNDF, TrkB, pTrkB, JNK levels in hippocampus, amygdala, and prefrontal tissue between model rats after rehabilitation training and model rats without rehabilitation training. RESULTS: On admission, there were no significant differences in the scores of Barthel index (BI), Fugl-Meyer motor function scale (FM), Montreal cognitive assessment scale (MoCA) and mini-mental state examination (MMSE) (p>0.05). 6 months later, the above scores and BNDF, Bcl-2, and norepinephrine were significantly higher in the research group (p<0.05), while CRP, Bax, 5-HT and glutamate in the research group were significantly lower than those in the control group (p<0.05). CONCLUSIONS: Rehabilitation training can improve the motor function, mental state and cognitive level of patients, reduce the levels of neurotoxic factors, pro-inflammatory factors and pro-apoptotic factors, and improve the levels of inhibiting apoptotic factors, neurotrophic factors and neurotransmitters. In animal experiments, rehabilitation training can increase BDNF and its activated receptors in hippocampus, amygdala and prefrontal lobe of rats, and decrease JNK of apoptotic protein, suggesting that rehabilitation training may regulate the expression of apoptotic proteins Bcl-2 and Bax by upregulating BDNF and its receptors and acting on JNK pathway, thereby inhibiting cell apoptosis and improving cognitive impairment after cerebrovascular accident.


Assuntos
Transtornos Cognitivos/reabilitação , Reabilitação do Acidente Vascular Cerebral , Acidente Vascular Cerebral/complicações , Idoso , Animais , Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/sangue , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteína C-Reativa/análise , Transtornos Cognitivos/sangue , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/metabolismo , Feminino , Ácido Glutâmico/sangue , Humanos , Sistema de Sinalização das MAP Quinases , Masculino , Aprendizagem em Labirinto , Testes de Estado Mental e Demência , Pessoa de Meia-Idade , Norepinefrina/sangue , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos Sprague-Dawley , Serotonina/sangue , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/metabolismo
17.
Int Immunopharmacol ; 96: 107744, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33993101

RESUMO

A wealth of evidence indicate that the peripheral immune activation alters brain development. However, it is still largely unclear whether and how peripheral immunosuppression affects neurodevelopment. Here, we found that the immunosuppressant cyclosporin A (CsA) decreased the number of BrdU+, BrdU+/DCX+, BrdU+/NeuN + cells in the hippocampus, impaired learning and memory and inhibited protein levels of the shh signaling pathway, including Shh, Smo and Gli1. However, the shh pathway receptor agonist SAG could block the impairment of cognitive ability and the decrease of hippocampal neurogenesis and brain-derived neurotrophic factor (BDNF) level induced by CsA. We also found that CsA decreased the level of interferon-gamma (IFN-γ), while up-regulation of IFN-γ altered the inhibitory effect of the shh signaling pathway and the decrease of BDNF induced by CsA. Collectively, these data indicate that peripheral CsA impairs neurogenesis and cognition in brain development through downregulating the IFN-γ-Shh-BDNF pathway. The present study guides us to correctly apply immunomodulatory drugs in early life and suggests that the IFN-γ-Shh-BDNF pathway may represent a novel protective target for neurodevelopment under the condition of immunosuppression.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Transtornos Cognitivos/induzido quimicamente , Ciclosporina/toxicidade , Proteínas Hedgehog/metabolismo , Hipocampo/efeitos dos fármacos , Interferon gama/metabolismo , Animais , Animais Recém-Nascidos , Fator Neurotrófico Derivado do Encéfalo/genética , Transtornos Cognitivos/metabolismo , Transtornos Cognitivos/patologia , Modelos Animais de Doenças , Proteínas Hedgehog/genética , Hipocampo/imunologia , Hipocampo/patologia , Imunossupressores/toxicidade , Interferon gama/genética , Camundongos , Camundongos Endogâmicos C57BL , Neurogênese , Transdução de Sinais
18.
Can J Physiol Pharmacol ; 99(10): 1079-1087, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33915055

RESUMO

Chronic cerebral hypoperfusion (CCH), as a critical factor of chronic cerebrovascular diseases, has greatly influenced the health of patients with vascular dementia. Vitexin, a flavone C-glycoside (apigenin-8-C-ß-D-glucopyranoside) that belongs to the flavone subclass of flavonoids, has been shown to possess antioxidant and anti-ischemic properties; however, the putative protective effects of vitexin on the CCH need further investigation. In the current study, the role of vitexin and its underlying mechanism were investigated with permanent bilateral common carotid artery occlusion (2VO) in rats as well as mouse hippocampal neuronal (HT22) cells with oxygen and glucose deprivation/reoxygenation (OGD/R) injury model. The results demonstrated that vitexin improved cognitive dysfunction as well as alleviated pathological neuronal damage in hematoxylin plus eosin (HE) and TUNEL results. The decreased levels of exchange protein directly activated by cAMP 1 (Epac1), Epac2, Ras-associated protein 1 (Rap1), and phospho-extracellular signal-regulated kinase (p-ERK) were reversed by vitexin in rats with CCH. Furthermore, this study indicated that vitexin alleviated CCH-induced inflammation injuries by reducing the expression of NOD-like receptor 3 (NLRP3), caspase-1, interleukin 1ß (IL-1ß), IL-6, and cleaved caspase-3. In vitro, vitexin increased the expression of Epac1 and Epac2, decreased the activation of the NLRP3-mediated inflammation, and improved cell viability. Taken together, our findings suggest that vitexin can reduce the degree of the progressing pathological damage in the cortex and hippocampus and inhibit further deterioration of cognitive function in rats with CCH. Epac and NLRP3 can be regulated by vitexin in vivo and in vitro, which provides enlightenment for the protection of CCH injury.


Assuntos
Apigenina/farmacologia , Transtornos Cerebrovasculares/tratamento farmacológico , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Hipocampo/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Neurônios/efeitos dos fármacos , Animais , Circulação Cerebrovascular , Transtornos Cerebrovasculares/metabolismo , Transtornos Cerebrovasculares/patologia , Doença Crônica , Transtornos Cognitivos/metabolismo , Transtornos Cognitivos/patologia , Transtornos Cognitivos/prevenção & controle , Fatores de Troca do Nucleotídeo Guanina/genética , Hipocampo/metabolismo , Hipocampo/patologia , Masculino , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Neurônios/metabolismo , Neurônios/patologia , Ratos , Ratos Sprague-Dawley
19.
Brain ; 144(8): 2243-2256, 2021 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-33725122

RESUMO

Many aspects of cognition and behaviour are regulated by noradrenergic projections to the forebrain originating from the locus coeruleus, acting through alpha and beta adrenoreceptors. Loss of these projections is common in neurodegenerative diseases and contributes to their cognitive and behavioural deficits. We review the evidence for a noradrenergic modulation of cognition in its contribution to Alzheimer's disease, Parkinson's disease and other cognitive disorders. We discuss the advances in human imaging and computational methods that quantify the locus coeruleus and its function in humans, and highlight the potential for new noradrenergic treatment strategies.


Assuntos
Transtornos Cognitivos/metabolismo , Cognição/fisiologia , Locus Cerúleo/metabolismo , Norepinefrina/metabolismo , Humanos
20.
Int J Mol Sci ; 22(3)2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33535376

RESUMO

Mesenchymal stem cell (MSC)-derived exosomes (MSC-Exo) are nano-sized extracellular vesicles enriched with MSC-sourced neuroprotective and immunomodulatory microRNAs, neural growth factors, and anti-inflammatory cytokines, which attenuate neuro-inflammation, promote neo-vascularization, induce neurogenesis, and reduce apoptotic loss of neural cells. Accordingly, a large number of experimental studies demonstrated MSC-Exo-dependent improvement of cognitive impairment in experimental animals. In this review article, we summarized current knowledge about molecular and cellular mechanisms that were responsible for MSC-Exo-based restoration of cognitive function, emphasizing therapeutic potential of MSC-Exos in the treatment of neurocognitive disorders.


Assuntos
Transtornos Cognitivos/metabolismo , Exossomos/metabolismo , Células-Tronco Mesenquimais/citologia , Doença de Alzheimer/metabolismo , Animais , Apoptose , Transtorno do Espectro Autista/metabolismo , Comportamento Animal , Lesões Encefálicas , Modelos Animais de Doenças , Vesículas Extracelulares/metabolismo , Humanos , Inflamação , Transplante de Células-Tronco Mesenquimais , Doenças Neurodegenerativas/metabolismo , Neurogênese , Neurônios/metabolismo , Neuroproteção , Doença de Parkinson/metabolismo , Esquizofrenia/metabolismo
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