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1.
Expert Opin Pharmacother ; 20(9): 1091-1107, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31002267

RESUMO

INTRODUCTION: Frontotemporal dementia (FTD) is a heterogeneous clinical entity that includes several disorders characterized by different cellular mechanisms. Distinctive clinical features in FTD include behavioral, affective, and cognitive symptoms. Unfortunately, little progress has been made over the past 20 years in terms of the development of effective disease-modifying drugs with the currently available symptomatic treatments having limited clinical utility. AREAS COVERED: This article reviews the principal pharmacological intervention studies for FTD. These are predominantly randomized clinical trials and include symptomatic treatments and potential disease-modifying drugs. EXPERT OPINION: There is insufficient evidence on effective treatments for FTD and studies with better methodological backgrounds are needed. Most studies reporting therapeutic benefits were conducted with selective serotonin reuptake inhibitors, while anti-dementia drugs have been ineffective in FTD. Since the underlying pathology of FTD mostly consists of abnormal tau protein or TDP-43 aggregates, treatments are being developed to interfere with their aggregation process or with the clearance of these proteins. Furthermore, disease-modifying treatments remain years away as demonstrated by the recent negative Phase III findings of a tau aggregation inhibitor (LMTM) for treating the behavioral variant of FTD. The results from current ongoing Phase I/II trials will hopefully give light to future treatment options.


Assuntos
Demência Frontotemporal/tratamento farmacológico , Demência Frontotemporal/terapia , Inibidores de Captação de Serotonina/uso terapêutico , Demência Frontotemporal/patologia , Humanos , Fenótipo , Inibidores de Captação de Serotonina/farmacologia
2.
Semin Neurol ; 39(2): 153-166, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30925609

RESUMO

Dementia is a state of cognitive dysfunction which leads to functional decline. It is a syndrome caused by several medical and neurological causes, but most cases of dementia are due to "primary dementias." Primary dementias are neurological diseases whose manifestations are predominantly cognitive. Most primary dementias are caused by neurodegenerative proteinopathies where an accumulation of misfolded proteins leads to neuronal loss, neuroinflammation and glial reaction. Each proteinopathy is characterized by the type of protein implicated in its pathophysiology. Neurodegenerative dementias include the most prevalent cause of dementia-Alzheimer's disease-as well as Lewy body dementia, Parkinson's disease dementia, frontotemporal dementias, and prion diseases. Vascular dementia, especially small vessel disease, though not a neurodegenerative condition, is often grouped together with primary dementias. Each type of proteinopathy, characterized by the location and nature of misfolded protein accumulation, may correspond to a particular clinical phenotype. The correspondence between pathologies and clinical phenotypes is not exclusive, and there is a large degree of overlap. Although in the research setting the clinicopathological construct is on the wane, in the clinic it is the most practical way of approaching primary dementias. In this article, we introduce the clinicopathological construct, the understanding of which will form the basis of the other articles in this volume.


Assuntos
Doença de Alzheimer , Demência Vascular , Demência , Demência Frontotemporal , Doença por Corpos de Lewy , Doenças Priônicas , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Doença de Alzheimer/fisiopatologia , Demência/tratamento farmacológico , Demência/metabolismo , Demência/patologia , Demência/fisiopatologia , Demência Vascular/tratamento farmacológico , Demência Vascular/metabolismo , Demência Vascular/patologia , Demência Vascular/fisiopatologia , Demência Frontotemporal/tratamento farmacológico , Demência Frontotemporal/metabolismo , Demência Frontotemporal/patologia , Demência Frontotemporal/fisiopatologia , Humanos , Doença por Corpos de Lewy/tratamento farmacológico , Doença por Corpos de Lewy/metabolismo , Doença por Corpos de Lewy/patologia , Doença por Corpos de Lewy/fisiopatologia , Doenças Priônicas/tratamento farmacológico , Doenças Priônicas/metabolismo , Doenças Priônicas/patologia , Doenças Priônicas/fisiopatologia
3.
Mini Rev Med Chem ; 18(1): 3-8, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-28019640

RESUMO

At present there are about 47.5 million people having different types of dementia and by 2030 this number would reach 75.6 million. This obviously brings about a serious social and economic burden for people who take care for those with any kind of dementia. The purpose of this article is to explore only semantic dementia (SD), more specifically called semantic variant of primary progressive aphasia, as one of the forms of frontotemporal dementia (FTD) and provide the latest information on its diagnosis and treatment which play a significant role in the maintenance of quality of life of both patients and their caregivers. Especially unimpaired communication is one of the key factors in the relationship between the patients and their caregivers. The methods used for this mini review include a literature review of available sources found in the world's acknowledged databases such as Web of Science, PubMed, Springer and Scopus from 2000 to 2015; and a comparison and evaluation of the selected studies. The findings of this mini review show that FTD, respectively SD, is a serious neurodegenerative disorder which has fatal consequences for the affected patients. In addition, the findings also indicate that there are not many possibilities of pharmacological treatment for semantic dementia and therefore more attention should be paid to alternative, non-pharmacological approaches. Although semantic dementia is a relatively rare neurodegenerative disorder if compared with other types of dementia, it has an irreversible impact on patient's and his/her caregiver's life in terms of quality.


Assuntos
Demência Frontotemporal , Demência Frontotemporal/diagnóstico , Demência Frontotemporal/tratamento farmacológico , Humanos
4.
Brain ; 140(12): 3081-3104, 2017 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-29053785

RESUMO

Progranulin, a secreted glycoprotein, is encoded in humans by the single GRN gene. Progranulin consists of seven and a half, tandemly repeated, non-identical copies of the 12 cysteine granulin motif. Many cellular processes and diseases are associated with this unique pleiotropic factor that include, but are not limited to, embryogenesis, tumorigenesis, inflammation, wound repair, neurodegeneration and lysosome function. Haploinsufficiency caused by autosomal dominant mutations within the GRN gene leads to frontotemporal lobar degeneration, a progressive neuronal atrophy that presents in patients as frontotemporal dementia. Frontotemporal dementia is an early onset form of dementia, distinct from Alzheimer's disease. The GRN-related form of frontotemporal lobar dementia is a proteinopathy characterized by the appearance of neuronal inclusions containing ubiquitinated and fragmented TDP-43 (encoded by TARDBP). The neurotrophic and neuro-immunomodulatory properties of progranulin have recently been reported but are still not well understood. Gene delivery of GRN in experimental models of Alzheimer's- and Parkinson's-like diseases inhibits phenotype progression. Here we review what is currently known concerning the molecular function and mechanism of action of progranulin in normal physiological and pathophysiological conditions in both in vitro and in vivo models. The potential therapeutic applications of progranulin in treating neurodegenerative diseases are highlighted.


Assuntos
Degeneração Lobar Frontotemporal/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Animais , Demência Frontotemporal/tratamento farmacológico , Demência Frontotemporal/genética , Demência Frontotemporal/metabolismo , Degeneração Lobar Frontotemporal/tratamento farmacológico , Degeneração Lobar Frontotemporal/metabolismo , Haploinsuficiência , Humanos , Técnicas In Vitro , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Camundongos , Modelos Neurológicos , Terapia de Alvo Molecular , Mutação , Progranulinas , Proteinopatias TDP-43/tratamento farmacológico , Proteinopatias TDP-43/genética , Proteinopatias TDP-43/metabolismo
5.
Adv Neurobiol ; 17: 103-131, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28956331

RESUMO

People in modern, affluent societies are living longer but also becoming increasingly overweight. With increased life expectancy comes increased risk of developing age-related cognitive decline and neurodegenerative diseases, such that an increasing proportion of life may be lived with cognitive impairment as age increases. Obesity is associated with poorer cognitive function in elderly subjects, and often leads to ill-health arising from various complications such as metabolic syndrome and type-2 diabetes mellitus. This chapter provides an overview of the effects of administering pan-phosphodiesterase-4 (PDE4) inhibitors to animal models of cognitive ageing, Alzheimer's disease, frontotemporal dementia, fragile X syndrome, obesity and diabetes. Inhibition of the PDE4B subtype specifically is discussed as an approach to avoid the emetic side effects of pan-PDE4 inhibitors, whilst retaining their therapeutic effects. Finally, the findings of rodent studies that employ genetic and pharmacological approaches to specifically target PDE4B are discussed in relation to the potential utility of PDE4B-selective inhibitors for the treatment of cognitive impairment and obesity-related metabolic diseases.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Envelhecimento Cognitivo , Disfunção Cognitiva/tratamento farmacológico , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Síndrome do Cromossomo X Frágil/tratamento farmacológico , Demência Frontotemporal/tratamento farmacológico , Síndrome Metabólica/tratamento farmacológico , Inibidores da Fosfodiesterase 4/uso terapêutico , Doença de Alzheimer/metabolismo , Animais , Disfunção Cognitiva/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Síndrome do Cromossomo X Frágil/metabolismo , Demência Frontotemporal/metabolismo , Humanos , Síndrome Metabólica/metabolismo , Obesidade/metabolismo
6.
Cell Chem Biol ; 24(7): 892-906.e5, 2017 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-28712747

RESUMO

Frontotemporal dementia (FTD) arises from neurodegeneration in the frontal, insular, and anterior temporal lobes. Autosomal dominant causes of FTD include heterozygous mutations in the GRN gene causing haploinsufficiency of progranulin (PGRN) protein. Recently, histone deacetylase (HDAC) inhibitors have been identified as enhancers of PGRN expression, although the mechanisms through which GRN is epigenetically regulated remain poorly understood. Using a chemogenomic toolkit, including optoepigenetic probes, we show that inhibition of class I HDACs is sufficient to upregulate PGRN in human neurons, and only inhibitors with apparent fast binding to their target HDAC complexes are capable of enhancing PGRN expression. Moreover, we identify regions in the GRN promoter in which elevated H3K27 acetylation and transcription factor EB (TFEB) occupancy correlate with HDAC-inhibitor-mediated upregulation of PGRN. These findings have implications for epigenetic and cis-regulatory mechanisms controlling human GRN expression and may advance translational efforts to develop targeted therapeutics for treating PGRN-deficient FTD.


Assuntos
Histona Desacetilases/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Acetilação/efeitos dos fármacos , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/química , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Células Cultivadas , Epigênese Genética , Demência Frontotemporal/tratamento farmacológico , Demência Frontotemporal/metabolismo , Demência Frontotemporal/patologia , Haploinsuficiência/genética , Heterozigoto , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Histona Desacetilases/química , Histona Desacetilases/genética , Histonas/metabolismo , Humanos , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/farmacologia , Ácidos Hidroxâmicos/uso terapêutico , Indóis/química , Indóis/farmacologia , Indóis/uso terapêutico , Células-Tronco Pluripotentes Induzidas/citologia , Peptídeos e Proteínas de Sinalização Intercelular/genética , Luz , Células-Tronco Neurais/citologia , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/metabolismo , Progranulinas , Regiões Promotoras Genéticas , Pirimidinas/química , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Interferência de RNA , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/efeitos da radiação
8.
Expert Opin Drug Discov ; 12(7): 659-671, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28571480

RESUMO

INTRODUCTION: Research into the pathogenic mechanisms behind frontotemporal dementia (FTD) has yielded several new targets for therapeutic intervention; such targets include specific new pathways uncovered by mutations as well as targets involving the modulation, formation and degradation of protein aggregates. Areas covered: Herein, the authors outline the principal molecular causes underlying FTD to date and the research that has been performed in these areas with respect to an eventual corrective strategy. Expert opinion: While it is worthwhile targeting pathways affected by specific mutations with a causative loss of function linked to FTD, research still has to contend with issues including the remaining presence of protein aggregates or that treatments are rarely universally applicable. Aiming to recover function in a downstream target caused by the protein aggregates will likely be insufficient due to the large cascade of events affected. It is our belief that the clearance of these aggregates and the inhibition of protein misfolding are more appropriate and direct routes to an eventual therapy.


Assuntos
Desenho de Drogas , Descoberta de Drogas/métodos , Demência Frontotemporal/tratamento farmacológico , Animais , Demência Frontotemporal/genética , Demência Frontotemporal/fisiopatologia , Humanos , Terapia de Alvo Molecular , Mutação , Agregados Proteicos/efeitos dos fármacos , Dobramento de Proteína/efeitos dos fármacos
9.
Eur J Pharmacol ; 817: 76-85, 2017 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-28579383

RESUMO

Frontotemporal Dementia (FTD) is a progressive neurodegenerative condition which encompasses a group of clinically, neuropathologically and genetically heterogeneous disorders characterized by selective involvement of the frontal and temporal lobes. FTD is characterized by changes in behaviour and personality, frontal executive deficits and language dysfunction. Different phenotypes have been defined on the basis of presenting clinical symptoms, behavioural variants of FTD (bvFTD) and primary progressive aphasia (PPA), which includes nonfluent/agrammatic variant PPA (avPPA) and semantic variant PPA (svPPA). These presentations can overlap with atypical parkinsonian disorders (i.e., corticobasal syndrome, progressive supranuclear palsy) and amyotrophic lateral sclerosis. Each syndrome can be associated with one or more neuropathological hallmark, and in some cases it may be due to autosomal inherited disorder caused by mutations in a number of genes. Currently, there is no specific treatment available to prevent disease progression. FTD treatment is based on symptomatic management, and most therapies lack quality evidence from randomized, placebo-controlled clinical trials. Recent advances in the understanding of FTD pathophysiology and genetics have led to the development of potentially disease-modifying therapies. In this review, we discussed current knowledge and recommendations with regards to symptomatic and disease-modifying therapies.


Assuntos
Demência Frontotemporal/tratamento farmacológico , Animais , Demência Frontotemporal/genética , Demência Frontotemporal/metabolismo , Humanos , Fenótipo
11.
Brain ; 140(6): 1768-1783, 2017 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-28430857

RESUMO

See Mercado and Hetz (doi:10.1093/brain/awx107) for a scientific commentary on this article.Signalling through the PERK/eIF2α-P branch of the unfolded protein response plays a critical role in controlling protein synthesis rates in cells. This pathway is overactivated in brains of patients with Alzheimer’s disease and related disorders and has recently emerged as a promising therapeutic target for these currently untreatable conditions. Thus, in mouse models of neurodegenerative disease, prolonged overactivation of PERK/eIF2α-P signalling causes sustained attenuation of protein synthesis, leading to memory impairment and neuronal loss. Re-establishing translation rates by inhibition of eIF2α-P activity, genetically or pharmacologically, restores memory and prevents neurodegeneration and extends survival. However, the experimental compounds used preclinically are unsuitable for use in humans, due to associated toxicity or poor pharmacokinetic properties. To discover compounds that have anti-eIF2α-P activity suitable for clinical use, we performed phenotypic screens on a NINDS small molecule library of 1040 drugs. We identified two compounds, trazodone hydrochloride and dibenzoylmethane, which reversed eIF2α-P-mediated translational attenuation in vitro and in vivo. Both drugs were markedly neuroprotective in two mouse models of neurodegeneration, using clinically relevant doses over a prolonged period of time, without systemic toxicity. Thus, in prion-diseased mice, both trazodone and dibenzoylmethane treatment restored memory deficits, abrogated development of neurological signs, prevented neurodegeneration and significantly prolonged survival. In tauopathy-frontotemporal dementia mice, both drugs were neuroprotective, rescued memory deficits and reduced hippocampal atrophy. Further, trazodone reduced p-tau burden. These compounds therefore represent potential new disease-modifying treatments for dementia. Trazodone in particular, a licensed drug, should now be tested in clinical trials in patients.


Assuntos
Chalconas/farmacologia , Demência Frontotemporal/tratamento farmacológico , Transtornos da Memória/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Doenças Priônicas/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais , Trazodona/farmacologia , eIF-2 Quinase/antagonistas & inibidores , Animais , Comportamento Animal , Chalconas/administração & dosagem , Modelos Animais de Doenças , Demência Frontotemporal/complicações , Transtornos da Memória/etiologia , Camundongos , Fármacos Neuroprotetores/administração & dosagem , Doenças Priônicas/complicações , Inibidores de Proteínas Quinases/administração & dosagem , Trazodona/administração & dosagem , Resposta a Proteínas não Dobradas
12.
J Geriatr Psychiatry Neurol ; 30(3): 162-169, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28351199

RESUMO

Psychiatric symptoms in patients with frontotemporal dementia (FTD) are highly prevalent and may complicate clinical management of these patients. Purpose of the present article is to present and discuss available data about the pharmacological treatment of psychiatric symptoms in patients with FTD. A research in the main database sources has been conducted to obtain an overview of the pharmacological management of psychiatric symptoms in patients with FTD. The search strategy included the following terms-"FTD and psychiatry," "FTD and behavioural disturbances," and "FTD and treatment". Pathophysiology of psychiatric symptoms in FTD is different from other types of dementia. Although drugs for Alzheimer disease appear to be ineffective for the treatment of psychiatric symptoms of FTD, preliminary evidence supports a possible usefulness of serotonergic antidepressants for these patients. Data are too scanty to draw definitive conclusions, but antidepressant treatment, particularly with serotonergic compounds, may improve psychiatric symptoms in patients with FTD. Large observational studies are needed to confirm this preliminary evidence, and a lot of effort and collaboration between neurologists and psychiatrists will be definitely crucial for future research of effective treatments for FTD.


Assuntos
Demência Frontotemporal/tratamento farmacológico , Demência Frontotemporal/psicologia , Antidepressivos/uso terapêutico , Humanos , Serotonina/metabolismo
13.
Curr Psychiatry Rep ; 19(1): 7, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28144880

RESUMO

Several international guidelines indicate stimulants, including methylphenidate (MPH), amphetamines and derivatives, modafinil, and armodafinil among the second-third-line choices for bipolar depression. Efficacy of stimulants has been also reported for the management of residual depressive symptoms such as fatigue and sleepiness and for the management of affective, cognitive, and behavioral symptoms in children and adult bipolar patients with comorbid ADHD. Few case reports show positive results with MPH in the treatment of resistant mania. Finally, MPH might be an option in some bipolar forms observed in psychiatric presentations of frontotemporal dementia and traumatic brain injury. In spite of these preliminary observations, the use of stimulants in bipolar patients is still controversial. Potential of misuse and abuse and mood destabilization with induction of (hypo)manic switches, mixed states, and rapid cycling are the concerns most frequently reported. Our aims are to summarize available literature on this topic and discuss practical management implications.


Assuntos
Transtorno Bipolar/tratamento farmacológico , Estimulantes do Sistema Nervoso Central/uso terapêutico , Adulto , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Transtorno Bipolar/diagnóstico , Transtorno Bipolar/psicologia , Lesões Encefálicas Traumáticas/diagnóstico , Lesões Encefálicas Traumáticas/tratamento farmacológico , Lesões Encefálicas Traumáticas/psicologia , Estimulantes do Sistema Nervoso Central/efeitos adversos , Criança , Comorbidade , Transtorno Depressivo Resistente a Tratamento/diagnóstico , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Transtorno Depressivo Resistente a Tratamento/psicologia , Demência Frontotemporal/diagnóstico , Demência Frontotemporal/tratamento farmacológico , Demência Frontotemporal/psicologia , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Transtornos Relacionados ao Uso de Substâncias/tratamento farmacológico , Resultado do Tratamento
15.
Expert Opin Pharmacother ; 17(12): 1669-82, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27356036

RESUMO

INTRODUCTION: Amyotrophic lateral sclerosis (ALS), one in a family of age-related neurodegenerative disorders, is marked by predominantly cryptogenic causes, partially elucidated pathophysiology, and elusive treatments. The challenges of ALS are illustrated by two decades of negative drug trials. AREAS COVERED: In this article, we lay out the current understanding of disease genesis and physiology in relation to drug development in ALS, stressing important accomplishments and gaps in knowledge. We briefly consider clinical ALS, the ongoing search for biomarkers, and the latest in trial design, highlighting major recent and ongoing clinical trials; and we discuss, in a concluding section on future directions, the prion-protein hypothesis of neurodegeneration and what steps can be taken to end the drought that has characterized drug discovery in ALS. EXPERT OPINION: Age-related neurodegenerative disorders are fast becoming major public health problems for the world's aging populations. Several agents offer promise in the near-term, but drug development is hampered by an interrelated cycle of obstacles surrounding etiological, physiological, and biomarkers discovery. It is time for the type of government-funded, public-supported offensive on neurodegenerative disease that has been effective in other fields.


Assuntos
Esclerose Amiotrófica Lateral/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Esclerose Amiotrófica Lateral/diagnóstico , Esclerose Amiotrófica Lateral/genética , Biomarcadores/metabolismo , Ensaios Clínicos como Assunto , Demência Frontotemporal/diagnóstico , Demência Frontotemporal/tratamento farmacológico , Demência Frontotemporal/genética , Humanos , Hidroxilaminas/uso terapêutico , Memantina/uso terapêutico , Riluzol/uso terapêutico , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Vitamina B 12/análogos & derivados , Vitamina B 12/uso terapêutico
16.
Neurobiol Aging ; 42: 35-40, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27143419

RESUMO

Mutations in the granulin (GRN) gene cause frontotemporal dementia (FTD) due to progranulin haploinsufficiency. Compounds that can increase progranulin production and secretion may be considered as potential therapeutic drugs; however, very few of them have been directly tested on human cortical neurons. To this end, we differentiated 9 induced pluripotent stem cell lines derived from a control subject, a sporadic FTD case and an FTD patient with progranulin S116X mutation. Treatment with 1 µM suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, increased the production of progranulin in cortical neurons of all subjects at both the mRNA and protein levels without affecting their viability. Microarray analysis revealed that SAHA treatment not only reversed some gene expression changes caused by progranulin haploinsufficiency but also caused massive alterations in the overall transcriptome. Thus, histone deacetylase inhibitors may be considered as therapeutic drugs for GRN mutation carriers. However, this class of drugs also causes drastic changes in overall gene expression in human cortical neurons and their side effects and potential impacts on other pathways should be carefully evaluated.


Assuntos
Demência Frontotemporal/patologia , Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos/farmacologia , Células-Tronco Pluripotentes Induzidas/citologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Neurônios/metabolismo , Diferenciação Celular , Sobrevivência Celular , Células Cultivadas , Córtex Cerebral/citologia , Demência Frontotemporal/tratamento farmacológico , Demência Frontotemporal/genética , Expressão Gênica/efeitos dos fármacos , Inibidores de Histona Desacetilases/uso terapêutico , Humanos , Ácidos Hidroxâmicos/uso terapêutico , Peptídeos e Proteínas de Sinalização Intercelular/genética , Terapia de Alvo Molecular , Mutação , Progranulinas , Vorinostat
17.
Mol Neurodegener ; 11(1): 36, 2016 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-27138926

RESUMO

BACKGROUND: Mutations in the progranulin gene (GRN) are the most common cause of frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP). TDP-43 pathology is characterized by the hyperphosphorylation of the protein at Serine 409/410 residues. Casein kinase-1δ (CK-1δ) was reported to phosphorylate TDP-43 directly. Previous works from our laboratory described the presence of CDK6/pRb-dependent cell cycle alterations, and cytosolic accumulation of TDP-43 protein in lymphoblast from FTLD-TDP patients carriers of a loss-of function mutation in GRN gene (c.709-1G > A). In this work, we have investigated the effects of two brain penetrant CK-1δ inhibitors (IGS-2.7 and IGS-3.27) designed and synthetized in our laboratory on cell proliferation, TDP-43 phosphorylation and subcellular localization, as well as their effects on the known nuclear TDP-43 function repressing the expression of CDK6. RESULTS: We report here that both CK-1δ inhibitors (IGS-2.7 and IGS-3.27) normalized the proliferative activity of PGRN-deficient lymphoblasts by preventing the phosphorylation of TDP-43 fragments, its nucleo-cytosol translocation and the overactivation of the CDK6/pRb cascade. Moreover, ours results show neuroprotective effects of CK-1δ inhibitors in a neuronal cell model of induced TDP-43 phosphorylation. CONCLUSIONS: Our results suggest that modulating CK-1δ activity could be considered a novel therapeutic approach for the treatment of FTLD-TDP and other TDP-43 proteinopathies.


Assuntos
Caseína Quinase Idelta/antagonistas & inibidores , Proliferação de Células/fisiologia , Demência Frontotemporal/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteinopatias TDP-43/metabolismo , Caseína Quinase Idelta/metabolismo , Células Cultivadas , Proteínas de Ligação a DNA/genética , Demência Frontotemporal/tratamento farmacológico , Demência Frontotemporal/genética , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Linfócitos/metabolismo , Mutação/genética , Fosforilação
18.
Molecules ; 21(4): 518, 2016 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-27110749

RESUMO

The word dementia describes a class of heterogeneous diseases which etiopathogenetic mechanisms are not well understood. There are different types of dementia, among which, Alzheimer's disease (AD), vascular dementia (VaD), dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD) are the more common. Currently approved pharmacological treatments for most forms of dementia seem to act only on symptoms without having profound disease-modifying effects. Thus, alternative strategies capable of preventing the progressive loss of specific neuronal populations are urgently required. In particular, the attention of researchers has been focused on phytochemical compounds that have shown antioxidative, anti-amyloidogenic, anti-inflammatory and anti-apoptotic properties and that could represent important resources in the discovery of drug candidates against dementia. In this review, we summarize the neuroprotective effects of the main phytochemicals belonging to the polyphenol, isothiocyanate, alkaloid and cannabinoid families in the prevention and treatment of the most common kinds of dementia. We believe that natural phytochemicals may represent a promising sources of alternative medicine, at least in association with therapies approved to date for dementia.


Assuntos
Demência/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Compostos Fitoquímicos/uso terapêutico , Doença de Alzheimer/tratamento farmacológico , Animais , Ensaios Clínicos como Assunto , Demência Vascular/tratamento farmacológico , Demência Frontotemporal/tratamento farmacológico , Humanos , Doença por Corpos de Lewy/tratamento farmacológico , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Compostos Fitoquímicos/farmacologia
19.
Neuron ; 90(3): 535-50, 2016 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-27112497

RESUMO

Hexanucleotide expansions in C9ORF72 are the most frequent genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Disease mechanisms were evaluated in mice expressing C9ORF72 RNAs with up to 450 GGGGCC repeats or with one or both C9orf72 alleles inactivated. Chronic 50% reduction of C9ORF72 did not provoke disease, while its absence produced splenomegaly, enlarged lymph nodes, and mild social interaction deficits, but not motor dysfunction. Hexanucleotide expansions caused age-, repeat-length-, and expression-level-dependent accumulation of RNA foci and dipeptide-repeat proteins synthesized by AUG-independent translation, accompanied by loss of hippocampal neurons, increased anxiety, and impaired cognitive function. Single-dose injection of antisense oligonucleotides (ASOs) that target repeat-containing RNAs but preserve levels of mRNAs encoding C9ORF72 produced sustained reductions in RNA foci and dipeptide-repeat proteins, and ameliorated behavioral deficits. These efforts identify gain of toxicity as a central disease mechanism caused by repeat-expanded C9ORF72 and establish the feasibility of ASO-mediated therapy.


Assuntos
Esclerose Amiotrófica Lateral/tratamento farmacológico , Demência Frontotemporal/tratamento farmacológico , Fatores de Troca do Nucleotídeo Guanina/genética , Oligonucleotídeos Antissenso/farmacologia , RNA/metabolismo , Esclerose Amiotrófica Lateral/genética , Animais , Proteína C9orf72 , Expansão das Repetições de DNA/genética , Demência Frontotemporal/genética , Camundongos Transgênicos , Neurônios/metabolismo , Oligonucleotídeos Antissenso/efeitos adversos , Oligonucleotídeos Antissenso/genética
20.
Lancet ; 386(10004): 1672-82, 2015 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-26595641

RESUMO

Frontotemporal dementia is an umbrella clinical term that encompasses a group of neurodegenerative diseases characterised by progressive deficits in behaviour, executive function, or language. Frontotemporal dementia is a common type of dementia, particularly in patients younger than 65 years. The disease can mimic many psychiatric disorders because of the prominent behavioural features. Various underlying neuropathological entities lead to the frontotemporal dementia clinical phenotype, all of which are characterised by the selective degeneration of the frontal and temporal cortices. Genetics is an important risk factor for frontotemporal dementia. Advances in clinical, imaging, and molecular characterisation have increased the accuracy of frontotemporal dementia diagnosis, thus allowing for the accurate differentiation of these syndromes from psychiatric disorders. As the understanding of the molecular basis for frontotemporal dementia improves, rational therapies are beginning to emerge.


Assuntos
Demência Frontotemporal , Adulto , Idoso , Doença de Alzheimer/diagnóstico , Afasia , Diagnóstico Diferencial , Diagnóstico por Imagem , Demência Frontotemporal/diagnóstico , Demência Frontotemporal/tratamento farmacológico , Demência Frontotemporal/genética , Degeneração Lobar Frontotemporal/patologia , Humanos , Transtornos Mentais/diagnóstico , Pessoa de Meia-Idade , Doença dos Neurônios Motores , Doenças Neurodegenerativas/diagnóstico
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