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1.
Alzheimers Dement ; 20(3): 2298-2308, 2024 03.
Artigo em Inglês | MEDLINE | ID: mdl-38265159

RESUMO

Despite its high prevalence among dementias, Lewy body dementia (LBD) remains poorly understood with a limited, albeit growing, evidence base. The public-health burden that LBD imposes is worsened by overlapping pathologies, which contribute to misdiagnosis, and lack of treatments. For this report, we gathered and analyzed public-domain information on advocacy, funding, research outputs, and the therapeutic pipeline to identify gaps in each of these key elements. To further understand the current gaps, we also conducted interviews with leading experts in regulatory/governmental agencies, LBD advocacy, academic research, and biopharmaceutical research, as well as with funding sources. We identified wide gaps across the entire landscape, the most critical being in research. Many of the experts participated in a workshop to discuss the prioritization of research areas with a view to accelerating therapeutic development and improving patient care. This white paper outlines the opportunities for bridging the major LBD gaps and creates the framework for collaboration in that endeavor. HIGHLIGHTS: A group representing academia, government, industry, and consulting expertise was convened to discuss current progress in Dementia with Lewy Body care and research. Consideration of expert opinion,natural language processing of the literature as well as publicly available data bases, and Delphi inspired discussion led to a proposed consensus document of priorities for the field.


Assuntos
Doença por Corpos de Lewy , Humanos , Doença por Corpos de Lewy/diagnóstico , Doença por Corpos de Lewy/terapia
2.
Clin Transl Sci ; 16(11): 2236-2252, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37817426

RESUMO

This single-center study administered MIJ821 (onfasprodil) as an intravenous infusion to healthy volunteers and included two parts: a single ascending dose study (Part 1) and a repeated intravenous dose study (Part 2). Primary objective was to evaluate the safety and tolerability of single ascending intravenous doses infused over a 40-min period and of two repeated doses (1 week apart) of MIJ821 in healthy volunteers. Secondary objectives were to assess the pharmacokinetics of MIJ821 after intravenous infusion in Part 1 and Part 2 of the study. Overall, 43 subjects in Part 1 and 12 subjects in Part 2 were randomized in the study. Median age in Part 1 and Part 2 was 45.0 and 43.5 years, respectively, with the majority being Caucasian (Part 1: 84%; Part 2: 92%). 19 subjects (44.2%) in Part 1 and 8 subjects (66.7%) in Part 2 experienced at least one adverse event (AE). Following single dose in Part 1 and Part 2, the AUCinf values of MIJ821 increased in a dose-proportional manner across the dose range 0.016-0.48 mg/kg and the Cmax values in a slight overproportional manner across the dose range 0.048-0.48 mg/kg. At the highest dose of 0.48 mg/kg, the geometric mean AUCinf was 708 h ng/mL and the geometric mean Cmax was 462 ng/mL. Inspection of 1-h post-dose resting electroencephalography activity across cohorts showed a relationship to administered dose, providing exploratory evidence of distal target engagement. In conclusion, MIJ821 showed a good safety and tolerability profile in healthy volunteers. Dissociative AEs were mild, transient, and dose-dependent.


Assuntos
Infusões Intravenosas , Humanos , Método Duplo-Cego , Área Sob a Curva , Voluntários Saudáveis , Relação Dose-Resposta a Droga
3.
JMIR Res Protoc ; 11(8): e35442, 2022 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-35947423

RESUMO

BACKGROUND: More sensitive and less burdensome efficacy end points are urgently needed to improve the effectiveness of clinical drug development for Alzheimer disease (AD). Although conventional end points lack sensitivity, digital technologies hold promise for amplifying the detection of treatment signals and capturing cognitive anomalies at earlier disease stages. Using digital technologies and combining several test modalities allow for the collection of richer information about cognitive and functional status, which is not ascertainable via conventional paper-and-pencil tests. OBJECTIVE: This study aimed to assess the psychometric properties, operational feasibility, and patient acceptance of 10 promising technologies that are to be used as efficacy end points to measure cognition in future clinical drug trials. METHODS: The Method for Evaluating Digital Endpoints in Alzheimer Disease study is an exploratory, cross-sectional, noninterventional study that will evaluate 10 digital technologies' ability to accurately classify participants into 4 cohorts according to the severity of cognitive impairment and dementia. Moreover, this study will assess the psychometric properties of each of the tested digital technologies, including the acceptable range to assess ceiling and floor effects, concurrent validity to correlate digital outcome measures to traditional paper-and-pencil tests in AD, reliability to compare test and retest, and responsiveness to evaluate the sensitivity to change in a mild cognitive challenge model. This study included 50 eligible male and female participants (aged between 60 and 80 years), of whom 13 (26%) were amyloid-negative, cognitively healthy participants (controls); 12 (24%) were amyloid-positive, cognitively healthy participants (presymptomatic); 13 (26%) had mild cognitive impairment (predementia); and 12 (24%) had mild AD (mild dementia). This study involved 4 in-clinic visits. During the initial visit, all participants completed all conventional paper-and-pencil assessments. During the following 3 visits, the participants underwent a series of novel digital assessments. RESULTS: Participant recruitment and data collection began in June 2020 and continued until June 2021. Hence, the data collection occurred during the COVID-19 pandemic (SARS-CoV-2 virus pandemic). Data were successfully collected from all digital technologies to evaluate statistical and operational performance and patient acceptance. This paper reports the baseline demographics and characteristics of the population studied as well as the study's progress during the pandemic. CONCLUSIONS: This study was designed to generate feasibility insights and validation data to help advance novel digital technologies in clinical drug development. The learnings from this study will help guide future methods for assessing novel digital technologies and inform clinical drug trials in early AD, aiming to enhance clinical end point strategies with digital technologies. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/35442.

4.
Nat Commun ; 13(1): 1150, 2022 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-35241644

RESUMO

Huntington's Disease (HD) is a progressive neurodegenerative disorder caused by CAG trinucleotide repeat expansions in exon 1 of the huntingtin (HTT) gene. The mutant HTT (mHTT) protein causes neuronal dysfunction, causing progressive motor, cognitive and behavioral abnormalities. Current treatments for HD only alleviate symptoms, but cerebral spinal fluid (CSF) or central nervous system (CNS) delivery of antisense oligonucleotides (ASOs) or virus vectors expressing RNA-induced silencing (RNAi) moieties designed to induce mHTT mRNA lowering have progressed to clinical trials. Here, we present an alternative disease modifying therapy the orally available, brain penetrant small molecule branaplam. By promoting inclusion of a pseudoexon in the primary transcript, branaplam lowers mHTT protein levels in HD patient cells, in an HD mouse model and in blood samples from Spinal Muscular Atrophy (SMA) Type I patients dosed orally for SMA (NCT02268552). Our work paves the way for evaluating branaplam's utility as an  HD therapy, leveraging small molecule splicing modulators to reduce expression of dominant disease genes by driving pseudoexon inclusion.


Assuntos
Doença de Huntington , Animais , Encéfalo/metabolismo , Modelos Animais de Doenças , Humanos , Proteína Huntingtina/genética , Proteína Huntingtina/metabolismo , Doença de Huntington/tratamento farmacológico , Doença de Huntington/genética , Doença de Huntington/metabolismo , Camundongos , Oligonucleotídeos Antissenso/metabolismo , Expansão das Repetições de Trinucleotídeos
5.
Front Psychiatry ; 12: 640741, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34025472

RESUMO

Background: Digital technologies have the potential to provide objective and precise tools to detect depression-related symptoms. Deployment of digital technologies in clinical research can enable collection of large volumes of clinically relevant data that may not be captured using conventional psychometric questionnaires and patient-reported outcomes. Rigorous methodology studies to develop novel digital endpoints in depression are warranted. Objective: We conducted an exploratory, cross-sectional study to evaluate several digital technologies in subjects with major depressive disorder (MDD) and persistent depressive disorder (PDD), and healthy controls. The study aimed at assessing utility and accuracy of the digital technologies as potential diagnostic tools for unipolar depression, as well as correlating digital biomarkers to clinically validated psychometric questionnaires in depression. Methods: A cross-sectional, non-interventional study of 20 participants with unipolar depression (MDD and PDD/dysthymia) and 20 healthy controls was conducted at the Centre for Human Drug Research (CHDR), the Netherlands. Eligible participants attended three in-clinic visits (days 1, 7, and 14), at which they underwent a series of assessments, including conventional clinical psychometric questionnaires and digital technologies. Between the visits, there was at-home collection of data through mobile applications. In all, seven digital technologies were evaluated in this study. Three technologies were administered via mobile applications: an interactive tool for the self-assessment of mood, and a cognitive test; a passive behavioral monitor to assess social interactions and global mobility; and a platform to perform voice recordings and obtain vocal biomarkers. Four technologies were evaluated in the clinic: a neuropsychological test battery; an eye motor tracking system; a standard high-density electroencephalogram (EEG)-based technology to analyze the brain network activity during cognitive testing; and a task quantifying bias in emotion perception. Results: Our data analysis was organized by technology - to better understand individual features of various technologies. In many cases, we obtained simple, parsimonious models that have reasonably high diagnostic accuracy and potential to predict standard clinical outcome in depression. Conclusion: This study generated many useful insights for future methodology studies of digital technologies and proof-of-concept clinical trials in depression and possibly other indications.

6.
Adv Ther ; 34(2): 524-541, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28044255

RESUMO

INTRODUCTION: To determine if mavoglurant (modified release) as an augmentation therapy to selective serotonin reuptake inhibitors (SSRIs) could have beneficial effects reducing Yale-Brown Obsessive Compulsive Scale (Y-BOCS) total score in patients with obsessive-compulsive disorder (OCD) resistant to SSRI treatment. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase 2 study. Patients remained on their SSRI treatment and mavoglurant or placebo was added on. Non-smoking men and women aged 18-65 years primarily diagnosed with OCD according to Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev.; DSM-IV-TR) criteria were randomized (1:1) to mavoglurant or placebo groups. After 50 patients were randomized, an interim analysis was conducted to determine whether the study should be continued. The primary outcome measure was absolute change in Y-BOCS from baseline at week 17. Safety was assessed by recording adverse events (AEs) and serious adverse events (SAEs). RESULTS: Interim analysis led to a decision to terminate the study. In total 38 (76.0%) participants completed 17 weeks of treatment and 37 (74.0%) completed the study. There was no significant difference in least squares (LS) mean change from baseline at week 17 in Y-BOCS total score for mavoglurant compared with placebo groups [-6.9 (1.75) vs. -8.0 (1.78), respectively; LS mean difference 1.1; 95% CI -3.9, 6.2; p = 0.671]. The incidence of AEs was higher in the mavoglurant compared with the placebo group (80.8% vs. 70.8%, respectively). CONCLUSION: This study of mavoglurant in OCD was terminated because of the lack of efficacy at interim analysis. The study did not support the use of an antagonist of mGluR5 receptors for OCD treatment. TRIAL REGISTRATION: The study was registered with ClinicalTrials.gov: NCT01813019. FUNDING: This study was sponsored by Novartis Pharma AG, Basel, Switzerland.


Assuntos
Indóis , Transtorno Obsessivo-Compulsivo , Receptor de Glutamato Metabotrópico 5/antagonistas & inibidores , Adulto , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/efeitos adversos , Manual Diagnóstico e Estatístico de Transtornos Mentais , Método Duplo-Cego , Resistência a Medicamentos , Sinergismo Farmacológico , Quimioterapia Combinada , Término Precoce de Ensaios Clínicos , Feminino , Humanos , Indóis/administração & dosagem , Indóis/efeitos adversos , Masculino , Pessoa de Meia-Idade , Transtorno Obsessivo-Compulsivo/diagnóstico , Transtorno Obsessivo-Compulsivo/tratamento farmacológico , Escalas de Graduação Psiquiátrica , Psicotrópicos/administração & dosagem , Psicotrópicos/efeitos adversos , Inibidores Seletivos de Recaptação de Serotonina/administração & dosagem , Inibidores Seletivos de Recaptação de Serotonina/efeitos adversos , Resultado do Tratamento
7.
J Clin Psychopharmacol ; 36(4): 314-23, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27253658

RESUMO

Suvorexant is a dual orexin receptor antagonist approved in the United States and Japan for the treatment of insomnia at a maximum dose of 20 mg. This randomized double-blind crossover study evaluated the abuse potential of suvorexant in 36 healthy recreational polydrug users with a history of sedative and psychedelic drug use. Single doses of suvorexant (40, 80, and 150 mg: 2-7.5 × maximum dose), zolpidem (15 and 30 mg: 1.5-3 × maximum dose), and placebo were administered, with a 10-day washout between treatments. Subjective and objective measures, including visual analog scales (VASs), Addiction Research Center Inventory, and cognitive/psychomotor tests, were evaluated for 24-hour postdose. Suvorexant had significantly greater peak effects on "drug liking" VAS (primary endpoint) than placebo. Although effects of suvorexant on abuse potential measures were generally similar to zolpidem, they remained constant across doses, whereas zolpidem often had greater effects at higher doses. Suvorexant (all doses) had significantly fewer effects than zolpidem 30 mg on secondary measures, such as "high" VAS, Bowdle VAS, and Addiction Research Center Inventory morphine-benzedrine group. The overall incidence of abuse-related adverse events, such as euphoric mood and hallucination, was numerically lower with suvorexant than zolpidem. In agreement with its classification as a schedule IV drug, suvorexant demonstrated abuse potential, compared with placebo. The abuse potential was similar to zolpidem using certain measures, but with a reduced incidence of abuse-related adverse events. Although this suggests that the overall abuse liability of suvorexant may be lower than zolpidem, the actual abuse rates will be assessed with the postmarketing experience.


Assuntos
Azepinas/farmacologia , Euforia/efeitos dos fármacos , Alucinações/induzido quimicamente , Hipnóticos e Sedativos/farmacologia , Antagonistas dos Receptores de Orexina/farmacologia , Piridinas/farmacologia , Triazóis/farmacologia , Adulto , Azepinas/administração & dosagem , Azepinas/efeitos adversos , Estudos Cross-Over , Método Duplo-Cego , Feminino , Humanos , Hipnóticos e Sedativos/administração & dosagem , Hipnóticos e Sedativos/efeitos adversos , Drogas Ilícitas , Masculino , Pessoa de Meia-Idade , Antagonistas dos Receptores de Orexina/administração & dosagem , Antagonistas dos Receptores de Orexina/efeitos adversos , Uso Indevido de Medicamentos sob Prescrição , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Triazóis/administração & dosagem , Triazóis/efeitos adversos , Zolpidem
8.
Ther Adv Drug Saf ; 6(3): 86-97, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26240742

RESUMO

OBJECTIVES: We sought to validate Cognitive Research Corporation's Driving Simulator (CRCDS Mini-Sim) for studies of drug safety with respect to driving ability. METHODS: A total of 30 healthy subjects were randomized to receive placebo or 7.5 mg zopiclone, a hypnotic known to impair driving, in random order during the 2 treatment periods of a 2 period crossover design. RESULTS: Evening administration of 7.5 mg zopiclone increased next-day standard deviation of lateral lane position (SDLP) by 2.62 cm on average compared with evening administration of placebo, and caused significant effects on symmetry analysis. The magnitude of the change in SDLP is highly similar to changes previously observed using on-the-road driving methods. CONCLUSIONS: Further validation of the CRCDS Mini-Sim is warranted to develop this platform for drug safety studies.

9.
Hum Mol Genet ; 23(4): 1036-44, 2014 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-24105466

RESUMO

Transcriptional dysregulation has been proposed to play a major role in the pathology of Huntington's disease (HD). However, the mechanisms that cause selective downregulation of target genes remain unknown. Previous studies have shown that mutant huntingtin (Htt) protein interacts with a number of transcription factors thereby altering transcription. Here we report that Htt directly interacts with methyl-CpG binding protein 2 (MeCP2) in mouse and cellular models of HD using complimentary biochemical and Fluorescent Lifetime Imaging to measure Förster Resonance Energy Transfer approaches. Htt-MeCP2 interactions are enhanced in the presence of the expanded polyglutamine (polyQ) tract and are stronger in the nucleus compared with the cytoplasm. Furthermore, we find increased binding of MeCP2 to the promoter of brain-derived neurotrophic factor (BDNF), a gene that is downregulated in HD, in the presence of mutant Htt. Finally, decreasing MeCP2 levels in mutant Htt-expressing cells using siRNA increases BDNF levels, suggesting that MeCP2 downregulates BDNF expression in HD. Taken together, these findings suggest that aberrant interactions between Htt and MeCP2 contribute to transcriptional dysregulation in HD.


Assuntos
Proteína 2 de Ligação a Metil-CpG/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Proteínas Nucleares/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Linhagem Celular , Corpo Estriado/metabolismo , Regulação para Baixo , Expressão Gênica , Humanos , Proteína Huntingtina , Doença de Huntington/metabolismo , Camundongos , Camundongos Transgênicos , Regiões Promotoras Genéticas , Mapeamento de Interação de Proteínas , Transcrição Gênica
10.
J Gastrointest Surg ; 17(4): 771-5, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23288715

RESUMO

BACKGROUND: Anastomotic leakage is a major cause of postoperative morbidity and mortality in the treatment of colorectal cancer. The aim of this study was to investigate the modified double-stapling technique (MDST), as an alternative for conventional double-stapling technique (DST), and whether it could reduce the anastomotic leakage rate in laparoscopic anterior resection (Lapa-AR). STUDY DESIGN: Between March 2009 and October 2010, a total of 189 patients who underwent Lapa-AR for the treatment of adenocarcinoma of the sigmoid colon or rectosigmoid colon were divided into the MDST group (n = 95) and the DST group (n = 94) according to the anastomotic technique. Data were analyzed retrospectively. Morbidity and anastomotic leakage rate were compared between the two groups. RESULTS: Patient demographics, preoperative comorbidity, tumor size, stage, and operative details were comparable between the two groups. There was no difference in operation time between the two groups. The overall complication rate was significantly lower in the MDST group than in the DST group (3.2 vs. 10.6 %, p = 0.042), including anastomotic leakage rate (0 vs.4.6 %, p = 0.029). The anastomotic technique was the only factor associated with anastomotic leakage in univariate analysis. CONCLUSIONS: Our comparative study demonstrates MDST to have better short-term outcome in reducing anastomotic leakage compared with DST. This technique could be an alternative approach to maximize the patients' benefit in laparoscopic anterior resection.


Assuntos
Neoplasias Colorretais/cirurgia , Laparoscopia , Grampeamento Cirúrgico/métodos , Procedimentos Cirúrgicos do Sistema Digestório/métodos , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento
11.
J Huntingtons Dis ; 2(3): 263-77, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-25062675

RESUMO

BACKGROUND: Huntington's disease (HD) is a neurodegenerative disorder with selective vulnerability of striatal neurons and involves extensive transcriptional dysregulation early in the disease process. Previous work in cell and mouse models has shown that histone modifications are altered in HD. Specifically, monoubiquitylated histone H2A (uH2A) is present at the promoters of downregulated genes which led to the hypothesis that uH2A plays a role in transcriptional silencing in HD. OBJECTIVE: To broaden our view of uH2A function in transcription in HD, we examined genome-wide binding sites of uH2A in 12-week old striatal tissue from R6/2 transgenic HD mouse model. METHODS: We used chromatin immunoprecipitation followed by genomic promoter microarray hybridization (ChIP-chip) and then interrogated how these binding sites correlate with transcribed genes. RESULTS: Our analysis reveals that, while uH2A levels are globally increased at the genome in the transgenic (TG) striatum, uH2A localization at a gene did not strongly correlate with the absence of its transcript. Furthermore, analysis of differential ubiquitylation in wild-type (WT) and TG striata did not reveal the expected enrichment of uH2A at genes with decreased expression in the TG striatum. CONCLUSIONS: This first description of genome-wide localization of uH2A in an HD model reveals that monoubiquitylation of histone H2A may not function at the level of the individual gene but may rather influence transcription through global chromatin structure.


Assuntos
Encéfalo/metabolismo , Histonas/genética , Histonas/metabolismo , Doença de Huntington/genética , Doença de Huntington/metabolismo , Ubiquitinação , Ubiquitinas/genética , Ubiquitinas/metabolismo , Animais , Imunoprecipitação da Cromatina , Modelos Animais de Doenças , Inativação Gênica , Camundongos , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transcrição Gênica , Transcriptoma
12.
PLoS One ; 7(7): e41423, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22848491

RESUMO

In Huntington's disease (HD; MIM ID #143100), a fatal neurodegenerative disorder, transcriptional dysregulation is a key pathogenic feature. Histone modifications are altered in multiple cellular and animal models of HD suggesting a potential mechanism for the observed changes in transcriptional levels. In particular, previous work has suggested an important link between decreased histone acetylation, particularly acetylated histone H3 (AcH3; H3K9K14ac), and downregulated gene expression. However, the question remains whether changes in histone modifications correlate with transcriptional abnormalities across the entire transcriptome. Using chromatin immunoprecipitation paired with microarray hybridization (ChIP-chip), we interrogated AcH3-gene interactions genome-wide in striata of 12-week old wild-type (WT) and transgenic (TG) R6/2 mice, an HD mouse model, and correlated these interactions with gene expression levels. At the level of the individual gene, we found decreases in the number of sites occupied by AcH3 in the TG striatum. In addition, the total number of genes bound by AcH3 was decreased. Surprisingly, the loss of AcH3 binding sites occurred within the coding regions of the genes rather than at the promoter region. We also found that the presence of AcH3 at any location within a gene strongly correlated with the presence of its transcript in both WT and TG striatum. In the TG striatum, treatment with histone deacetylase (HDAC) inhibitors increased global AcH3 levels with concomitant increases in transcript levels; however, AcH3 binding at select gene loci increased only slightly. This study demonstrates that histone H3 acetylation at lysine residues 9 and 14 and active gene expression are intimately tied in the rodent brain, and that this fundamental relationship remains unchanged in an HD mouse model despite genome-wide decreases in histone H3 acetylation.


Assuntos
Corpo Estriado/metabolismo , Regulação para Baixo/genética , Loci Gênicos , Genoma , Histonas/metabolismo , Acetilação/efeitos dos fármacos , Animais , Corpo Estriado/patologia , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Estudo de Associação Genômica Ampla , Inibidores de Histona Desacetilases/farmacologia , Histonas/genética , Doença de Huntington , Masculino , Camundongos , Camundongos Transgênicos
13.
J Neurochem ; 120(2): 202-9, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22043863

RESUMO

Recent evidence suggests that the persistence of cocaine seeking during periods of protracted drug abstinence following chronic cocaine exposure is mediated, in part, by neuroadaptations in the mesolimbic dopamine system. Specifically, incubation of cocaine-seeking behavior coincides with increased brain-derived neurotrophic factor (BDNF) protein expression in the ventral tegmental area (VTA). However, the molecular mechanisms that regulate time-dependent changes in VTA BDNF protein expression during cocaine abstinence are unclear. The goal of these experiments was to determine whether VTA BDNF transcript levels are altered following cocaine abstinence and identify the molecular mechanisms regulating cocaine-induced changes in VTA BDNF transcription. Rats were allowed to self-administer cocaine (0.25 mg/infusion, i.v.) for 14 days on a fixed-ratio schedule of reinforcement followed by 7 days of forced drug abstinence. BDNF protein and exon I-containing transcripts were significantly increased in the VTA of cocaine-experienced rats following 7 days of forced drug abstinence compared to yoked saline controls. Cocaine-induced changes in BDNF mRNA were associated with increased acetylation of histone 3 and binding of CREB-binding protein to exon I-containing promoters in the VTA. Taken together, these results suggest that drug abstinence following cocaine self-administration remodels chromatin in the VTA resulting in increased expression of BDNF, which may contribute to neuroadaptations underlying cocaine craving and relapse.


Assuntos
Anestésicos Locais/administração & dosagem , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteína de Ligação a CREB/metabolismo , Cocaína/administração & dosagem , Regulação da Expressão Gênica/efeitos dos fármacos , Histonas/metabolismo , Área Tegmentar Ventral/metabolismo , Acetilação/efeitos dos fármacos , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Imunoprecipitação da Cromatina , Transtornos Relacionados ao Uso de Cocaína , Condicionamento Operante/efeitos dos fármacos , Ensaio de Imunoadsorção Enzimática/métodos , Masculino , Regiões Promotoras Genéticas/efeitos dos fármacos , Regiões Promotoras Genéticas/fisiologia , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Esquema de Reforço , Autoadministração , Estatísticas não Paramétricas , Síndrome de Abstinência a Substâncias/metabolismo , Fatores de Tempo , Área Tegmentar Ventral/efeitos dos fármacos
14.
Handb Clin Neurol ; 100: 25-81, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21496570

RESUMO

It has been more than 17 years since the causative mutation for Huntington's disease was discovered as the expansion of the triplet repeat in the N-terminal portion of the Huntingtin (HTT) gene. In the intervening time, researchers have discovered a great deal about Huntingtin's involvement in a number of cellular processes. However, the role of Huntingtin in the key pathogenic mechanism leading to neurodegeneration in the disease process has yet to be discovered. Here, we review the body of knowledge that has been uncovered since gene discovery and include discussions of the HTT gene, CAG triplet repeat expansion, HTT expression, protein features, posttranslational modifications, and many of its known protein functions and interactions. We also highlight potential pathogenic mechanisms that have come to light in recent years.


Assuntos
Doença de Huntington/genética , Biologia Molecular , Animais , Modelos Animais de Doenças , História do Século XIX , Humanos , Doença de Huntington/epidemiologia , Doença de Huntington/história , Proteínas do Tecido Nervoso/genética , Expansão das Repetições de Trinucleotídeos/genética
15.
J Neurosci ; 30(35): 11735-44, 2010 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-20810894

RESUMO

Cocaine self-administration alters patterns of gene expression in the brain that may underlie cocaine-induced neuronal plasticity. In the present study, male Sprague Dawley rats were allowed to self-administer cocaine (0.25 mg/infusion) 2 h/d for 14 d, followed by 7 d of forced abstinence. Compared with yoked saline control rats, cocaine self-administration resulted in increased brain-derived neurotrophic factor (BDNF) protein levels in the rat medial prefrontal cortex (mPFC). To examine the functional relevance of this finding, cocaine self-administration maintained under a progressive ratio schedule of reinforcement was assessed after short hairpin RNA-induced suppression of BDNF expression in the mPFC. Decreased BDNF expression in the mPFC increased the cocaine self-administration breakpoint. Next, the effect of cocaine self-administration on specific BDNF exons was assessed; results revealed selectively increased BDNF exon IV-containing transcripts in the mPFC. Moreover, there were significant cocaine-induced increases in acetylated histone H3 (AcH3) and phospho-cAMP response element binding protein (pCREB) association with BDNF promoter IV. In contrast, there was decreased methyl-CpG-binding protein 2 (MeCP2) association with BDNF promoter IV in the mPFC of rats that previously self-administered cocaine. Together, these results indicate that cocaine-induced increases in BDNF promoter IV transcript in the mPFC are driven by increased binding of AcH3 and pCREB as well as decreased MeCP2 binding at this BDNF promoter. Collectively, these results indicate that cocaine self-administration remodels chromatin in the mPFC, resulting in increased expression of BDNF, which appears to represent a compensatory neuroadaptation that reduces the reinforcing efficacy of cocaine.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/biossíntese , Fator Neurotrófico Derivado do Encéfalo/genética , Montagem e Desmontagem da Cromatina/efeitos dos fármacos , Montagem e Desmontagem da Cromatina/fisiologia , Cocaína/administração & dosagem , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Reforço Psicológico , Animais , Comportamento Aditivo/metabolismo , Comportamento Aditivo/psicologia , Cocaína/farmacologia , Transtornos Relacionados ao Uso de Cocaína/metabolismo , Transtornos Relacionados ao Uso de Cocaína/psicologia , Masculino , Ratos , Ratos Sprague-Dawley , Autoadministração , Transcrição Gênica/efeitos dos fármacos , Transcrição Gênica/fisiologia , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/fisiologia
16.
J Neuropathol Exp Neurol ; 69(8): 817-27, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20613636

RESUMO

Huntington disease (HD) is a fatal neurodegenerative disease with no effective treatment. In the R6/1 mouse model of HD, environmental enrichment delays the neurologic phenotype onset and prevents cerebral volume loss by unknown molecular mechanisms. We examined the effects of environmental enrichment on well-characterized neuropathological parameters in a mouse model of HD. We found a trend toward preservation of downregulated neurotransmitter receptors in striatum of environmentally enriched mice and assessed possible enrichment-related modifications in gene expression using microarrays. We observed similar gene expression changes in R6/1 and R6/2 transgenic mice but found no specific changes in enrichment-related microarray expression profiles in either transgenic or wild-type mice. Furthermore, specific corrections in transprotein-induced transcriptional dysregulation in R6/1 mice were not detected by microarray profiling. However, gene-specific analyses suggested that long-term environmental enrichment may beneficially modulate gene expression dysregulation. Finally, environmental enrichment significantly decreased neuronal intranuclear inclusion load, despite unaffected transgene expression levels. Thus, the therapeutic effects of environmental enrichment likely contribute to decreasing aggregated polyglutamine protein levels without exerting strong effects on gene expression.


Assuntos
Meio Ambiente , Regulação da Expressão Gênica/fisiologia , Doença de Huntington/patologia , Corpos de Inclusão Intranuclear/metabolismo , Neurônios/patologia , RNA Mensageiro/metabolismo , Fatores Etários , Animais , Corpo Estriado/patologia , Modelos Animais de Doenças , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica/genética , Proteína Huntingtina , Doença de Huntington/genética , Doença de Huntington/fisiopatologia , Doença de Huntington/terapia , Corpos de Inclusão Intranuclear/ultraestrutura , Masculino , Camundongos , Camundongos Transgênicos , Microscopia Eletrônica de Transmissão/métodos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neurônios/ultraestrutura , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Ensaio Radioligante/métodos , Receptores de Neurotransmissores/metabolismo , Expansão das Repetições de Trinucleotídeos/genética
17.
Neuroimage ; 49(4): 2995-3004, 2010 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-19850138

RESUMO

The corpus callosum (CC) is the major conduit for information transfer between the cerebral hemispheres and plays an integral role in relaying sensory, motor and cognitive information between homologous cortical regions. The majority of fibers that make up the CC arise from large pyramidal neurons in layers III and V, which project contra-laterally. These neurons degenerate in Huntington's disease (HD) in a topographically and temporally selective way. Since any focus of cortical degeneration could be expected to secondarily de-afferent homologous regions of cortex, we hypothesized that regionally selective cortical degeneration would be reflected in regionally selective degeneration of the CC. We used conventional T1-weighted, diffusion tensor imaging (DTI), and a modified corpus callosum segmentation scheme to examine the CC in healthy controls, huntingtin gene-carriers and symptomatic HD subjects. We measured mid-sagittal callosal cross-sectional thickness and several DTI parameters, including fractional anisotropy (FA), which reflects the degree of white matter organization, radial diffusivity, a suggested index of myelin integrity, and axial diffusivity, a suggested index of axonal damage of the CC. We found a topologically selective pattern of alterations in these measures in pre-manifest subjects that were more extensive in early symptomatic HD subjects and that correlated with performance on distinct cognitive measures, suggesting an important role for disrupted inter-hemispheric transfer in the clinical symptoms of HD. Our findings provide evidence for early degeneration of commissural pyramidal neurons in the neocortex, loss of cortico-cortical connectivity, and functional compromise of associative cortical processing.


Assuntos
Corpo Caloso/patologia , Doença de Huntington/patologia , Imageamento por Ressonância Magnética/métodos , Fibras Nervosas Mielinizadas/patologia , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
18.
J Neurosci ; 28(42): 10720-33, 2008 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-18923047

RESUMO

Transcriptional dysregulation is a central pathogenic mechanism in Huntington's disease, a fatal neurodegenerative disorder associated with polyglutamine (polyQ) expansion in the huntingtin (Htt) protein. In this study, we show that mutant Htt alters the normal expression of specific mRNA species at least partly by disrupting the binding activities of many transcription factors which govern the expression of the dysregulated mRNA species. Chromatin immunoprecipitation (ChIP) demonstrates Htt occupation of gene promoters in vivo in a polyQ-dependent manner, and furthermore, ChIP-on-chip and ChIP subcloning reveal that wild-type and mutant Htt exhibit differential genomic distributions. Exon 1 Htt binds DNA directly in the absence of other proteins and alters DNA conformation. PolyQ expansion increases Htt-DNA interactions, with binding to recognition elements of transcription factors whose function is altered in HD. Together, these findings suggest mutant Htt modulates gene expression through abnormal interactions with genomic DNA, altering DNA conformation and transcription factor binding.


Assuntos
Proteínas de Ligação a DNA/fisiologia , DNA/metabolismo , Proteínas do Tecido Nervoso/fisiologia , Proteínas Nucleares/fisiologia , Peptídeos/fisiologia , Regiões Promotoras Genéticas/fisiologia , Transcrição Gênica/fisiologia , Animais , Linhagem Celular Transformada , DNA/antagonistas & inibidores , DNA/química , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Humanos , Proteína Huntingtina , Doença de Huntington/genética , Doença de Huntington/metabolismo , Doença de Huntington/patologia , Camundongos , Camundongos Transgênicos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Conformação de Ácido Nucleico , Peptídeos/química , Peptídeos/genética , Ligação Proteica/fisiologia , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/metabolismo
19.
J Neurosci ; 28(43): 11061-70, 2008 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-18945913

RESUMO

A growing body of evidence indicates that enhanced AMPA-mediated glutamate transmission in the core of the nucleus accumbens is critically involved in cocaine priming-induced reinstatement of drug seeking, an animal model of relapse. However, the extent to which increased glutamate transmission in the other major subregion of the nucleus accumbens, the shell, contributes to the reinstatement of cocaine seeking remains unclear. In the present experiments, administration of the AMPA/kainate receptor antagonist CNQX (0, 0.03, or 0.3 mug) into either the core or the shell of the nucleus accumbens before a systemic cocaine priming injection (10 mg/kg, i.p.) dose-dependently attenuated the reinstatement of drug seeking. Cocaine priming-induced reinstatement of cocaine seeking also was associated with increases in GluR2-pSer880 in the nucleus accumbens shell. The phosphorylation of GluR2 by PKC at Ser880 plays an important role in the trafficking of GluR2-containing AMPA receptors from the plasma membrane. The current results showed that administration of a cell-permeable peptide that disrupts GluR2 trafficking (Pep2-EVKI) into either the accumbens core or shell attenuated cocaine-induced reinstatement of drug seeking. Together, these findings indicate that changes in AMPA receptor-mediated glutamate transmission in both the nucleus accumbens core and shell are necessary for the reinstatement of drug seeking induced by a priming injection of cocaine. The present results also demonstrate that the reinstatement of cocaine seeking is associated with increases in the phosphorylation-dependent trafficking of GluR2-containing AMPA receptors in the nucleus accumbens.


Assuntos
Transtornos Relacionados ao Uso de Cocaína/patologia , Transtornos Relacionados ao Uso de Cocaína/psicologia , Núcleo Accumbens/metabolismo , Receptores de AMPA/metabolismo , Reforço Psicológico , 6-Ciano-7-nitroquinoxalina-2,3-diona/farmacologia , Análise de Variância , Animais , Comportamento Animal/efeitos dos fármacos , Cocaína/administração & dosagem , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Antagonistas de Aminoácidos Excitatórios/farmacologia , Preferências Alimentares , Masculino , Núcleo Accumbens/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Transporte Proteico/efeitos dos fármacos , Transporte Proteico/fisiologia , Ratos , Ratos Sprague-Dawley , Esquema de Reforço , Autoadministração , Serina/metabolismo
20.
Nat Methods ; 5(11): 951-3, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18931668

RESUMO

Allele-specific silencing using small interfering RNAs targeting heterozygous single-nucleotide polymorphisms (SNPs) is a promising therapy for human trinucleotide repeat diseases such as Huntington's disease. Linking SNP identities to the two HTT alleles, normal and disease-causing, is a prerequisite for allele-specific RNA interference. Here we describe a method, SNP linkage by circularization (SLiC), to identify linkage between CAG repeat length and nucleotide identity of heterozygous SNPs using Huntington's disease patient peripheral blood samples.


Assuntos
Doença de Huntington/genética , Polimorfismo de Nucleotídeo Único/genética , Repetições de Trinucleotídeos/genética , Humanos , Dados de Sequência Molecular
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