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1.
Ideggyogy Sz ; 72(11-12): 367-379, 2019 Nov 30.
Artigo em Húngaro | MEDLINE | ID: mdl-31834680

RESUMO

Trace elements are found in the living organism in small (trace) amounts and are mainly essential for living functions. Essential trace elements are in humans the chromium (Cr), cobalt (Co), copper (Cu), fluorine (F), iodine (I), iron (Fe), manganese (Mn), molybdenum (Mo), selenium (Se), zinc (Zn), and questionably the boron (B) and vanadium (V). According to the biopsychosocial concept, mental functions have biological underpinnings, therefore the impairment of certain neurochemical processes due to shortage of trace elements may have mental consequences. Scientific investigations indicate the putative role of trace element deficiency in psychiatric disorders such in depression (Zn, Cr, Se, Fe, Co, I), premenstrual dysphoria (Cr), schizophrenia (Zn, Se), cognitive deterioration/de-mentia (B, Zn, Fe, Mn, Co, V), mental retardation (I, Mo, Cu), binge-eating (Cr), autism (Zn, Mn, Cu, Co) and attention deficit hyperactivity disorder (Fe). At the same time, the excess quantity (chronic exposure, genetic error) of certain trace elements (Cu, Mn, Co, Cr, Fe, V) can also lead to mental disturbances (depression, anxiety, psychosis, cognitive dysfunction, insomnia). Lithium (Li), being efficacious in the treatment of bipolar mood disorder, is not declared officially as a trace element. Due to nutrition (drinking water, food) the serum Li level is about a thousand times less than that used in therapy. However, Li level in the red cells is lower as the membrane sodium-Li countertransport results in a Li efflux. Nevertheless, the possibility that Li is a trace element has emerged as studies indicate its potential efficacy in such a low concentration, since certain geographic regions show an inverse correlation between the Li level of drinking water and the suicide rate in that area.


Assuntos
Transtornos Cognitivos/metabolismo , Oligoelementos/metabolismo , Transtornos Cognitivos/fisiopatologia , Humanos , Ferro
2.
Int J Mol Sci ; 20(20)2019 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-31614739

RESUMO

Recent findings have led to the discovery of many signaling pathways that link nuclear receptors with human conditions, including mental decline and neurodegenerative diseases. PPARγ agonists have been indicated as neuroprotective agents, supporting synaptic plasticity and neurite outgrowth. For these reasons, many PPARγ ligands have been proposed for the improvement of cognitive performance in different pathological conditions. In this review, the research on this issue is extensively discussed.


Assuntos
Transtorno Autístico/metabolismo , Transtornos Cognitivos/metabolismo , Cognição , PPAR gama/metabolismo , Doença de Parkinson/metabolismo , Esquizofrenia/metabolismo , Animais , Transtorno Autístico/genética , Transtornos Cognitivos/genética , Humanos , PPAR gama/genética , Doença de Parkinson/genética , Esquizofrenia/genética
3.
J Pharmacol Sci ; 140(3): 263-272, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31474557

RESUMO

Atypical antipsychotics improve positive and negative symptoms but are not effective for treating cognitive impairments in patients with schizophrenia. We previously reported that cognitive impairments in neonatal ventral hippocampus (NVH)-lesioned rats show resistance to atypical antipsychotics risperidone and are associated with reduced calcium/calmodulin-dependent protein kinase II (CaMKII) and protein kinase C (PKC) signaling in memory-related regions. The cognitive enhancer ST101 (spiro[imi-dazo[1,2-a]pyridine-3,2-indan]-2(3H)-one) stimulates CaMKII activity in the hippocampus and medial prefrontal cortex (mPFC). We thus tested ST101 on cognitive impairments in NVH-lesioned rats. Chronic ST101 administration (0.1 and/or 0.5 mg/kg, p.o.) significantly improved deficits in prepulse inhibition (PPI), social interaction, and cognitive function in NVH-lesioned rats. ST101 administration (0.5 mg/kg, p.o.) significantly restored the decreased CaMKII autophosphorylation (Thr-286) in the mPFC and hippocampal CA1 regions of NVH-lesioned rats when assessed by immunohistochemistry. Chronic ST101 administration (0.1 mg/kg, p.o.) improved the decline in phosphorylation levels of CaMKII (Thr-286), PKCα (Ser-657), α-amino-3-hydroxy-5-methyl-4-isoxazol- propionic acid (AMPA)-type glutamate receptor subunit 1 (GluA1: Ser-831), and N-methyl-d-aspartate (NMDA) receptor subunit 1 (GluN1: Ser-896) in the mPFC and hippocampal CA1 regions. Taken together, these results suggest that ST101 improves schizophrenia-like behaviors and cognitive impairment by enhancing CaMKII/PKCα signaling in the mPFC and hippocampus in NVH-lesioned rats.


Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Transtornos Cognitivos/tratamento farmacológico , Hipocampo/efeitos dos fármacos , Indanos/farmacologia , Proteína Quinase C-alfa/metabolismo , Esquizofrenia/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Compostos de Espiro/farmacologia , Animais , Animais Recém-Nascidos , Antipsicóticos/farmacologia , Cognição/efeitos dos fármacos , Transtornos Cognitivos/metabolismo , Feminino , Hipocampo/metabolismo , Masculino , Memória/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/metabolismo , Risperidona/farmacologia , Esquizofrenia/metabolismo
4.
Psychiatr Danub ; 31(Suppl 3): 517-519, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31488783

RESUMO

BACKGROUND: In the literature we can find evidence that sex hormones are involved the alterations of cognition in schizophrenic patients. Another factor, which may have an impact on cognitive domains in this clinical group inflammatory processes. The objective of this review was to explore studies, in which the role of both immunological factors and sex hormones on cognitive functions in schizophrenia are analyzed. METHODS: The search of papers covering this topic in PubMed and Google Scholar was performed. RESULTS: Endocrine factors like: testosteron, estrogen, as well as immunomodulatory are observed to play a role in cognitive functioning in schizophrenia. CONCLUSIONS: More studies are necessary to confirm these possible co-relations.


Assuntos
Transtornos Cognitivos , Cognição , Hormônios Esteroides Gonadais , Inflamação , Esquizofrenia , Psicologia do Esquizofrênico , Transtornos Cognitivos/complicações , Transtornos Cognitivos/metabolismo , Transtornos Cognitivos/patologia , Hormônios Esteroides Gonadais/metabolismo , Humanos , Inflamação/metabolismo , Esquizofrenia/complicações , Esquizofrenia/metabolismo , Esquizofrenia/patologia
5.
Eur J Med Chem ; 179: 449-469, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31271958

RESUMO

In this paper we describe the design and synthesis of bis(Het)Aryl-1,2,3-triazole quinuclidine α7R ligands using an efficient three-step sequence including a Suzuki-Miyaura cross coupling reaction with commercially available and home-made boron derivatives. The exploration of SAR required the preparation of uncommon boron derivatives. Forty final drugs were tested for their ability to bind the target and nine of them exhibited Ki values below nanomolar concentrations. The best scores were always obtained when the 5-phenyl-2-thiophenyl core was attached to the triazole. The selectivity of these compounds towards the nicotinic α4ß2 and serotoninergic 5HT3 receptors was assessed and their brain penetration was quantified by the preparation and in vivo evaluation of two [18F] radiolabelled derivatives. It can be expected from our results that some of these compounds will be suitable for further developments and will have effects on cognitive disorders.


Assuntos
Encéfalo/diagnóstico por imagem , Transtornos Cognitivos/tratamento farmacológico , Radioisótopos de Flúor/química , Marcação por Isótopo , Agonistas Nicotínicos/farmacologia , Tomografia por Emissão de Pósitrons , Quinuclidinas/farmacologia , Triazóis/farmacologia , Receptor Nicotínico de Acetilcolina alfa7/agonistas , Animais , Encéfalo/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Transtornos Cognitivos/metabolismo , Relação Dose-Resposta a Droga , Ligantes , Estrutura Molecular , Agonistas Nicotínicos/síntese química , Agonistas Nicotínicos/química , Quinuclidinas/síntese química , Quinuclidinas/química , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/química , Células Tumorais Cultivadas , Receptor Nicotínico de Acetilcolina alfa7/metabolismo
6.
Medicine (Baltimore) ; 98(28): e16405, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31305452

RESUMO

Our study investigated the association of five genes with MCI in the Xinjiang Uygur population in China. In addition, we also analyzed the association between APOE methylation and MCI.Forty-three MCI and 125 controls were included in the present study. Genotyping was done by Sanger sequencing. DNA methylation assay was done using quantitative methylation-specific polymerase chain reaction (qMSP).The distribution of HMGCR rs3846662 allele frequencies was significantly different between the MCI group and the control group (P = .04), especially in women (P = .032). Subgroup analysis showed that there was a statistically significant association of HMGCR rs3846662 with MCI in the non-APOE ε4 group (P = .024), especially in the females with non-APOE ε4. Similarly, HMGCR rs3846662 genotype and allele frequency in the ApoE E2 protein group were significantly different in the MCI group and the control group (genotype P = .021; allele P = .007). In addition, SIRT1 rs7895833 genotype frequency in the APOE ε4 group was found to be significantly different between the MCI and the control group (P = .005). We also observed a significant association of SIRT1 rs7895833 with MCI in the ApoE E4 protein subgroup (P = .005). In addition, APOE methylation levels were significantly different between the MCI group and the control group (P = .021), especially in men (P = .006). Subgroup analysis showed that APOE methylation levels were significantly associated with MCI in the non-APOE ε4 group (P = .009), especially in men (P = .015).This study found a significant association of HMGCR rs3846662 with MCI in females independent of APOE ε4. In contrast, we revealed that the association of SIRT1 rs7895833 with MCI was dependent on with APOE ε4. We also showed that hypermethylation of APOE in MCI was independent of APOE ε4.


Assuntos
Apolipoproteínas E/genética , Transtornos Cognitivos/genética , Transtornos Cognitivos/metabolismo , Metilação de DNA , Hidroximetilglutaril-CoA Redutases/genética , Sirtuína 1/genética , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Masculino
7.
Pharmacol Rep ; 71(4): 614-623, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31176103

RESUMO

BACKGROUND: Obesity is commonly found to be co-morbid with type 2 Diabetes Mellitus. In obese diabetic patients, TLR-2 receptor induced inflammation leads to the development of insulin resistance (IR). Furthermore, the IR is considered to be the most important cause for promoting cognitive decline which is evident in brain of patients with Alzheimer's disease related dementia (ADRD). METHODS: In this study, the effect of α-lipoic acid (ALA) has been examined in rodent model of zymosan induced insulin resistance and cognitive deficits, targeting at TLR-2 signalling. TLR-2 agonist, Zymosan initiates inflammatory cascade, resulting in IR and cognitive dysfunction. Zymosan (50 mg/kg ip) was given to mice on 1st, 8th, 15th and 22nd day to induce IR which was confirmed by hyperglycaemia, hyperinsulinemia, hyperlipidimea, increased glycated haemoglobin and HOMA-IR. Further the cognitive performance was assessed in Morris water maze revealing cognitive deficit in zymosan treated mice. RESULTS: Daily treatment with ALA for 28 days (50, 100, 200 mg/kg, ip) significantly improved insulin sensitivity and cognitive performance in mice by decreasing insulin resistance, corticosterone, IL-6 levels, acetylcholinesterase enzyme activity and oxidative stress in liver, cortex and hippocampus. ALA also increased adiponectin level and reduced body weight. Combination of ALA (100 mg/kg, ip) with metformin (100 mg/kg, ip) exhibited a potentiating effect in improving cognitive performance and insulin signalling. CONCLUSION: The findings of the study supported the hypothesis that TLR-2 induced inflammation leads to insulin resistance and cognitive impairment and provides an evidence for the therapeutic effect of ALA in IR and ADRD patients.


Assuntos
Anti-Inflamatórios/farmacologia , Transtornos Cognitivos/prevenção & controle , Resistência à Insulina/imunologia , Metformina/farmacologia , Ácido Tióctico/farmacologia , Receptor 2 Toll-Like/metabolismo , Animais , Anti-Inflamatórios/administração & dosagem , Transtornos Cognitivos/imunologia , Transtornos Cognitivos/metabolismo , Modelos Animais de Doenças , Insulina/sangue , Interleucina-6/sangue , Peroxidação de Lipídeos/efeitos dos fármacos , Peroxidação de Lipídeos/imunologia , Lipídeos/sangue , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Metformina/administração & dosagem , Camundongos , Transdução de Sinais , Ácido Tióctico/administração & dosagem , Zimosan
8.
Behav Neurol ; 2019: 3248519, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30944661

RESUMO

There has been growing awareness of the correlation between an episode of traumatic brain injury (TBI) and the development of Alzheimer's disease (AD) later in life. It has been reported that TBI accelerated amyloid-ß (Aß) pathology and cognitive decline in the several lines of AD model mice. However, the short-term and long-term effects of TBI by the weight-drop method on amyloid-ß pathology and cognitive performance are unclear in wild-type (WT) mice. Hence, we examined AD-related histopathological changes and cognitive impairment after TBI in wild-type C57BL6J mice. Five- to seven-month-old WT mice were subjected to either TBI by the weight-drop method or a sham treatment. Seven days after TBI, the WT mice exhibited significantly lower spatial learning than the sham-treated WT mice. However, 28 days after TBI, the cognitive impairment in the TBI-treated WT mice recovered. Correspondingly, while significant amyloid-ß (Aß) plaques and amyloid precursor protein (APP) accumulation were observed in the TBI-treated mouse hippocampus 7 days after TBI, the Aß deposition was no longer apparent 28 days after TBI. Thus, TBI induced transient amyloid-ß deposition and acute cognitive impairments in the WT mice. The present study suggests that the TBI could be a risk factor for acute cognitive impairment even when genetic and hereditary predispositions are not involved. The system might be useful for evaluating and developing a pharmacological treatment for the acute cognitive deficits.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Lesões Encefálicas Traumáticas/metabolismo , Transtornos Cognitivos/patologia , Disfunção Cognitiva/patologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Lesões Encefálicas Traumáticas/patologia , Cognição/fisiologia , Transtornos Cognitivos/metabolismo , Disfunção Cognitiva/metabolismo , Modelos Animais de Doenças , Masculino , Camundongos Endogâmicos C57BL
9.
Nutrients ; 11(4)2019 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-30986970

RESUMO

Cognitive impairment is strongly associated with functional outcomes in psychiatric patients. Involvement of n-3 long chain polyunsaturated fatty acid (n-3 LC-PUFA), in particular docosahexaenoic acid (DHA), in brain functions is largely documented. DHA is incorporated into membrane phospholipids as structural component, especially in the central nervous system where it also has important functional effects. The aim of this review is to investigate the relationship between DHA and cognitive function in relation to mental disorders. Results from few randomized controlled trials (RCTs) on the effects of DHA (alone or in combination) in psychotic, mood and neurodevelopmental disorders, respectively, suggest that no conclusive remarks can be drawn.


Assuntos
Encéfalo/efeitos dos fármacos , Fármacos do Sistema Nervoso Central/uso terapêutico , Transtornos Cognitivos/tratamento farmacológico , Cognição/efeitos dos fármacos , Ácidos Docosa-Hexaenoicos/uso terapêutico , Transtornos Mentais/tratamento farmacológico , Afeto/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Transtornos Cognitivos/metabolismo , Transtornos Cognitivos/fisiopatologia , Transtornos Cognitivos/psicologia , Ácidos Docosa-Hexaenoicos/metabolismo , Humanos , Transtornos Mentais/metabolismo , Transtornos Mentais/fisiopatologia , Transtornos Mentais/psicologia , Transtornos do Humor/tratamento farmacológico , Transtornos do Humor/metabolismo , Transtornos do Humor/fisiopatologia , Transtornos do Humor/psicologia , Transtornos do Neurodesenvolvimento/tratamento farmacológico , Transtornos do Neurodesenvolvimento/metabolismo , Transtornos do Neurodesenvolvimento/fisiopatologia , Transtornos do Neurodesenvolvimento/psicologia
10.
PLoS Pathog ; 15(3): e1007617, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30870531

RESUMO

Herpes simplex virus type 1 (HSV-1) is a DNA neurotropic virus, usually establishing latent infections in the trigeminal ganglia followed by periodic reactivations. Although numerous findings suggested potential links between HSV-1 and Alzheimer's disease (AD), a causal relation has not been demonstrated yet. Hence, we set up a model of recurrent HSV-1 infection in mice undergoing repeated cycles of viral reactivation. By virological and molecular analyses we found: i) HSV-1 spreading and replication in different brain regions after thermal stress-induced virus reactivations; ii) accumulation of AD hallmarks including amyloid-ß protein, tau hyperphosphorylation, and neuroinflammation markers (astrogliosis, IL-1ß and IL-6). Remarkably, the progressive accumulation of AD molecular biomarkers in neocortex and hippocampus of HSV-1 infected mice, triggered by repeated virus reactivations, correlated with increasing cognitive deficits becoming irreversible after seven cycles of reactivation. Collectively, our findings provide evidence that mild and recurrent HSV-1 infections in the central nervous system produce an AD-like phenotype and suggest that they are a risk factor for AD.


Assuntos
Transtornos Cognitivos/metabolismo , Transtornos Cognitivos/virologia , Herpesvirus Humano 1/patogenicidade , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides , Animais , Encéfalo/virologia , Cognição/fisiologia , Transtornos Cognitivos/etiologia , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/virologia , Modelos Animais de Doenças , Feminino , Herpesvirus Humano 1/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Doenças Neurodegenerativas/etiologia , Doenças Neurodegenerativas/virologia , Gânglio Trigeminal/virologia , Ativação Viral/fisiologia , Replicação Viral/fisiologia
11.
J Affect Disord ; 250: 313-318, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30875674

RESUMO

BACKGROUND: Brain proteins, including Insulin-like Growth Factor Binding Protein 5 (IGFBP-5), have been associated with cognitive dysfunction in aging. Mechanisms linking depression with cognition are poorly understood. We hypothesize that the association of depressive symptoms with cognition is mediated or modified by brain proteins. METHODS: IGFBP-5, HSPB2, AK4, ITPK1 and PLXNB1 were measured in dorsolateral prefrontal cortex in 1057 deceased participants, who underwent annual assessments of depressive symptoms and cognition for a mean of 8.9 years. The average number of depressive symptoms per year before a dementia diagnosis was calculated for each person. RESULTS: A one standard deviation above the mean IGFBP-5 was associated with a 14% higher odds of having more depressive symptoms (p < 0.031). Higher IGFBP-5 was associated with faster decline in global cognition (p < 0.001) and five cognitive domains (p < 0.008), controlling for depressive symptoms. IGFBP-5 moderated the association of depressive symptoms with decline in global cognition (p = 0.045). IGFBP-5 mediated ten percent or less of the total effect of depressive symptoms on decline in global cognition and the cognitive domains (p > 0.070). LIMITATIONS: Participants were volunteers and self-selection bias limits the generalizability of our findings. In addition, we used self-reported data on depressive symptoms. However, we also used data on depression medications as sensitivity analyses to confirm findings. CONCLUSIONS: In old age, brain IGFBP-5 is associated with depressive symptoms and cognition. The association of depressive symptoms with cognitive decline is conditional on IGFBP-5.


Assuntos
Encéfalo/metabolismo , Transtornos Cognitivos/metabolismo , Transtorno Depressivo/metabolismo , Proteína 5 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Idoso , Idoso de 80 Anos ou mais , Transtornos Cognitivos/psicologia , Transtorno Depressivo/psicologia , Feminino , Proteínas de Choque Térmico HSP27/metabolismo , Humanos , Masculino , Córtex Pré-Frontal , Proteômica
12.
Mol Med Rep ; 19(5): 3783-3790, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30864708

RESUMO

Alzheimer's disease (AD) is an irreversible, progressive neurodegenerative disorder of the central nervous system that causes severe cognitive impairment. One of the most significant pathological features of AD is the accumulation of ß­amyloid (Aß) peptide in the brain. Resveratrol (Res) is a polyphenol derived from peanuts, red grapes and other plants, which has received increasing attention due to its neuroprotective features. Tg6799 mice are transgenic mice with five familial AD (FAD) mutations that are also known as 5XFAD mice. The present study aimed to investigate the effects of Res on Tg6799 mice. The transgenic mice were randomly divided into the Res treatment group and the vehicle control group, and were treated with 0.5% Res solution (60 mg/kg) or volume­matched normal saline, respectively. Treatment was administered by oral gavage daily for 60 consecutive days. Res reduced amyloid plaque formation and the levels of Aß42, and ß­secretase 1 levels were also significantly decreased. Furthermore, Res was able to reduce the expression of amyloid precursor protein and its cleavage products. The administration of Res to Tg6799 mice also improved their spatial working memory, as measured by the Y­maze test, and rescued spatial memory deficits, as measured using the Morris water maze test; however, Res did not affect their motor function. In conclusion, this study suggested that Res may reduce Aß­induced neuronal damage, thus preventing memory loss.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Precursor de Proteína beta-Amiloide/fisiologia , Transtornos Cognitivos/prevenção & controle , Modelos Animais de Doenças , Placa Amiloide/prevenção & controle , Presenilina-1/fisiologia , Resveratrol/farmacologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Comportamento Animal/efeitos dos fármacos , Transtornos Cognitivos/metabolismo , Transtornos Cognitivos/patologia , Masculino , Transtornos da Memória/metabolismo , Transtornos da Memória/patologia , Transtornos da Memória/prevenção & controle , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Placa Amiloide/metabolismo , Placa Amiloide/patologia
13.
J Neurol ; 266(5): 1203-1210, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30820739

RESUMO

OBJECTIVES: To investigate whether baseline [123I]FP-CIT SPECT and CSF markers can predict cognitive impairment (CI) in PD patients, and provide a profile of those most at risk. METHODS: 262 de novo PD patients from the Parkinson's Progression Markers Initiative database were stratified into two CI groups at the 36-month follow-up: MoCA-defined diagnosis: PD patients who had a MoCA score < 26; neuropsychological test-defined diagnosis: PD patients with MoCA-defined diagnosis and at least two test scores (of six; irrespective of test domain) greater than 1.5 standard deviation below the mean score in healthy controls. Predictive variables of CI were divided into deciles, providing us with ideal cutoff values for each variable. RESULTS: At the 36-month follow-up, 108/262 (41.2%) PD patients had CI as defined by the MoCA, of which 40/108 (37.0%) had neuropsychological test-defined CI. Baseline CSF Aß42 (hazard ratio [HR]: 0.996, confidence interval [CI]: 0.992-0.999, p = 0.025), CSF total tau ([HR]: 1.023, [CI]: 1.002-1.044, p = 0.031) and caudate [123I]FP-CIT SPECT uptake ([HR]: 0.332, [CI]: 0.115-0.960, p = 0.042) were predictors of CI. Patients with reduced CSF Aß42 (< 384.6 pg/mL), increased CSF total tau (> 45.0 pg/mL) and reduced caudate [123I]FP-CIT SPECT uptake (< 1.82) had a 65% risk of developing CI at 36-month follow-up. CONCLUSION: We report a characteristic profile (reduced CSF Aß42, increased CSF total tau and reduced caudate [123I]FP-CIT SPECT uptake) that enables identification of early PD patients at risk of developing CI. These findings confirm previous reports of low CSF Aß42, elevated CSF total tau and reduced dopaminergic integrity being associated with cognitive decline in PD.


Assuntos
Transtornos Cognitivos/etiologia , Transtornos Cognitivos/metabolismo , Doença de Parkinson/complicações , Doença de Parkinson/metabolismo , Idoso , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Precursor de Proteína beta-Amiloide/sangue , Apolipoproteína A-I/sangue , Núcleo Caudado/diagnóstico por imagem , Transtornos Cognitivos/diagnóstico por imagem , Fator de Crescimento Epidérmico/sangue , Feminino , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Doença de Parkinson/diagnóstico por imagem , Fragmentos de Peptídeos/líquido cefalorraquidiano , Valor Preditivo dos Testes , Tomografia Computadorizada de Emissão de Fóton Único , Tropanos/farmacocinética
14.
Int J Mol Sci ; 20(6)2019 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-30901926

RESUMO

Schizophrenia is a chronic mental disease, affecting around 1% of the general population. Schizophrenia is characterized by productive, negative, affective, and disorganization symptoms, and cognitive deficits. Cognitive deficits prevail in most of the schizophrenia patients and are one of the most disabling symptoms. They usually occur before the acute episode of the disease and tend to become chronic with no satisfactory treatment from antipsychotic drugs. Because of their early manifestation in patients' lives, cognitive deficits are suggested to be the primary symptom of schizophrenia. The pathogenesis of cognitive deficits in schizophrenia is not fully understood. They are linked with hypofrontality, which is a decrease in blood flow and glucose metabolism in the prefrontal lobe of schizophrenia-suffering patients. Hypofrontality is linked with disturbances of the corticolimbothalamic circuit, important for cognition and memory in humans. The circuit consists of a group of neuroanatomic structures and hypothetically any disturbance in them may result in cognitive deficits. We present a translational preclinical model of understanding how antipsychotic medication may decrease the N-methyl-D-aspartic acid (NMDA) receptors' activity and produce dysfunctions in the corticolimbothalamic circuit and hypofrontality. From several pharmacological experiments on rats, including mainly our own recent findings, we collected data that suggest that antipsychotic medication may maintain and escalate hypofrontality in schizophrenia, decreasing NMDA receptor activity in the corticolimbothalamic circuit in the human brain. We discuss our findings within the literature of the subject.


Assuntos
Antipsicóticos/química , Córtex Pré-Frontal/irrigação sanguínea , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Receptores de N-Metil-D-Aspartato/química , Animais , Antipsicóticos/efeitos adversos , Antipsicóticos/farmacologia , Cognição/efeitos dos fármacos , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Glutamatos/metabolismo , Humanos , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Esquizofrenia/etiologia , Esquizofrenia/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos
15.
Inflamm Res ; 68(4): 311-323, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30706110

RESUMO

OBJECTIVE: Traumatic brain injury (TBI) is a significant cause of death and long-term deficits in motor and cognitive functions for which there are currently no effective chemotherapeutic drugs. Bazedoxifene (BZA) is a third-generation selective estrogen receptor modulator (SERM) and has been investigated as a treatment for postmenopausal osteoporosis. It is generally safe and well tolerated, with favorable endometrial and breast safety profiles. Recent findings have shown that SERMs may have therapeutic benefits; however, the role of BZA in the treatment of TBI and its molecular and cellular mechanisms remain poorly understood. The aim of the present study was to examine the neuroprotective effects of BZA on early TBI in rats and to explore the underlying mechanisms of these effects. MATERIALS AND METHODS: TBI was induced using a modified weight-drop method. Neurological deficits were evaluated according to the neurological severity score (NSS). Morris water maze and open-field behavioral tests were used to test cognitive functions. Brain edema was measured by brain water content, and impairments in the blood-brain barrier (BBB) were evaluated by expression analysis of tight junction-associated proteins, such as occludin and zonula occludens-1 (ZO-1). Neuronal injury was assessed by hematoxylin and eosin (H&E) staining. LC-MS/MS analysis was performed to determine the ability of BZA to cross the BBB. RESULTS: Our results indicated that BZA attenuated the impaired cognitive functions and the increased BBB permeability of rats subjected to TBI through activation of inflammatory cascades. In vivo experiments further revealed that BZA provided this neuroprotection by suppressing TBI-induced activation of the MAPK/NF-κB signaling pathway. Thus, mechanically, the anti-inflammatory effects of BZA in TBI may be partially mediated by blocking the MAPK signaling pathway. CONCLUSIONS: These findings suggest that BZA might attenuate neurological deficits and BBB damage to protect against TBI by blocking the MAPK/NF-κB signaling pathway.


Assuntos
Anti-Inflamatórios/uso terapêutico , Lesões Encefálicas Traumáticas/tratamento farmacológico , Indóis/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Animais , Anti-Inflamatórios/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Lesões Encefálicas Traumáticas/metabolismo , Transtornos Cognitivos/tratamento farmacológico , Transtornos Cognitivos/metabolismo , Feminino , Homeostase/efeitos dos fármacos , Indóis/farmacologia , Masculino , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fármacos Neuroprotetores/farmacologia , Ocludina/genética , Ocludina/metabolismo , Ratos Sprague-Dawley , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Transdução de Sinais/efeitos dos fármacos , Proteína da Zônula de Oclusão-1/genética , Proteína da Zônula de Oclusão-1/metabolismo
16.
EMBO J ; 38(5)2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30692134

RESUMO

Aberrant function of the RNA-binding protein TDP-43 has been causally linked to multiple neurodegenerative diseases. Due to its large number of targets, the mechanisms through which TDP-43 malfunction cause disease are unclear. Here, we report that knockdown, aggregation, or disease-associated mutation of TDP-43 all impair intracellular sorting and activity-dependent secretion of the neurotrophin brain-derived neurotrophic factor (BDNF) through altered splicing of the trafficking receptor Sortilin. Adult mice lacking TDP-43 specifically in hippocampal CA1 show memory impairment and synaptic plasticity defects that can be rescued by restoring Sortilin splicing or extracellular BDNF. Human neurons derived from patient iPSCs carrying mutated TDP-43 also show altered Sortilin splicing and reduced levels of activity-dependent BDNF secretion, which can be restored by correcting the mutation. We propose that major disease phenotypes caused by aberrant TDP-43 activity may be explained by the abnormal function of a handful of critical proteins, such as BDNF.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Transtornos Cognitivos/patologia , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/fisiologia , Plasticidade Neuronal , Processamento de RNA , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/metabolismo , Proteínas de Ligação a DNA/genética , Células-Tronco Embrionárias/metabolismo , Células-Tronco Embrionárias/patologia , Feminino , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação , Neurônios/metabolismo , Neurônios/patologia
17.
Phytomedicine ; 56: 57-63, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30668354

RESUMO

BACKGROUND: Tetraclinis articulata is used in traditional medicine and has been reported to possess antibacterial, antifungal, cytotoxic, anti-inflammatory and antioxidant properties. PURPOSE: This study investigated the effects of T. articulata essential oil on memory and brain oxidative stress in amyloid-ß peptide 1-42 (Aß1-42)-induced an Alzheimer's disease amyloidosis model. Moreover, the underlying mechanism for memory enhancement and antioxidant activity was investigated, thus supporting its traditional use with scientific evidence for further studies. METHODS: T. articulata essential oil was administered by inhalation to male Wistar rats once daily for 15 min period at doses of 1% and 3% for 21 days after the intracerebroventricular administration of Aß1-42 right-unilaterally to induce memory deficits. The chemical composition of the essential oil was done by GC-MS and GC-FID. Spatial memory of rats was tested using Y-maze and radial arm maze tests. The possible underlying mechanism for memory improvement exhibited by T. articulata essential oil was investigated by in vivo brain antioxidant effect and acetylcholinesterase (AChE) inhibitory effect. In vitro, experimental evaluations were assessed through DPPH and ABTS tests. RESULTS: The GC-MS and GC-FID data showed that the essential oil has a high percent of monoterpene hydrocarbons. Also, we demonstrated the essential oil reversed the Aß1-42-induced decreasing of the spontaneous alternation in the Y-maze test and the Aß1-42-induced increasing of the working and reference memory errors in the radial arm maze test. Furthermore, the Aß1-42-decreased the acetylcholinesterase activity and the oxidant-antioxidant status in the rat hippocampus was retrieved by the treatment with the essential oil. CONCLUSION: The study demonstrates that the essential oil could be a potent pharmacological agent against dementia by modulating cholinergic activity and promoting antioxidant action in the rat hippocampus.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Encéfalo/efeitos dos fármacos , Transtornos Cognitivos/tratamento farmacológico , Cupressaceae/química , Óleos Voláteis/farmacologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/toxicidade , Amiloidose/induzido quimicamente , Animais , Antioxidantes/farmacologia , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Inibidores da Colinesterase/farmacologia , Transtornos Cognitivos/metabolismo , Disfunção Cognitiva/tratamento farmacológico , Modelos Animais de Doenças , Masculino , Transtornos da Memória/tratamento farmacológico , Óleos Voláteis/química , Estresse Oxidativo/efeitos dos fármacos , Fragmentos de Peptídeos/toxicidade , Ratos Wistar , Memória Espacial/efeitos dos fármacos
18.
Horm Behav ; 108: 50-61, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30597139

RESUMO

Males and females can respond differentially to the same environmental stimuli and experimental conditions. Chronic sleep loss is a frequent and growing problem in many modern societies and has a broad variety of negative outcomes for health and well-being. While much has been done to explore the deleterious effects of sleep deprivation (SD) on cognition in both human and animal studies over the last few decades, very little attention has been paid to the part played by sex differences and gonadal steroids in respect of changes in cognitive functions caused by sleep loss. The effects of gonadal hormones on sleep regulation and cognitive performances are well established. Reduced gonadal function in menopausal women and elderly men is associated with sleep disturbances and cognitive decline as well as dementia, which suggests that sex steroids play a key role in modulating these conditions. Finding out whether there are sex differences in respect of the effect of insufficient sleep on cognition, and how neuroendocrine mediators influence cognitive impairment induced by SD could provide valuable insights into the best therapies for each sex. In this review, we aim to highlight the involvement of sex differences and gonadal hormone status on the severity of cognitive deficits induced by sleep deficiency in both human and animal studies.


Assuntos
Transtornos Cognitivos/etiologia , Hormônios Gonadais/fisiologia , Privação do Sono/complicações , Privação do Sono/psicologia , Sono/fisiologia , Idoso , Idoso de 80 Anos ou mais , Animais , Cognição/efeitos dos fármacos , Cognição/fisiologia , Transtornos Cognitivos/metabolismo , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/metabolismo , Feminino , Hormônios Gonadais/farmacologia , Hormônios Esteroides Gonadais/farmacologia , Hormônios Esteroides Gonadais/fisiologia , Humanos , Masculino , Menopausa/efeitos dos fármacos , Menopausa/fisiologia , Menopausa/psicologia , Sistemas Neurossecretores/efeitos dos fármacos , Sistemas Neurossecretores/fisiopatologia , Caracteres Sexuais , Privação do Sono/metabolismo
19.
Epigenetics Chromatin ; 12(1): 7, 2019 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-30616667

RESUMO

Epigenetic modifications such as histone methylation permit change in chromatin structure without accompanying change in the underlying genomic sequence. A number of studies in animal models have shown that dysregulation of various components of the epigenetic machinery causes cognitive deficits at the behavioral level, suggesting that proper epigenetic control is necessary for the fundamental processes of learning and memory. Histone H3 lysine K4 (H3K4) methylation comprises one component of such epigenetic control, and global levels of this mark are increased in the hippocampus during memory formation. Modifiers of H3K4 methylation are needed for memory formation, shown through animal studies, and many of the same modifiers are mutated in human cognitive diseases. Indeed, all of the known H3K4 methyltransferases and four of the known six H3K4 demethylases have been associated with impaired cognition in a neurologic or psychiatric disorder. Cognitive impairment in such patients often manifests as intellectual disability, consistent with a role for H3K4 methylation in learning and memory. As a modification quintessentially, but not exclusively, associated with transcriptional activity, H3K4 methylation provides unique insights into the regulatory complexity of writing, reading, and erasing chromatin marks within an activated neuron. The following review will discuss H3K4 methylation and connect it to transcriptional events required for learning and memory within the developed nervous system. This will include an initial discussion of the most recent advances in the developing methodology to analyze H3K4 methylation, namely mass spectrometry and deep sequencing, as well as how these methods can be applied to more deeply understand the biology of this mark in the brain. We will then introduce the core enzymatic machinery mediating addition and removal of H3K4 methylation marks and the resulting epigenetic signatures of these marks throughout the neuronal genome. We next foray into the brain, discussing changes in H3K4 methylation marks within the hippocampus during memory formation and retrieval, as well as the behavioral correlates of H3K4 methyltransferase deficiency in this region. Finally, we discuss the human cognitive diseases connected to each H3K4 methylation modulator and summarize advances in developing drugs to target them.


Assuntos
Transtornos Cognitivos/genética , Código das Histonas , Histonas/metabolismo , Memória , Animais , Transtornos Cognitivos/metabolismo , Histonas/química , Humanos , Metilação
20.
Neurotox Res ; 35(3): 516-529, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30607903

RESUMO

The cannabinoid system has the ability to modulate cellular and molecular mechanisms, including excitotoxicity, oxidative stress, apoptosis, and inflammation, acting as a neuroprotective agent, by its relationship with signaling pathways associated to the control of cell proliferation, differentiation, and survival. Recent reports have raised new perspectives on the possible role of cannabinoid system in neurodegenerative diseases like Alzheimer disease's (AD). AD is a neurodegenerative disorder characterized by the presence of amyloid plaques, neurofibrillary tangles, neuronal death, and progressive cognitive loss, which could be caused by energy metabolism impairment, changes in insulin signaling, chronic oxidative stress, neuroinflammation, Tau hyperphosphorylation, and Aß deposition in the brain. Thus, we investigated the presumptive protective effect of the cannabinoid type 1 (CB1)-selective receptor agonist arachidonyl-2'-chloroethylamide (ACEA) against streptozotocin (STZ) exposure stimuli in an in vitro neuronal model (Neuro-2a neuroblastoma cells) and in vivo model (intracerebroventricular STZ injection), experimental models of sporadic AD. Our results demonstrated that ACEA treatment reversed cognitive impairment and increased activity of Akt and ERK triggered by STZ, and increased IR expression and increased the anti-apoptotic proteins levels, Bcl-2. In the in vitro model, ACEA was able to rescue cells from STZ-triggered death and modulated the NO release by STZ. Our study has demonstrated a participation of the cannabinoid system in cellular survival, involving the CB1 receptor, which occurs by positive regulation of the anti-apoptotic proteins, suggesting the participation of this system in neurodegenerative processes. Our data suggest that the cannabinoid system is an interesting therapeutic target for the treatment of neurodegenerative diseases.


Assuntos
Ácidos Araquidônicos/farmacologia , Agonistas de Receptores de Canabinoides/farmacologia , Transtornos Cognitivos/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Nootrópicos/farmacologia , Receptor CB1 de Canabinoide/agonistas , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Transtornos Cognitivos/metabolismo , Masculino , Camundongos , Degeneração Neural/tratamento farmacológico , Degeneração Neural/metabolismo , Óxido Nítrico/metabolismo , Ratos Wistar , Receptor CB1 de Canabinoide/metabolismo , Estreptozocina
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