RESUMO
Specialized proresolving mediators and, in particular, 5(S), (6)R, 7-trihydroxyheptanoic acid methyl ester (BML-111) emerge as new therapeutic tools to prevent cardiac dysfunction and deleterious cardiac damage associated with myocarditis progression. The cardioprotective role of BML-111 is mainly caused by the prevention of increased oxidative stress and nuclear factor erythroid-derived 2-like 2 (NRF2) down-regulation induced by myocarditis. At the molecular level, BML-111 activates NRF2 signaling, which prevents sarcoplasmic reticulum-adenosine triphosphatase 2A down-regulation and Ca2+ mishandling, and attenuates the cardiac dysfunction and tissue damage induced by myocarditis.
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Parkinson's disease (PD) is a common neurodegenerative disorder primarily characterized by the death of dopaminergic neurons that project from the substantia nigra pars compacta. Although the molecular bases for PD development are still little defined, extensive evidence from human samples and animal models support the involvement of inflammation in onset or progression. However, the exact trigger for this response remains unclear. Here, we provide a systematic review of the cellular mediators, i.e., microglia, astroglia and endothelial cells. We also discuss the genetic and transcriptional control of inflammation in PD and the immunomodulatory role of dopamine and reactive oxygen species. Finally, we summarize the preclinical and clinical approaches targeting neuroinflammation in PD.
Assuntos
Inflamação/patologia , Inflamação/terapia , Doença de Parkinson/patologia , Doença de Parkinson/terapia , Animais , Barreira Hematoencefálica/patologia , Humanos , Imunomodulação , Inflamação/complicações , Inflamação/genética , Microglia/patologia , Doença de Parkinson/complicações , Doença de Parkinson/genética , Transcrição GênicaRESUMO
Acute respiratory distress syndrome (ARDS) caused by SARS-CoV-2 is largely the result of a dysregulated host response, followed by damage to alveolar cells and lung fibrosis. Exacerbated proinflammatory cytokines release (cytokine storm) and loss of T lymphocytes (leukopenia) characterize the most aggressive presentation. We propose that a multifaceted anti-inflammatory strategy based on pharmacological activation of nuclear factor erythroid 2 p45-related factor 2 (NRF2) can be deployed against the virus. The strategy provides robust cytoprotection by restoring redox and protein homeostasis, promoting resolution of inflammation, and facilitating repair. NRF2 activators such as sulforaphane and bardoxolone methyl are already in clinical trials. The safety and efficacy information of these modulators in humans, together with their well-documented cytoprotective and anti-inflammatory effects in preclinical models, highlight the potential of this armamentarium for deployment to the battlefield against COVID-19.
Assuntos
Anti-Inflamatórios/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Fator 2 Relacionado a NF-E2/metabolismo , Pneumonia Viral/tratamento farmacológico , COVID-19 , Citoproteção , Granulócitos/efeitos dos fármacos , Granulócitos/virologia , Homeostase , Humanos , Oxirredução , PandemiasRESUMO
Repurposing drugs to target M1 macrophages inflammatory response in depression constitutes a bright alternative for commonly used antidepressants. Depression is a significant type of mood disorder, where patients suffer from pathological disturbances associated with a proinflammatory M1 macrophage phenotype. Presently, the most commonly used antidepressants such as Zoloft and Citalopram can reduce inflammation, but suffer from dangerous side effects without offering specificity toward macrophages. We employed a new strategy for drug repurposing based on the integration of RNA-seq analysis and text mining using deep neural networks. Our system employs a Google semantic AI universal encoder to compute sentences embedding. Sentences similarity is calculated using a sorting function to identify drug compounds. Then sentence relevance is computed using a custom-built convolution differential network. Our system highlighted the NRF2 pathway as a critical drug target to reprogram M1 macrophage response toward an anti-inflammatory profile (M2). Using our approach, we were also able to predict that lipoxygenase inhibitor drug zileuton could modulate NRF2 pathway in vitro. Taken together, our results indicate that reorienting zileuton usage to modulate M1 macrophages could be a novel and safer therapeutic option for treating depression.
Assuntos
Anti-Inflamatórios/farmacologia , Antidepressivos/farmacologia , Hidroxiureia/análogos & derivados , Macrófagos/metabolismo , Animais , Inteligência Artificial , Células Cultivadas , Mineração de Dados , Reposicionamento de Medicamentos , Hidroxiureia/farmacologia , Lipopolissacarídeos/efeitos adversos , Macrófagos/efeitos dos fármacos , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , Redes Neurais de Computação , Células RAW 264.7 , Semântica , Análise de Sequência de RNA , Transdução de Sinais/efeitos dos fármacosRESUMO
Transcription factor NRF2 orchestrates a cellular defense against oxidative stress and, so far, has been involved in tumor progression by providing a metabolic adaptation to tumorigenic demands and resistance to chemotherapeutics. In this study, we discover that NRF2 also propels tumorigenesis in gliomas and glioblastomas by inducing the expression of the transcriptional co-activator TAZ, a protein of the Hippo signaling pathway that promotes tumor growth. The expression of the genes encoding NRF2 (NFE2L2) and TAZ (WWTR1) showed a positive correlation in 721 gliomas from The Cancer Genome Atlas database. Moreover, NRF2 and TAZ protein levels also correlated in immunohistochemical tissue arrays of glioblastomas. Genetic knock-down of NRF2 decreased, while NRF2 overexpression or chemical activation with sulforaphane, increased TAZ transcript and protein levels. Mechanistically, we identified several NRF2-regulated functional enhancers in the regulatory region of WWTR1. The relevance of the new NRF2/TAZ axis in tumorigenesis was demonstrated in subcutaneous and intracranial grafts. Thus, intracranial inoculation of NRF2-depleted glioma stem cells did not develop tumors as determined by magnetic resonance imaging. Forced TAZ overexpression partly rescued both stem cell growth in neurospheres and tumorigenicity. Hence, NRF2 not only enables tumor cells to be competent to proliferate but it also propels tumorigenesis by activating the TAZ-mediated Hippo transcriptional program.
Assuntos
Neoplasias Encefálicas/patologia , Glioblastoma/patologia , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Transativadores/genética , Animais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Bases de Dados Genéticas , Feminino , Regulação Neoplásica da Expressão Gênica , Glioblastoma/genética , Glioblastoma/metabolismo , Células HEK293 , Via de Sinalização Hippo , Humanos , Masculino , Camundongos , Transplante de Neoplasias , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais , Análise Serial de Tecidos , Proteínas com Motivo de Ligação a PDZ com Coativador TranscricionalRESUMO
Chronic neuroinflammation is a hallmark of the onset and progression of brain proteinopathies such as Alzheimer disease (AD) and it is suspected to participate in the neurodegenerative process. Transcription factor NRF2, a master regulator of redox homeostasis, controls acute inflammation but its relevance in low-grade chronic inflammation of AD is inconclusive due to lack of good mouse models. We have addressed this question in a transgenic mouse that combines amyloidopathy and tauopathy with either wild type (AT-NRF2-WT) or NRF2-deficiency (AT-NRF2-KO). AT-NRF2-WT mice died prematurely, at around 14 months of age, due to motor deficits and a terminal spinal deformity but AT-NRF2-KO mice died roughly 2 months earlier. NRF2-deficiency correlated with exacerbated astrogliosis and microgliosis, as determined by an increase in GFAP, IBA1 and CD11b levels. The immunomodulatory molecule dimethyl fumarate (DMF), a drug already used for the treatment of multiple sclerosis whose main target is accepted to be NRF2, was tested in this preclinical model. Daily oral gavage of DMF during six weeks reduced glial and inflammatory markers and improved cognition and motor complications in the AT-NRF2-WT mice compared with the vehicle-treated animals. This study demonstrates the relevance of the inflammatory response in experimental AD, tightly regulated by NRF2 activity, and provides a new strategy to fight AD.
Assuntos
Doença de Alzheimer/genética , Encéfalo/patologia , Deleção de Genes , Inflamação/genética , Fator 2 Relacionado a NF-E2/genética , Tauopatias/genética , Doença de Alzheimer/patologia , Animais , Modelos Animais de Doenças , Feminino , Humanos , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Tauopatias/patologiaRESUMO
Chaperone-mediated autophagy (CMA) is a selective degradative process for cytosolic proteins that contributes to the maintenance of proteostasis. The signaling mechanisms that control CMA are not fully understood but might involve response to stress conditions including oxidative stress. Considering the role of CMA in redoxtasis and proteostasis, we sought to determine if the transcription factor NFE2L2/NRF2 (nuclear factor, erythroid derived 2, like 2) has an impact on CMA modulation. In this work, we identified and validated 2 NFE2L2 binding sequences in the LAMP2 gene and demonstrated in several human and mouse cell types that NFE2L2 deficiency and overexpression was linked to reduced and increased LAMP2A levels, respectively. Accordingly, lysosomal LAMP2A levels were drastically reduced in nfe2l2-knockout hepatocytes, which also displayed a marked decrease in CMA activity. Oxidant challenge with paraquat or hydrogen peroxide, or pharmacological activation of NFE2L2 with sulforaphane or dimethyl fumarate also increased LAMP2A levels and CMA activity. Overall, our study identifies for the first time basal and inducible regulation of LAMP2A, and consequently CMA activity, by NFE2L2. ABBREVIATIONS: ACTB: actin, beta, ARE: antioxidant response element; ATG5: autophagy related 5; BACH1: BTB domain and CNC homolog 1; ChIP: chromatin immunoprecipitation; CMA: chaperone-mediated autophagy; DHE: dihydroethidium; DMF: dimethyl fumarate; ENCODE: Encyclopedia of DNA elements at the University of California, Santa Cruz; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GBA: glucosylceramidase beta; GFP: green fluorescent protein; HMOX1: heme oxygenase 1; H2O2: hydrogen peroxide; HSPA8/HSC70: heat shock protein family A (Hsp70) member 8; KEAP1: kelch like ECH associated protein 1; LAMP2A: lysosomal associated membrane protein 2A; LAMP2B: lysosomal associated membrane protein 2B; LAMP2C: lysosomal associated membrane protein 2C; LAMP1: lysosomal associated membrane protein 1; MAFF: MAF bZIP transcription factor F; MAFK: MAF bZIP transcription factor K; NFE2L2/NRF2: nuclear factor, erythroid derived 2, like 2; NQO1: NAD(P)H quinone dehydrogenase 1; PQ: paraquat; PI: protease inhibitors; qRT-PCR: quantitative real-time polymerase chain reaction; RNASE: ribonuclease A family member; SFN: sulforaphane; SQSTM1/p62: sequestosome 1; TBP: TATA-box binding protein.
Assuntos
Autofagia , Proteína 2 de Membrana Associada ao Lisossomo/metabolismo , Chaperonas Moleculares/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Células A549 , Animais , Elementos de Resposta Antioxidante/genética , Autofagia/efeitos dos fármacos , Células HEK293 , Humanos , Proteína 2 de Membrana Associada ao Lisossomo/genética , Camundongos Knockout , Oxidantes/toxicidade , Paraquat/toxicidade , Ligação Proteica/efeitos dos fármacosRESUMO
Systems medicine has a mechanism-based rather than a symptom- or organ-based approach to disease and identifies therapeutic targets in a nonhypothesis-driven manner. In this work, we apply this to transcription factor nuclear factor (erythroid-derived 2)-like 2 (NRF2) by cross-validating its position in a protein-protein interaction network (the NRF2 interactome) functionally linked to cytoprotection in low-grade stress, chronic inflammation, metabolic alterations, and reactive oxygen species formation. Multiscale network analysis of these molecular profiles suggests alterations of NRF2 expression and activity as a common mechanism in a subnetwork of diseases (the NRF2 diseasome). This network joins apparently heterogeneous phenotypes such as autoimmune, respiratory, digestive, cardiovascular, metabolic, and neurodegenerative diseases, along with cancer. Importantly, this approach matches and confirms in silico several applications for NRF2-modulating drugs validated in vivo at different phases of clinical development. Pharmacologically, their profile is as diverse as electrophilic dimethyl fumarate, synthetic triterpenoids like bardoxolone methyl and sulforaphane, protein-protein or DNA-protein interaction inhibitors, and even registered drugs such as metformin and statins, which activate NRF2 and may be repurposed for indications within the NRF2 cluster of disease phenotypes. Thus, NRF2 represents one of the first targets fully embraced by classic and systems medicine approaches to facilitate both drug development and drug repurposing by focusing on a set of disease phenotypes that appear to be mechanistically linked. The resulting NRF2 drugome may therefore rapidly advance several surprising clinical options for this subset of chronic diseases.
Assuntos
Doença Crônica/tratamento farmacológico , Terapia de Alvo Molecular/métodos , Fator 2 Relacionado a NF-E2/metabolismo , Análise de Sistemas , Animais , Anti-Inflamatórios/uso terapêutico , Descoberta de Drogas , Reposicionamento de Medicamentos , Humanos , Fator 2 Relacionado a NF-E2/genéticaRESUMO
Failure to translate successful neuroprotective preclinical data to a clinical setting in Alzheimer's disease (AD) indicates that amyloidopathy and tauopathy alone provide an incomplete view of disease. We have tested here the relevance of additional homeostatic deviations that result from loss of activity of transcription factor NRF2, a crucial regulator of multiple stress responses whose activity declines with ageing. A transcriptomic analysis demonstrated that NRF2-KO mouse brains reproduce 7 and 10 of the most dysregulated pathways of human ageing and AD brains, respectively. Then, we generated a mouse that combines amyloidopathy and tauopathy with either wild type (AT-NRF2-WT) or NRF2-deficiency (AT-NRF2-KO). AT-NRF2-KO brains presented increased markers of oxidative stress and neuroinflammation as well as higher levels of insoluble phosphorylated-TAU and Aß*56 compared to AT-NRF2-WT mice. Young adult AT-NRF2-KO mice exhibited deficits in spatial learning and memory and reduced long term potentiation in the perforant pathway. This study demonstrates the relevance of normal homeostatic responses that decline with ageing, such as NRF2 activity, in the protection against proteotoxic, inflammatory and oxidative stress and provide a new strategy to fight AD.
Assuntos
Doença de Alzheimer/metabolismo , Fator 2 Relacionado a NF-E2/genética , Transcriptoma , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/fisiopatologia , Humanos , Potenciação de Longa Duração , Aprendizagem em Labirinto , Camundongos , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2/deficiência , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Proteínas tau/genética , Proteínas tau/metabolismoRESUMO
Neurodegenerative diseases are linked to the accumulation of specific protein aggregates, suggesting an intimate connection between injured brain and loss of proteostasis. Proteostasis refers to all the processes by which cells control the abundance and folding of the proteome thanks to a wide network that integrates the regulation of signaling pathways, gene expression and protein degradation systems. This review attempts to summarize the most relevant findings about the transcriptional modulation of proteostasis exerted by the transcription factor NRF2 (nuclear factor (erythroid-derived 2)-like 2). NRF2 has been classically considered as the master regulator of the antioxidant cell response, although it is currently emerging as a key component of the transduction machinery to maintain proteostasis. As we will discuss, NRF2 could be envisioned as a hub that compiles emergency signals derived from misfolded protein accumulation in order to build a coordinated and perdurable transcriptional response. This is achieved by functions of NRF2 related to the control of genes involved in the maintenance of the endoplasmic reticulum physiology, the proteasome and autophagy.
Assuntos
Encéfalo/metabolismo , Fator 2 Relacionado a NF-E2/genética , Doenças Neurodegenerativas/metabolismo , Proteoma/genética , Autofagia/genética , Encéfalo/patologia , Retículo Endoplasmático/genética , Retículo Endoplasmático/metabolismo , Humanos , Fator 2 Relacionado a NF-E2/metabolismo , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/patologia , Complexo de Endopeptidases do Proteassoma/genética , Complexo de Endopeptidases do Proteassoma/metabolismo , Agregação Patológica de ProteínasRESUMO
Autophagy is a highly coordinated process that is controlled at several levels including transcriptional regulation. Here, we identify the transcription factor NFE2L2/NRF2 (nuclear factor, erythroid 2 like 2) as a regulator of autophagy gene expression and its relevance in a mouse model of Alzheimer disease (AD) that reproduces impaired APP (amyloid ß precursor protein) and human (Hs)MAPT/TAU processing, clearance and aggregation. We screened the chromatin immunoprecipitation database ENCODE for 2 proteins, MAFK and BACH1, that bind the NFE2L2-regulated enhancer antioxidant response element (ARE). Using a script generated from the JASPAR's consensus ARE sequence, we identified 27 putative AREs in 16 autophagy-related genes. Twelve of these sequences were validated as NFE2L2 regulated AREs in 9 autophagy genes by additional ChIP assays and quantitative RT-PCR on human and mouse cells after NFE2L2 activation with sulforaphane. Mouse embryo fibroblasts of nfe2l2-knockout mice exhibited reduced expression of autophagy genes, which was rescued by an NFE2L2 expressing lentivirus, and impaired autophagy flux when exposed to hydrogen peroxide. NFE2L2-deficient mice co-expressing HsAPPV717I and HsMAPTP301L, exhibited more intracellular aggregates of these proteins and reduced neuronal levels of SQSTM1/p62, CALCOCO2/NDP52, ULK1, ATG5 and GABARAPL1. Also, colocalization of HsAPPV717I and HsMAPTP301L with the NFE2L2-regulated autophagy marker SQSTM1/p62 was reduced in the absence of NFE2L2. In AD patients, neurons expressing high levels of APP or MAPT also expressed SQSTM1/p62 and nuclear NFE2L2, suggesting their attempt to degrade intraneuronal aggregates through autophagy. This study shows that NFE2L2 modulates autophagy gene expression and suggests a new strategy to combat proteinopathies.
Assuntos
Autofagia/genética , Regulação da Expressão Gênica , Fator 2 Relacionado a NF-E2/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Animais , Elementos de Resposta Antioxidante/genética , Modelos Animais de Doenças , Células HEK293 , Humanos , Camundongos Transgênicos , Proteínas Associadas aos Microtúbulos/metabolismo , Pessoa de Meia-Idade , Fator 2 Relacionado a NF-E2/deficiência , Neurônios/metabolismo , Neurônios/patologia , Regiões Promotoras Genéticas/genéticaRESUMO
Intracellular proteolysis is critical to maintain timely degradation of altered proteins including oxidized proteins. This review attempts to summarize the most relevant findings about oxidant protein modification, as well as the impact of reactive oxygen species on the proteolytic systems that regulate cell response to an oxidant environment: the ubiquitin-proteasome system (UPS), autophagy and the unfolded protein response (UPR). In the presence of an oxidant environment, these systems are critical to ensure proteostasis and cell survival. An example of altered degradation of oxidized proteins in pathology is provided for neurodegenerative diseases. Future work will determine if protein oxidation is a valid target to combat proteinopathies.
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Doença de Alzheimer/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Doença de Parkinson/metabolismo , Doenças Priônicas/metabolismo , Processamento de Proteína Pós-Traducional , Espécies Reativas de Oxigênio/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Autofagia/genética , Humanos , Proteínas do Tecido Nervoso/genética , Oxirredução , Doença de Parkinson/genética , Doença de Parkinson/patologia , Doenças Priônicas/genética , Doenças Priônicas/patologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteólise , Ubiquitina/genética , Ubiquitina/metabolismo , Ubiquitinação , Resposta a Proteínas não Dobradas/genéticaRESUMO
Glioblastomas (GBM) are devastating tumors in which there has been little clinical improvement in the last decades. New molecularly directed therapies are under development. EGFR is one of the most promising targets, as this receptor is mutated and/or overexpressed in nearly half of the GBMs. However, the results obtained with first-generation tyrosine-kinase inhibitors have been disappointing with no clear predictive markers of tumor response. Here, we have tested the antitumoral efficacy of a second-generation inhibitor, dacomitinib (PF299804, Pfizer), that binds in an irreversible way to the receptor. Our results confirm that dacomitinib has an effect on cell viability, self-renewal, and proliferation in EGFR-amplified ± EGFRvIII GBM cells. Moreover, systemic administration of dacomitinib strongly impaired the in vivo tumor growth rate of these EGFR-amplified cell lines, with a decrease in the expression of stem cell-related markers. However, continuous administration of the compound was required to maintain the antitumor effect. The data presented here confirm that dacomitinib clearly affects receptor signaling in vivo and that its strong antitumoral effect is independent of the presence of mutant receptor isoforms although it could be affected by the PTEN status (as it is less effective in a PTEN-deleted GBM line). Dacomitinib is being tested in second line for EGFR-amplified GBMs. We hope that our results could help to select retrospectively molecular determinants of this response and to implement future trials with dacomitinib (alone or in combination with other inhibitors) in newly diagnosed GBMs.
Assuntos
Receptores ErbB/antagonistas & inibidores , Glioblastoma/tratamento farmacológico , Quinazolinonas/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Western Blotting , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/genética , Receptores ErbB/metabolismo , Amplificação de Genes , Glioblastoma/genética , Glioblastoma/metabolismo , Humanos , Camundongos Nus , Fosforilação/efeitos dos fármacos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/efeitos dos fármacos , Análise de Sobrevida , Fatores de Tempo , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/genética , Células Tumorais CultivadasRESUMO
BACKGROUND: Quality of life (QoL) is an important outcome in the treatment of schizophrenia. Cognitive deficits have an impact on functional outcomes. Cognitive remediation therapy is emerging as a psychological intervention that targets cognitive impairment, but the effect of computer-assisted cognitive remediation on neuropsychology and social functioning and wellbeing remains unclear. The aim of the current study is to investigate the neurocognitive outcomes of computer-assisted cognitive remediation (CACR) therapy in a sample of schizophrenia patients, and to measure the quality of life and self-esteem as secondary outcomes. METHODS: Sixty-seven people with schizophrenia were randomly assigned to computer-assisted cognitive remediation or an active control condition. The main outcomes were neuropsychological measures and secondary outcomes (self-esteem and quality of life). Measurements were recorded at baseline and post-treatment. RESULTS: The CACR therapy group improved in speed of processing, working memory and reasoning and problem-solving cognitive domains. QoL and self-esteem measures also showed significant improvements over time in this group. CONCLUSIONS: Computer-assisted cognitive remediation therapy for people with schizophrenia achieved improvements in neuropsychological performance and in QoL and self-esteem measurements.
Assuntos
Transtornos Cognitivos/reabilitação , Terapia Cognitivo-Comportamental/métodos , Qualidade de Vida/psicologia , Psicologia do Esquizofrênico , Autoimagem , Terapia Assistida por Computador , Adulto , Análise de Variância , Transtornos Cognitivos/etiologia , Feminino , Humanos , Estudos Longitudinais , Masculino , Testes Neuropsicológicos , Avaliação de Resultados em Cuidados de Saúde , Esquizofrenia/complicações , Adulto JovemRESUMO
An accurate representation of task-set information is needed for successful goal directed behavior. Recent studies point to disturbances in the early processing stages as plausible causes for task-switching deficits in schizophrenia. A task-cueing protocol was administered to a group of schizophrenic patients and compared with a sample of age-matched healthy controls. Patients responded slower and less accurate compared with controls in all conditions. The concurrent recording of event-related brain potentials to contextual cues and target events revealed abnormalities in the early processing of both cue-locked and target-locked N1 potentials. Abnormally enhanced target-locked P2 amplitudes were observed in schizophrenic patients for task-switch trials only, suggesting disrupted stimulus evaluation and memory retrieval processes. The endogenous P3 potentials discriminated between task conditions but without further differences between groups. These results suggest that the observed impairments in task-switching behavior were not specifically related to anticipatory set-shifting, but derived from a deficit in the implementation of task-set representations at target onset in the presence of irrelevant and conflicting information.
Assuntos
Encéfalo/fisiopatologia , Potenciais Evocados/fisiologia , Desempenho Psicomotor/fisiologia , Esquizofrenia/fisiopatologia , Adulto , Cognição/fisiologia , Sinais (Psicologia) , Eletroencefalografia , Feminino , Humanos , Masculino , Testes Neuropsicológicos , Tempo de Reação/fisiologiaRESUMO
Behavioral and electrophysiological brain responses were used to examine the relationship between the vulnerability to distraction and the orienting response in schizophrenia. Nineteen schizophrenics and nineteen matched healthy controls were instructed to ignore task-irrelevant auditory stimuli while they classified capital letters and digits. The auditory sequences contained repetitive standard tones occasionally replaced by complex novel sounds. Relative to controls, patients showed an increased behavioral distraction, as indicated by a larger response time increase caused by novel sounds, and a disturbance in the attention orienting toward distracting stimuli, as indicated by a reduced novelty-P3. This behavioral-electrophysiological dissociation may stem from a limited pool of available resources. Thus, the few attentional resources directed toward novel stimuli would be sufficient to cause an important decrease of the similarly reduced amount of resources assigned to task-relevant stimuli, resulting in a striking impairment of the ongoing task performance.