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1.
J Med Chem ; 62(22): 10062-10097, 2019 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-31487175

RESUMO

Inhibition of O-GlcNAcase (OGA) has emerged as a promising therapeutic approach to treat tau pathology in neurodegenerative diseases such as Alzheimer's disease and progressive supranuclear palsy. Beginning with carbohydrate-based lead molecules, we pursued an optimization strategy of reducing polar surface area to align the desired drug-like properties of potency, selectivity, high central nervous system (CNS) exposure, metabolic stability, favorable pharmacokinetics, and robust in vivo pharmacodynamic response. Herein, we describe the medicinal chemistry and pharmacological studies that led to the identification of (3aR,5S,6S,7R,7aR)-5-(difluoromethyl)-2-(ethylamino)-3a,6,7,7a-tetrahydro-5H-pyrano[3,2-d]thiazole-6,7-diol 42 (MK-8719), a highly potent and selective OGA inhibitor with excellent CNS penetration that has been advanced to first-in-human phase I clinical trials.

2.
Hum Mol Genet ; 28(19): 3244-3254, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31261387

RESUMO

Multiple genome-wide association studies (GWAS) in Parkinson disease (PD) have identified a signal at chromosome 4p16.3; however, the causal variant has not been established for this locus. Deep investigation of the region resulted in one identified variant, the rs34311866 missense SNP (p.M393T) in TMEM175, which is 20 orders of magnitude more significant than any other SNP in the region. Because TMEM175 is a lysosomal gene that has been shown to influence α-synuclein phosphorylation and autophagy, the p.M393T variant is an attractive candidate, and we have examined its effect on TMEM175 protein and PD-related biology. After knocking down each of the genes located under the GWAS peak via multiple shRNAs, only TMEM175 was found to consistently influence accumulation of phosphorylated α-synuclein (p-α-syn). Examination of the p.M393T variant showed effects on TMEM175 function that were intermediate between the wild-type (WT) and knockout phenotypes, with reduced regulation of lysosomal pH in response to starvation and minor changes in clearance of autophagy substrates, reduced lysosomal localization, and increased accumulation of p-α-syn. Finally, overexpression of WT TMEM175 protein reduced p-α-syn, while overexpression of the p.M393T variant resulted in no change in α-synuclein phosphorylation. These results suggest that the main signal in the chromosome 4p16.3 PD risk locus is driven by the TMEM175 p.M393T variant. Modulation of TMEM175 may impact α-synuclein biology and therefore may be a rational therapeutic strategy for PD.

3.
J Neuroinflammation ; 15(1): 256, 2018 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-30189875

RESUMO

BACKGROUND: Alzheimer's disease (AD) is a chronic neurodegenerative disease with pathological hallmarks including the formation of extracellular aggregates of amyloid-beta (Aß) known as plaques and intracellular tau tangles. Coincident with the formation of Aß plaques is recruitment and activation of glial cells to the plaque forming a plaque niche. In addition to histological data showing the formation of the niche, AD genetic studies have added to the growing appreciation of how dysfunctional glia pathways drive neuropathology, with emphasis on microglia pathways. Genomic approaches enable comparisons of human disease profiles between different mouse models informing on their utility to evaluate secondary changes to triggers such as Aß deposition. METHODS: In this study, we utilized two animal models of AD to examine and characterize the AD-associated pathology: the Tg2576 Swedish APP (KM670/671NL) and TgCRND8 Swedish plus Indiana APP (KM670/671NL + V717F) lines. We used laser capture microscopy (LCM) to isolate samples surrounding Thio-S positive plaques from distal non-plaque tissue. These samples were then analyzed using RNA sequencing. RESULTS: We determined age-associated transcriptomic differences between two similar yet distinct APP transgenic mouse models, known to differ in proportional amyloidogenic species and plaque deposition rates. In Tg2576, human AD gene signatures were not observed despite profiling mice out to 15 months of age. TgCRND8 mice however showed progressive and robust induction of lysomal, neuroimmune, and ITIM/ITAM-associated gene signatures overlapping with prior human AD brain transcriptomic studies. Notably, RNAseq analyses highlighted the vast majority of transcriptional changes observed in aging TgCRND8 cortical brain homogenates were in fact specifically enriched within the plaque niche samples. Data uncovered plaque-associated enrichment of microglia-related genes such as ITIM/ITAM-associated genes and pathway markers of phagocytosis. CONCLUSION: This work may help guide improved translational value of APP mouse models of AD, particularly for strategies aimed at targeting neuroimmune and neurodegenerative pathways, by demonstrating that TgCRND8 more closely recapitulates specific human AD-associated transcriptional responses.


Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Córtex Cerebral/metabolismo , Citocinas/metabolismo , Regulação da Expressão Gênica/genética , Fatores Etários , Doença de Alzheimer/genética , Doença de Alzheimer/imunologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/genética , Animais , Proteínas de Ligação ao Cálcio/metabolismo , Córtex Cerebral/patologia , Correlação de Dados , Modelos Animais de Doenças , Humanos , Microdissecção e Captura a Laser , Camundongos , Camundongos Transgênicos , Proteínas dos Microfilamentos/metabolismo , Mutação/genética , Placa Amiloide/patologia , RNA Mensageiro/metabolismo , Transcriptoma
4.
ACS Med Chem Lett ; 9(8): 815-820, 2018 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-30128073

RESUMO

Herein we describe the development of a series of pyrazolopyrimidinone phosphodiesterase 2A (PDE2) inhibitors using structure-guided lead identification and design. The series was derived from informed chemotype replacement based on previously identified internal leads. The initially designed compound 3, while potent on PDE2, displayed unsatisfactory selectivity against the other PDE2 isoforms. Compound 3 was subsequently optimized for improved PDE2 activity and isoform selectivity. Insights into the origins of PDE2 selectivity are described and verified using cocrystallography. An optimized lead, 4, demonstrated improved performance in both a rodent and a nonhuman primate cognition model.

5.
PLoS One ; 13(4): e0195486, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29624602

RESUMO

Although tau pathology, behavioral deficits, and neuronal loss are observed in patients with tauopathies, the relationship between these endpoints has not been clearly established. Here we found that rTg4510 mice, which overexpress human mutant tau in the forebrain, develop progressive age-dependent increases in locomotor activity (LMA), which correlates with neurofibrillary tangle (NFT) pathology, hyperphosphorylated tau levels, and brain atrophy. To further clarify the relationship between these endpoints, we treated the rTg4510 mice with either doxycycline to reduce mutant tau expression or an O-GlcNAcase inhibitor Thiamet G, which has been shown to ameliorate tau pathology in animal models. We found that both doxycycline and Thiamet G treatments starting at 2 months of age prevented the progression of hyperactivity, slowed brain atrophy, and reduced brain hyperphosphorylated tau. In contrast, initiating doxycycline treatment at 4 months reduced neither brain hyperphosphorylated tau nor hyperactivity, further confirming the relationship between these measures. Collectively, our results demonstrate a unique behavioral phenotype in the rTg4510 mouse model of tauopathy that strongly correlates with disease progression, and that early interventions which reduce tau pathology ameliorate the progression of the locomotor dysfunction. These findings suggest that better understanding the relationship between locomotor deficits and tau pathology in the rTg4510 model may improve our understanding of the mechanisms underlying behavioral disturbances in patients with tauopathies.


Assuntos
Tauopatias/tratamento farmacológico , Proteínas tau/metabolismo , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Modelos Animais de Doenças , Progressão da Doença , Doxiciclina/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Camundongos da Linhagem 129 , Camundongos Transgênicos , Atividade Motora/genética , Atividade Motora/fisiologia , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Emaranhados Neurofibrilares/patologia , Fosforilação , Piranos/uso terapêutico , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Tauopatias/patologia , Tauopatias/fisiopatologia , Tiazóis/uso terapêutico , beta-N-Acetil-Hexosaminidases/antagonistas & inibidores , Proteínas tau/genética
6.
Bioorg Med Chem Lett ; 26(17): 4362-6, 2016 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-27491711

RESUMO

Inhibition of microtubule affinity regulating kinase (MARK) represents a potentially attractive means of arresting neurofibrillary tangle pathology in Alzheimer's disease. This manuscript outlines efforts to optimize a pyrazolopyrimidine series of MARK inhibitors by focusing on improvements in potency, physical properties and attributes amenable to CNS penetration. A unique cylcyclohexyldiamine scaffold was identified that led to remarkable improvements in potency, opening up opportunities to reduce MW, Pgp efflux and improve pharmacokinetic properties while also conferring improved solubility.


Assuntos
Inibidores Enzimáticos/síntese química , Compostos Heterocíclicos/química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Animais , Cristalografia por Raios X , Cães , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Compostos Heterocíclicos/farmacologia , Humanos , Concentração Inibidora 50 , Peso Molecular , Ratos , Solubilidade
7.
Front Neurol ; 6: 140, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26157418

RESUMO

The mesencephalic (or midbrain) locomotor region (MLR) was first described in 1966 by Shik and colleagues, who demonstrated that electrical stimulation of this region induced locomotion in decerebrate (intercollicular transection) cats. The pedunculopontine tegmental nucleus (PPT) cholinergic neurons and midbrain extrapyramidal area (MEA) have been suggested to form the neuroanatomical basis for the MLR, but direct evidence for the role of these structures in locomotor behavior has been lacking. Here, we tested the hypothesis that the MLR is composed of non-cholinergic spinally projecting cells in the lateral pontine tegmentum. Our results showed that putative MLR neurons medial to the PPT and MEA in rats were non-cholinergic, glutamatergic, and express the orexin (hypocretin) type 2 receptors. Fos mapping correlated with motor behaviors revealed that the dorsal and ventral MLR are activated, respectively, in association with locomotion and an erect posture. Consistent with these findings, chemical stimulation of the dorsal MLR produced locomotion, whereas stimulation of the ventral MLR caused standing. Lesions of the MLR (dorsal and ventral regions together) resulted in cataplexy and episodic immobility of gait. Finally, trans-neuronal tracing with pseudorabies virus demonstrated disynaptic input to the MLR from the substantia nigra via the MEA. These findings offer a new perspective on the neuroanatomic basis of the MLR, and suggest that MLR dysfunction may contribute to the postural and gait abnormalities in Parkinsonism.

8.
Neurodegener Dis ; 14(2): 53-66, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24158021

RESUMO

BACKGROUND: N-terminally truncated, pyroglutamate-modified amyloid-ß (Aß) peptides are major constituents of amyloid deposits in Alzheimer's disease (AD). METHODS: Using a newly developed ELISA for Aß modified at glutamate 3 with a pyroglutamate (pE3Aß), brain pE3Aß was characterized in human AD in an AD mouse model harboring double knock-in amyloid precursor protein (APP)-KM670/671NL and presenilin 1 (PS1)-P264L (APP/PS1-dKI) mutations, and in a second mouse model with transgenic overexpression of human APP695 with APP-KM670/671NL (Tg2576). RESULTS: pE3Aß increased in the AD brain versus age-matched controls, with pE3Aß/total Aß at 45 and 10%, respectively. Compared to controls, the AD brain demonstrated 8.5-fold increased pE3Aß compared to non-pE3Aß species, which increased 2.7-fold. In the APP/PS1-dKI brain, pE3Aß/total Aß increased from 7% at 3 months to 16 and 19% at 15 and 19 months, respectively. In Tg2576, pE3Aß/total Aß was only 1.5% at 19 months, suggesting that APP/PS1-dKI, despite less total Aß compared to Tg2576 at comparable ages, more closely mimics AD brain pathology. CONCLUSION: This report supports a significant role for pE3Aß in AD pathogenesis by confirming that pE3Aß represents a large fraction of Aß within the AD brain. Compared to the age-matched control brain, pE3Aß increased to a greater extent compared to Aß species without this N-terminal modification. Further, the APP/PS1-dKI model more closely resembles the AD brain in this regard, compared to the Tg2576 model.


Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Modelos Animais de Doenças , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/imunologia , Precursor de Proteína beta-Amiloide/genética , Animais , Anticorpos , Ensaio de Imunoadsorção Enzimática , Técnicas de Introdução de Genes , Humanos , Camundongos , Camundongos Transgênicos , Presenilina-1/genética , Ácido Pirrolidonocarboxílico/química
9.
J Biol Chem ; 288(7): 4844-53, 2013 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-23288850

RESUMO

Male Anopheles mosquitoes coagulate their seminal fluids via cross-linking of a substrate, called Plugin, by the seminal transglutaminase AgTG3. Formation of the "mating plug" by cross-linking Plugin is necessary for efficient sperm storage by females. AgTG3 has a similar degree of sequence identity (~30%) to both human Factor XIII (FXIII) and tissue transglutaminase 2 (hTG2). Here we report the solution structure and in vitro activity for the cross-linking reaction of AgTG3 and Plugin. AgTG3 is a dimer in solution and exhibits Ca(2+)-dependent nonproteolytic activation analogous to cytoplasmic FXIII. The C-terminal domain of Plugin is predominantly α-helical with extended tertiary structure and oligomerizes in solution. The specific activity of AgTG3 was measured as 4.25 × 10(-2) units mg(-1). AgTG3 is less active than hTG2 assayed using the general substrate TVQQEL but has 8-10× higher relative activity when Plugin is the substrate. Mass spectrometric analysis of cross-linked Plugin detects specific peptides including a predicted consensus motif for cross-linking by AgTG3. These results support the development of AgTG3 inhibitors as specific and effective chemosterilants for A. gambiae.


Assuntos
Anopheles/enzimologia , Transglutaminases/química , Sequência de Aminoácidos , Animais , Cálcio/química , Reagentes para Ligações Cruzadas/química , Citoplasma/metabolismo , Dimerização , Feminino , Masculino , Espectrometria de Massas/métodos , Modelos Químicos , Dados de Sequência Molecular , Peptídeos/química , Ligação Proteica , Estrutura Terciária de Proteína , Homologia de Sequência de Aminoácidos , Relação Estrutura-Atividade , Transglutaminases/metabolismo
10.
Lancet ; 380(9859): 2071-94, 2012 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-23245603

RESUMO

BACKGROUND: Estimation of the number and rate of deaths by age and sex is a key first stage for calculation of the burden of disease in order to constrain estimates of cause-specific mortality and to measure premature mortality in populations. We aimed to estimate life tables and annual numbers of deaths for 187 countries from 1970 to 2010. METHODS: We estimated trends in under-5 mortality rate (children aged 0-4 years) and probability of adult death (15-59 years) for each country with all available data. Death registration data were available for more than 100 countries and we corrected for undercount with improved death distribution methods. We applied refined methods to survey data on sibling survival that correct for survivor, zero-sibling, and recall bias. We separately estimated mortality from natural disasters and wars. We generated final estimates of under-5 mortality and adult mortality from the data with Gaussian process regression. We used these results as input parameters in a relational model life table system. We developed a model to extrapolate mortality to 110 years of age. All death rates and numbers have been estimated with 95% uncertainty intervals (95% UIs). FINDINGS: From 1970 to 2010, global male life expectancy at birth increased from 56·4 years (95% UI 55·5-57·2) to 67·5 years (66·9-68·1) and global female life expectancy at birth increased from 61·2 years (60·2-62·0) to 73·3 years (72·8-73·8). Life expectancy at birth rose by 3-4 years every decade from 1970, apart from during the 1990s (increase in male life expectancy of 1·4 years and in female life expectancy of 1·6 years). Substantial reductions in mortality occurred in eastern and southern sub-Saharan Africa since 2004, coinciding with increased coverage of antiretroviral therapy and preventive measures against malaria. Sex-specific changes in life expectancy from 1970 to 2010 ranged from gains of 23-29 years in the Maldives and Bhutan to declines of 1-7 years in Belarus, Lesotho, Ukraine, and Zimbabwe. Globally, 52·8 million (95% UI 51·6-54·1 million) deaths occurred in 2010, which is about 13·5% more than occurred in 1990 (46·5 million [45·7-47·4 million]), and 21·9% more than occurred in 1970 (43·3 million [42·2-44·6 million]). Proportionally more deaths in 2010 occurred at age 70 years and older (42·8% in 2010 vs 33·1% in 1990), and 22·9% occurred at 80 years or older. Deaths in children younger than 5 years declined by almost 60% since 1970 (16·4 million [16·1-16·7 million] in 1970 vs 6·8 million [6·6-7·1 million] in 2010), especially at ages 1-59 months (10·8 million [10·4-11·1 million] in 1970 vs 4·0 million [3·8-4·2 million] in 2010). In all regions, including those most affected by HIV/AIDS, we noted increases in mean ages at death. INTERPRETATION: Despite global and regional health crises, global life expectancy has increased continuously and substantially in the past 40 years. Yet substantial heterogeneity exists across age groups, among countries, and over different decades. 179 of 187 countries have had increases in life expectancy after the slowdown in progress in the 1990s. Efforts should be directed to reduce mortality in low-income and middle-income countries. Potential underestimation of achievement of the Millennium Development Goal 4 might result from limitations of demographic data on child mortality for the most recent time period. Improvement of civil registration system worldwide is crucial for better tracking of global mortality. FUNDING: Bill & Melinda Gates Foundation.


Assuntos
Saúde Global , Expectativa de Vida/tendências , Mortalidade/tendências , Adolescente , Adulto , Mortalidade da Criança/tendências , Pré-Escolar , Feminino , Humanos , Lactente , Mortalidade Infantil/tendências , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Adulto Jovem
11.
J Neurogenet ; 25(4): 127-33, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22091726

RESUMO

Alzheimer's disease (AD) is a neurodegenerative disorder that causes early memory impairment, followed by profound progressive cognitive decline, and eventually death. Neurofibrillary tangles (NFTs) are one of the histopathological hallmarks of AD. NFTs are deposits of insoluble aggregates of the microtubule-binding protein tau, left behind following neuronal loss. Intracellular aggregates of tau, either in soluble or insoluble forms, are thought to disrupt cellular machinery and synaptic function and ultimately lead to neuronal death. As the ultimate pathological endpoint in AD is neuronal loss, there is significant interest in understanding the causes of tau aggregation and deposition in the brain as a potential therapeutic avenue for AD. Post-translational modifications on tau are thought to be an important regulatory mechanism that may contribute to the propensity of tau to aggregate and form NFTs. In addition to phosphorylation, numerous other post-translational modifications have been observed on tau protein. The mechanisms that cause aggregation of tau are unknown, but it is likely that post-translational modifications other than phosphorylation also regulate this process. This review will discuss several post-translational modifications of tau and their roles in modulation of tau function and aggregation in AD.


Assuntos
Doença de Alzheimer , Processamento de Proteína Pós-Traducional/genética , Proteínas tau/genética , Proteínas tau/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Animais , Desenho de Drogas , Humanos , Degeneração Neural/tratamento farmacológico , Degeneração Neural/metabolismo , Degeneração Neural/fisiopatologia , Emaranhados Neurofibrilares/efeitos dos fármacos , Emaranhados Neurofibrilares/genética , Emaranhados Neurofibrilares/metabolismo , Fosforilação/efeitos dos fármacos , Fosforilação/fisiologia , Processamento de Proteína Pós-Traducional/efeitos dos fármacos
12.
Popul Health Metr ; 9(1): 55, 2011 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-21989074

RESUMO

BACKGROUND: Mortality from cardiovascular and other chronic diseases has increased in Iran. Our aim was to estimate the effects of smoking and high systolic blood pressure (SBP), fasting plasma glucose (FPG), total cholesterol (TC), and high body mass index (BMI) on mortality and life expectancy, nationally and subnationally, using representative data and comparable methods. METHODS: We used data from the Non-Communicable Disease Surveillance Survey to estimate means and standard deviations for the metabolic risk factors, nationally and by region. Lung cancer mortality was used to measure cumulative exposure to smoking. We used data from the death registration system to estimate age-, sex-, and disease-specific numbers of deaths in 2005, adjusted for incompleteness using demographic methods. We used systematic reviews and meta-analyses of epidemiologic studies to obtain the effect of risk factors on disease-specific mortality. We estimated deaths and life expectancy loss attributable to risk factors using the comparative risk assessment framework. RESULTS: In 2005, high SBP was responsible for 41,000 (95% uncertainty interval: 38,000, 44,000) deaths in men and 39,000 (36,000, 42,000) deaths in women in Iran. High FPG, BMI, and TC were responsible for about one-third to one-half of deaths attributable to SBP in men and/or women. Smoking was responsible for 9,000 deaths among men and 2,000 among women. If SBP were reduced to optimal levels, life expectancy at birth would increase by 3.2 years (2.6, 3.9) and 4.1 years (3.2, 4.9) in men and women, respectively; the life expectancy gains ranged from 1.1 to 1.8 years for TC, BMI, and FPG. SBP was also responsible for the largest number of deaths in every region, with age-standardized attributable mortality ranging from 257 to 333 deaths per 100,000 adults in different regions. DISCUSSION: Management of blood pressure through diet, lifestyle, and pharmacological interventions should be a priority in Iran. Interventions for other metabolic risk factors and smoking can also improve population health.

13.
Behav Brain Res ; 222(2): 289-94, 2011 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-21377495

RESUMO

The orexin/hypocretin system has the potential to significantly modulate affect, based on both the neuroanatomical projection patterns of these neurons and on the sites of orexin receptor expression. However, there is little data supporting the role of specific orexin receptors in the modulation of depression-like behavior. Here we report behavioral profiling of mice after genetic or pharmacologic inhibition of hcrtr1 and 2 receptor signaling. Hcrtr1 null mice displayed a significant reduction in behavioral despair in the forced swim test and tail suspension test. Wild-type mice treated with the hcrtr1 antagonist SB-334867 also displayed a similar reduction in behavioral despair. No difference in anxiety-like behavior was noted following hcrtr1 deletion. In contrast, hcrtr2-null mice displayed an increase in behavioral despair with no effect on measures of anxiety. These studies suggest that the balance of orexin action at either the hcrtr1 or the hcrtr2 receptor produces an anti-depressant or pro-depressant like effect, depending on the receptor subtype activated.


Assuntos
Depressão/fisiopatologia , Receptores Acoplados a Proteínas-G/fisiologia , Receptores de Neuropeptídeos/fisiologia , Transdução de Sinais/fisiologia , Animais , Ansiedade/genética , Benzoxazóis/farmacologia , Benzoxazóis/uso terapêutico , Comportamento de Escolha/efeitos dos fármacos , Comportamento de Escolha/fisiologia , Depressão/tratamento farmacológico , Depressão/genética , Modelos Animais de Doenças , Resposta de Imobilidade Tônica/efeitos dos fármacos , Resposta de Imobilidade Tônica/fisiologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Naftiridinas , Receptores de Orexina , Receptores Acoplados a Proteínas-G/antagonistas & inibidores , Receptores Acoplados a Proteínas-G/genética , Receptores de Neuropeptídeos/antagonistas & inibidores , Receptores de Neuropeptídeos/genética , Transdução de Sinais/genética , Natação/fisiologia , Ureia/análogos & derivados , Ureia/farmacologia , Ureia/uso terapêutico
14.
Proc Natl Acad Sci U S A ; 108(11): 4471-6, 2011 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-21368172

RESUMO

Narcolepsy is caused by a loss of orexin/hypocretin signaling, resulting in chronic sleepiness, fragmented non-rapid eye movement sleep, and cataplexy. To identify the neuronal circuits underlying narcolepsy, we produced a mouse model in which a loxP-flanked gene cassette disrupts production of the orexin receptor type 2 (OX2R; also known as HCRTR2), but normal OX2R expression can be restored by Cre recombinase. Mice lacking OX2R signaling had poor maintenance of wakefulness indicative of sleepiness and fragmented sleep and lacked any electrophysiological response to orexin-A in the wake-promoting neurons of the tuberomammillary nucleus. These defects were completely recovered by crossing them with mice that express Cre in the female germline, thus globally deleting the transcription-disrupter cassette. Then, by using an adeno-associated viral vector coding for Cre recombinase, we found that focal restoration of OX2R in neurons of the tuberomammillary nucleus and adjacent parts of the posterior hypothalamus completely rescued the sleepiness of these mice, but their fragmented sleep was unimproved. These observations demonstrate that the tuberomammillary region plays an essential role in the wake-promoting effects of orexins, but orexins must stabilize sleep through other targets.


Assuntos
Antígenos de Superfície/metabolismo , Hipotálamo/metabolismo , Narcolepsia/prevenção & controle , Narcolepsia/fisiopatologia , Receptores de Superfície Celular/metabolismo , Sono/fisiologia , Animais , Dependovirus/genética , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Feminino , Região Hipotalâmica Lateral/efeitos dos fármacos , Região Hipotalâmica Lateral/patologia , Região Hipotalâmica Lateral/fisiopatologia , Hipotálamo/efeitos dos fármacos , Hipotálamo/patologia , Hipotálamo/fisiopatologia , Integrases/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/farmacologia , Camundongos , Camundongos Transgênicos , Microinjeções , Narcolepsia/patologia , Neuropeptídeos/farmacologia , Receptores de Orexina , Orexinas , Transdução de Sinais/efeitos dos fármacos , Sono/efeitos dos fármacos , Transcrição Genética/efeitos dos fármacos , Vigília/efeitos dos fármacos , Vigília/fisiologia
15.
Am J Pathol ; 178(1): 284-95, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21224065

RESUMO

Mutations resulting in progranulin haploinsufficiency cause disease in patients with a subset of frontotemporal lobar degeneration; however, the biological functions of progranulin in the brain remain unknown. To address this subject, the present study initially assessed changes in gene expression and cytokine secretion in rat primary cortical neurons treated with progranulin. Molecular pathways enriched in the progranulin gene set included cell adhesion and cell motility pathways and pathways involved in growth and development. Secretion of cytokines and several chemokines linked to chemoattraction but not inflammation were also increased from progranulin-treated primary neurons. Therefore, whether progranulin is involved in recruitment of immune cells in the brain was investigated. Localized lentiviral expression of progranulin in C57BL/6 mice resulted in an increase of Iba1-positive microglia around the injection site. Moreover, progranulin alone was sufficient to promote migration of primary mouse microglia in vitro. Primary microglia and C4B8 cells demonstrated more endocytosis of amyloid ß1-42 when treated with progranulin. These data demonstrate that progranulin acts as a chemoattractant in the brain to recruit or activate microglia and can increase endocytosis of extracellular peptides such as amyloid ß.


Assuntos
Encéfalo/fisiologia , Fatores Quimiotáticos/fisiologia , Endocitose , Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Microglia/fisiologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Fatores Quimiotáticos/genética , Fatores Quimiotáticos/farmacologia , Citocinas/metabolismo , Endocitose/efeitos dos fármacos , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Camundongos , Camundongos Mutantes , Proteínas dos Microfilamentos , Microglia/efeitos dos fármacos , Microglia/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/fisiologia , Progranulinas , Ratos
16.
PLoS Med ; 7(4): e1000262, 2010 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-20405002

RESUMO

BACKGROUND: One of the fundamental building blocks for determining the burden of disease in populations is to reliably measure the level and pattern of mortality by age and sex. Where well-functioning registration systems exist, this task is relatively straightforward. Results from many civil registration systems, however, remain uncertain because of a lack of confidence in the completeness of death registration. Incomplete registration systems mean not all deaths are counted, and resulting estimates of death rates for the population are then underestimated. Death distribution methods (DDMs) are a suite of demographic methods that attempt to estimate the fraction of deaths that are registered and counted by the civil registration system. Although widely applied and used, the methods have at least three types of limitations. First, a wide range of variants of these methods has been applied in practice with little scientific literature to guide their selection. Second, the methods have not been extensively validated in real population conditions where violations of the assumptions of the methods most certainly occur. Third, DDMs do not generate uncertainty intervals. METHODS AND FINDINGS: In this paper, we systematically evaluate the performance of 234 variants of DDM methods in three different validation environments where we know or have strong beliefs about the true level of completeness of death registration. Using these datasets, we identify three variants of the DDMs that generally perform the best. We also find that even these improved methods yield uncertainty intervals of roughly +/- one-quarter of the estimate. Finally, we demonstrate the application of the optimal variants in eight countries. CONCLUSIONS: There continues to be a role for partial vital registration data in measuring adult mortality levels and trends, but such results should only be interpreted alongside all other data sources on adult mortality and the uncertainty of the resulting levels, trends, and age-patterns of adult death considered. Please see later in the article for the Editors' Summary.


Assuntos
Sistema de Registros/estatística & dados numéricos , Atestado de Óbito , Humanos , Mortalidade , Dinâmica Populacional
18.
Behav Brain Res ; 204(1): 67-76, 2009 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-19416740

RESUMO

Sustained attention is defined as the ability or capacity to remain focused on the occurrence of rare events over long periods of time. We describe here the development of a novel, operant-based attention task that can be learned by mice in 8-10 days. Mice were trained on a 2-choice visual discrimination task in an operant chamber, wherein the correct response on any given trial was a lever-press cued by a stimulus light. Upon reaching a criterion of greater than 80% correct responses, all subjects were tested in a mixed-trial attention paradigm combining four different stimulus durations within a single session (0.5, 1, 2, or 10 s). During attention testing, the percentage of correct responses decreased as a function of stimulus duration, indicating a performance decrement which parallels increasing attentional demand within the task. Pretreatment with the muscarinic-receptor antagonist scopolamine yielded a reliable, dose-dependent performance deficit whereas nicotine treatment improved the percentage of correct responses during trials with the greatest attentional demand. Moreover, medial prefrontal cortex lesions impaired attention performance without affecting acquisition or retention of the discrimination rule. These results underscore the utility of this task as a novel means of assessing attentional processes in mice in a relatively high-throughput manner.


Assuntos
Atenção/fisiologia , Córtex Pré-Frontal/fisiologia , Receptores Muscarínicos/metabolismo , Animais , Atenção/efeitos dos fármacos , Condicionamento Operante/fisiologia , /fisiologia , Relação Dose-Resposta a Droga , Aprendizagem/fisiologia , Masculino , Memória/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Antagonistas Muscarínicos/farmacologia , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Estimulação Luminosa , Córtex Pré-Frontal/efeitos dos fármacos , Escopolamina/farmacologia , Fatores de Tempo , Percepção Visual/efeitos dos fármacos , Percepção Visual/fisiologia
19.
Neurobiol Learn Mem ; 90(2): 426-33, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18602845

RESUMO

Recent studies in patients with hippocampal lesions have indicated that the degree of memory impairment is proportional to the extent of damage within the hippocampus. Particularly, patients with damage restricted to the CA1 field demonstrate moderate to severe anterograde amnesia with only slight retrograde amnesia. Comparable results are also seen in other species such as non-human primates and rats; however, the effect of selective damage to CA1 has not yet been characterized in mice. In the present study, we investigated the effects of excitotoxic (NMDA) lesions of dorsal CA1 on several aspects of learning and memory performance in mice. Our data indicate that dorsal CA1 lesioned mice are hyperactive upon exposure to a novel environment, have spatial working memory impairments in the Y-maze spontaneous alternation task, and display deficits in an 8-arm spatial discrimination learning task. Lesioned mice are able to acquire an operant lever-press task but demonstrate extinction learning deficits in this appetitive operant paradigm. Taken together, our results indicate that lesions to dorsal CA1 in mice induce selective learning and memory performance deficits similar to those observed in other species, and extend previous findings indicating that this region of the hippocampus is critically involved in the processing of spatial information and/or the processing of inhibitory responses.


Assuntos
Extinção Psicológica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Aprendizagem em Labirinto/efeitos dos fármacos , Rememoração Mental/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , N-Metilaspartato/farmacologia , Orientação/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Animais , Comportamento Apetitivo/efeitos dos fármacos , Mapeamento Encefálico , Condicionamento Operante/efeitos dos fármacos , Aprendizagem por Discriminação/efeitos dos fármacos , Dominância Cerebral/efeitos dos fármacos , Masculino , Memória de Curto Prazo/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL
20.
Neuron ; 50(5): 665-7, 2006 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-16731504

RESUMO

Relatively little is known about the mechanisms that link changing levels of glucose and neuronal activity. A paper in the current issue of Neuron by Burdakov et al. demonstrates that orexin/hypocretin neurons are inhibited by rising glucose in part due to membrane potential effects mediated by tandem-pore K(+) (K(2P)) channels. The findings may shed light on the mechanisms that link hypoglycemia and coordinated arousal and autonomic responses.


Assuntos
Glucose/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neurônios/fisiologia , Neuropeptídeos/metabolismo , Canais de Potássio de Domínios Poros em Tandem/fisiologia , Transdução de Sinais/fisiologia , Animais , Proteínas do Tecido Nervoso , Orexinas
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