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1.
J Neural Transm (Vienna) ; 126(7): 871-878, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31222606

RESUMO

Polypharmacy is common practice in Parkinson's disease. Medical treatment targeting the dopaminergic system alone may include up to five different compounds: L-DOPA (in combination with a DOPA decarboxylase inhibitor), a catechol-O-methyltransferase (COMT) and a monoamine oxidase (MAO-B) inhibitor and a dopamine agonist. Particular motor and non-motor symptoms may require additional specific therapeutics, such as drugs aimed at tremor control and to treat depression, dementia and orthostatic and autonomic dysfunction. No prospective studies have yet been performed with regard to the efficacy or the long-term benefit of combining such different treatments in Parkinson's disease and retrospective analyses are sparse. We thus tried to compile the available evidence for polypharmacy strategies in Parkinson's disease and devised an expert opinion statement.


Assuntos
Antiparkinsonianos/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Polimedicação , Humanos
2.
Nervenarzt ; 90(2): 160-166, 2019 Feb.
Artigo em Alemão | MEDLINE | ID: mdl-30171304

RESUMO

The vast majority of Parkinson's disease (PD) cases are of sporadic origin and despite extensive research in recent years, the etiology still remains unclear. Several current case control studies are aiming to characterize a putative PD-specific composition of the gut microbiome, reflecting the potential relevance of microbiota in the pathogenesis of PD. Although methodologies and cohort sizes differed, the currently available studies showed reproducible or consistent results in terms of PD-specific alterations to the intestinal bacteria. By applying metagenomic sequencing procedures, it is even possible to distinguish PD cases from healthy individuals at a very early disease stage by means of individually modified microbiota. Among others, microbiota that are associated with an altered intestinal barrier or immune function, such as Akkermansia, Lactobacillus, Faecalibacterium and Prevotella were significantly over-represented or under-represented. There may even be a prodromal microbiome, as a comparable microbial shift is also found in patients with rapid eye movement (REM) sleep behavior disorder (RBD), a risk factor for the later development of synucleinopathies, such as PD.


Assuntos
Microbioma Gastrointestinal , Doença de Parkinson , Estudos de Casos e Controles , Humanos , Metagenoma , Doença de Parkinson/diagnóstico , Doença de Parkinson/microbiologia , Transtorno do Comportamento do Sono REM/microbiologia
3.
Fortschr Neurol Psychiatr ; 84 Suppl 1: S3-7, 2016 Jul.
Artigo em Alemão | MEDLINE | ID: mdl-27299943

RESUMO

The genetic information encoded in the DNA sequence provides a blueprint of the entire organism. The epigenetic modifications, in particular DNA methylation and histone modifications, determine how and when this information is made available and define the specific gene transcription pattern of a given cell. Epigenetic modifications determine the functional differences of genetically identical cells in multicellular organisms and are important factors in various processes from embryonic development to learning and memory consolidation. DNA methylation patterns are altered by environmental conditions and some alterations are preserved through mitosis and meiosis. Thus, DNA methylation can mediate environmental impact on health and disease, contributes to the severity of diseases and probably contributes to the effects and side effects of drugs. In addition to the classical monogenic epigenetic diseases such as Prader-Willi syndrome and Rett syndrome, recent data point to an epigenetic component also in sporadic neuro-psychiatric disorders.


Assuntos
Epigênese Genética/genética , Doença de Parkinson/genética , Humanos
4.
Cerebellum ; 13(2): 237-42, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24197754

RESUMO

Whole body vibration (WBV) is a biomechanical treatment used widely in professional sports and rehabilitation. We examined the effect of stochastic WBV on ataxia in spinocerebellar ataxia types 1, 2, 3, and 6 (SCA 1, 2, 3 and 6) in a single-center double-blind sham-controlled study. Stochastic WBV was applied on four sequent days, each treatment consisting of five stimulus trains of 60-s duration at a frequency of 6.5 Hz and 60-s resting time between stimuli (n = 17). Patients allocated to the sham group received the same treatment with 1 Hz (n = 15). All patients were rated at baseline and after the last treatment using clinical scores (SARA, SCAFI, and INAS). After treatment, we found significant improvements of gait, posture, and speed of speech in the verum group while limb kinetics and ataxia of speech did not respond. Stochastic WBV might act on proprioceptive mechanisms and could also stimulate non-cerebellar/compensatory mechanisms. But at present, the involved cellular mechanism and the presumed neuronal loops cannot be deciphered. Thus, future work is needed to understand the mechanisms of whole body vibration. Finally, the use of stochastic WBV could provide a supplementation to treat ataxia in SCA and can be combined with physiotherapeutical motor training.


Assuntos
Ataxias Espinocerebelares/terapia , Vibração/uso terapêutico , Método Duplo-Cego , Feminino , Marcha , Humanos , Cinética , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Postura , Índice de Gravidade de Doença , Fala , Processos Estocásticos , Resultado do Tratamento
6.
Anaesthesist ; 61(2): 97-105, 2012 Feb.
Artigo em Alemão | MEDLINE | ID: mdl-22354395

RESUMO

Approximately 10,000-15,000 Parkinson's disease (PD) patients per year undergo surgery in Germany. The demographic developments along with further surgical progress and procedural refinements will lead to increasing numbers of PD patients in the operating theatre (OR). There are several perioperative risk factors for PD patients, they more often require prolonged intensive care treatment and warrant particular anesthesiological attention with regard to the choice of drugs and equipment. Careful evaluation of concomitant diseases, maintenance of oral Parkinson therapeutic drugs up to the time of surgery and continuous perioperative dopaminergic therapy are key factors for reducing postoperative morbidity in PD patients undergoing surgery.


Assuntos
Anestesia , Doença de Parkinson/complicações , Assistência Perioperatória , Anestésicos/efeitos adversos , Antiparkinsonianos/efeitos adversos , Antiparkinsonianos/uso terapêutico , Cuidados Críticos , Eletrocardiografia , Humanos , Complicações Intraoperatórias/epidemiologia , Complicações Intraoperatórias/terapia , Imageamento por Ressonância Magnética , Doença de Parkinson/fisiopatologia , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/terapia , Medição de Risco
7.
Fortschr Neurol Psychiatr ; 78 Suppl 1: S34-6, 2010 Mar.
Artigo em Alemão | MEDLINE | ID: mdl-20195940

RESUMO

In this workshop report, the N-methyl-D-aspartate (NMDA) receptor antagonists and the monoamine oxidase (MAO) type B inhibitors are discussed with respect to their role in the pharmacotherapy of Parkinson's Disease (PD). For the NMDA antagonist amantadine, studies demonstrated beneficial effects in various symptoms of the PD complex, while memantine seems to be beneficial in the treatment of cognitive deficits in PD-associated dementia. The MAO B inhibitors selegiline and rasagiline are in use for PD pharmacotherapy; for rasagiline, studies have demonstrated a possible disease-modifying effect. Although not supported by specific controlled studies, a "triple" early therapy is discussed which consists of a dopamine agonist, a MAO B inhibitor and amantadine, in order to try to delay the start of levodopa therapy.


Assuntos
Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Inibidores da Monoaminoxidase/uso terapêutico , Monoaminoxidase/metabolismo , N-Metilaspartato/antagonistas & inibidores , Doença de Parkinson/tratamento farmacológico , Amantadina/uso terapêutico , Humanos , Indanos/uso terapêutico , Memantina/uso terapêutico , Piperidinas/uso terapêutico , Selegilina/uso terapêutico
9.
J Neural Transm (Vienna) ; 114(9): 1161-5, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17510732

RESUMO

We identified 221 patients with probable multiple system atrophy (MSA) among 4770 patients enrolled in the multicentre registry of the German Competence Network on Parkinson's disease (PD) according to the established consensus criteria to characterize their clinical presentation. Analyses of more than 100 recorded clinical items revealed several specifics: I) 50% of patients with probable MSA had asymmetry of symptoms at disease onset and tremor at rest was present in 25%; II) a positive response to levodopa was recorded in 51% of patients identified initially with severe autonomic failure and cerebellar ataxia; III) a positive family history was recorded in 11% (n = 23), two of these patients were identified with spinocerebellar ataxia type 3 (SCA3). Thus asymmetry of symptoms, tremor at rest and a positive response to levodopa are not as specific for idiopathic PD as believed previously. Patients with SCA3 may present with the clinical features of MSA.


Assuntos
Atrofia de Múltiplos Sistemas/epidemiologia , Atrofia de Múltiplos Sistemas/fisiopatologia , Doença de Parkinson/epidemiologia , Doença de Parkinson/fisiopatologia , Sistema de Registros , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Alemanha/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Atrofia de Múltiplos Sistemas/genética , Doença de Parkinson/genética
10.
Eur J Neurol ; 14(12): 1405-8, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17941852

RESUMO

We analysed non-motor symptoms (NMS) related to autonomic dysfunction in 3414 patients with Parkinson's disease (PD) enrolled in the multicentre registry of the German Competence Network on PD. Orthostatic hypotension (> 20 mmHg systolic or > 10 mmHg diastolic) was reported for 10% of women and 11% of men, urinary incontinence for 22% of women and 21% of men, sexual dysfunction for 8% of women and 30% of men (50% of whom reported erectile dysfunction) and sleep disturbances for 43% of women and 35% of men. Autonomic symptoms occurred in a frequency similar to severe disabling dyskinesia which was reported for 16% of women and 11% of men. A logistic regression analyses with age, sex and disease duration as covariates revealed a significant correlation of orthostatic hypotension and urinary incontinence with age and disease duration whilst sexual dysfunction was related to age only. These observations suggests that the effects of the PD process and ageing contribute to non-levodopa responsive NMS. Sleep disturbances were more common in women and a correlation was found with disease duration only supporting the notion that sleep is specifically affected in PD.


Assuntos
Envelhecimento/fisiologia , Doenças do Sistema Nervoso Autônomo/epidemiologia , Doença de Parkinson/epidemiologia , Distribuição por Idade , Idade de Início , Idoso , Doenças do Sistema Nervoso Autônomo/fisiopatologia , Estudos de Coortes , Comorbidade , Progressão da Doença , Disfunção Erétil/epidemiologia , Disfunção Erétil/fisiopatologia , Feminino , Alemanha/epidemiologia , Humanos , Hipotensão Ortostática/epidemiologia , Hipotensão Ortostática/fisiopatologia , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/fisiopatologia , Sistema de Registros , Caracteres Sexuais , Distribuição por Sexo , Transtornos do Sono-Vigília/epidemiologia , Transtornos do Sono-Vigília/fisiopatologia , Incontinência Urinária/epidemiologia , Incontinência Urinária/fisiopatologia
11.
J Pharm Pharm Sci ; 10(2): 312s-320s, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17718934

RESUMO

PURPOSE: The purpose of this study was a) to present a facilitated method for the preparation and workup of [11C]d-threo-methylphenidate ([11C]d-threo-MP) (a ligand that was shown to bind selectively to the presynaptic dopaminergic transporters) from [11C]methyliodide ([11C]CH3I), b) to demonstrate that the ligand can as well be produced by an alternative labeling method employing [11C]diazomethane as the labeling agent and c) to present biodistribution data for this tracer obtained in rats. METHODS: 11C-labeling with [11C]CH3I was performed using either [d-threo-1-(2-nitrophenylsulfanyl)piperidin-2-yl]phenyl-acetic acid (d-threo-N-NPS-ritalinic acid) under addition of sodium hydroxide as base or the previously prepared sodium salt of d-threo-N-NPS-ritalinic acid. The two approaches were compared with regard to radiochemical yield and purification procedures needed in order to obtain a sufficiently pure tracer solution for human use. For the alternative reaction pathway using [11C]diazo-methane as the labeling agent the reaction was performed with d-threo-N-NPS-ritalinic acid. The biodistribution of [11C]d-threo-MP was determined in rats at 5, 10 and 30 min post injection of the tracer. RESULTS: The application of the sodium salt of d-threo-N-NPS-ritalinic acid as precursor resulted in higher radiochemical yields than the use of the free acid under basic conditions, the yields were 20 +/- 8% and 6 +/- 3%, respectively for the final isolated product (based on [11C]CH3I starting activity). The alternative labeling approach by means of [11C]diazomethane as the labeling agent was demonstrated to give radiochemical yields of 76 +/- 8% (based on [11C]diazomethane starting activity, determined by HPLC analysis of the crude reaction mixture before final work-up) within shorter process times. Based on [11C]methane starting activity both approaches result in similar yields (17% and 15%, respectively) Biodistribution studies in rats revealed a low blood activity (0.09% injected dose/g (% ID/g)) at 5 min post injection (p.i.), as well as a relatively high liver uptake (15.9% ID at 30 min) compared to a lower kidney uptake (3.2% ID at 30 min). Brain uptake was 0.9% ID/g already 5 and 10 min p.i.. CONCLUSIONS: The application of the sodium salt of d-threo-N-NPS-ritalinic acid as precursor for the radiosynthesis of [11C]d-threo-MP reduces the amount of [11C]methanol formed from the reaction of [11C]CH3I with sodium hydroxide, that is added to generate the carboxylic anion of d-threo-N-NPS-ritalinic acid needed for labeling with [11C]CH3I. The purification process could be simplified (omission of one solid phase extraction step), resulting in an easily automated process for the production of the tracer. The preparation of [11C]d-threo-MP by means of [11C]diazomethane as the labeling agent appears to be an interesting alternative to the [11C]CH3I methods because of shorter overall process times and high labeling yields. Biodistribution data show a rapid extraction of the tracer from the blood pool. Tracer excretion seems to take place predominantly via the hepatic pathway since liver uptake at 30 min was considerably higher than kidney uptake. [11C]d-threo-MP exhibits a rapid and sufficiently high brain uptake in rats.


Assuntos
Dopaminérgicos/farmacocinética , Marcação por Isótopo/métodos , Metilfenidato/farmacocinética , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/farmacocinética , Animais , Transporte Biológico , Encéfalo/metabolismo , Radioisótopos de Carbono , Dopamina/metabolismo , Dopaminérgicos/química , Proteínas da Membrana Plasmática de Transporte de Dopamina , Injeções Intravenosas , Ligantes , Masculino , Metilfenidato/química , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/normas , Ratos , Ratos Sprague-Dawley , Distribuição Tecidual
12.
Genome Med ; 9(1): 39, 2017 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-28449715

RESUMO

BACKGROUND: Parkinson's disease (PD) presently is conceptualized as a protein aggregation disease in which pathology involves both the enteric and the central nervous system, possibly spreading from one to another via the vagus nerves. As gastrointestinal dysfunction often precedes or parallels motor symptoms, the enteric system with its vast diversity of microorganisms may be involved in PD pathogenesis. Alterations in the enteric microbial taxonomic level of L-DOPA-naïve PD patients might also serve as a biomarker. METHODS: We performed metagenomic shotgun analyses and compared the fecal microbiomes of 31 early stage, L-DOPA-naïve PD patients to 28 age-matched controls. RESULTS: We found increased Verrucomicrobiaceae (Akkermansia muciniphila) and unclassified Firmicutes, whereas Prevotellaceae (Prevotella copri) and Erysipelotrichaceae (Eubacterium biforme) were markedly lowered in PD samples. The observed differences could reliably separate PD from control with a ROC-AUC of 0.84. Functional analyses of the metagenomes revealed differences in microbiota metabolism in PD involving the ẞ-glucuronate and tryptophan metabolism. While the abundances of prophages and plasmids did not differ between PD and controls, total virus abundance was decreased in PD participants. Based on our analyses, the intake of either a MAO inhibitor, amantadine, or a dopamine agonist (which in summary relates to 90% of PD patients) had no overall influence on taxa abundance or microbial functions. CONCLUSIONS: Our data revealed differences of colonic microbiota and of microbiota metabolism between PD patients and controls at an unprecedented detail not achievable through 16S sequencing. The findings point to a yet unappreciated aspect of PD, possibly involving the intestinal barrier function and immune function in PD patients. The influence of the parkinsonian medication should be further investigated in the future in larger cohorts.


Assuntos
Bactérias/genética , Microbioma Gastrointestinal/genética , Metagenoma , Doença de Parkinson/microbiologia , Vírus/genética , Idoso , Bactérias/isolamento & purificação , Humanos , Levodopa , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/virologia , Análise de Sequência de DNA , Vírus/isolamento & purificação
13.
Brain ; 128(Pt 8): 1855-60, 2005 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-15947063

RESUMO

The recent identification of fragile X-associated tremor ataxia syndrome (FXTAS) associated with premutations in the FMR1 gene and the possibility of clinical overlap with multiple system atrophy (MSA) has raised important questions, such as whether genetic testing for FXTAS should be performed routinely in MSA and whether positive cases might affect the specificity of current MSA diagnostic criteria. We genotyped 507 patients with clinically diagnosed or pathologically proven MSA for FMR1 repeat length. Among the 426 clinically diagnosed cases, we identified four patients carrying FMR1 premutations (0.94%). Within the subgroup of patients with probable MSA-C, three of 76 patients (3.95%) carried premutations. We identified no premutation carriers among 81 patients with pathologically proven MSA and only one carrier among 622 controls (0.16%). Our results suggest that, with proper application of current diagnostic criteria, FXTAS is very unlikely to be confused with MSA. However, slowly progressive disease or predominant tremor are useful red flags and should prompt the consideration of FXTAS. On the basis of our data, the EMSA Study Group does not recommend routine FMR1 genotyping in typical MSA patients.


Assuntos
Ataxia/genética , Síndrome do Cromossomo X Frágil/genética , Atrofia de Múltiplos Sistemas/genética , Tremor/genética , Idoso , Ataxia/complicações , Ataxia/diagnóstico , Ataxia Cerebelar/complicações , Ataxia Cerebelar/diagnóstico , Ataxia Cerebelar/genética , Estudos de Coortes , Diagnóstico Diferencial , Feminino , Proteína do X Frágil da Deficiência Intelectual , Síndrome do Cromossomo X Frágil/complicações , Síndrome do Cromossomo X Frágil/diagnóstico , Frequência do Gene , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Atrofia de Múltiplos Sistemas/diagnóstico , Mutação , Proteínas do Tecido Nervoso/genética , Doenças do Sistema Nervoso Periférico/complicações , Doenças do Sistema Nervoso Periférico/genética , Proteínas de Ligação a RNA/genética , Sequências Repetitivas de Ácido Nucleico/genética , Tremor/complicações , Tremor/diagnóstico
14.
Clin Neuropathol ; 25(6): 272-81, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-17140157

RESUMO

OBJECTIVE: We analyzed the expression of the inflammatory mediators IL-1beta, IL-1ra, IL-6 and the transcription factors IRF-1 and C/EBPdelta (previously identified in a transgenic model of spinocerebellar ataxia type 3 (SCA3) by gene expression profiling) in the central nervous system of SCA3 patients in relation to neuronal cell loss and ataxin-3-positive neuronal intranuclear inclusions (NI), to identify a putative upregulation of cytokines or microglia in SCA3 brains and to investigate whether enhanced cytokine expression was a generalized event mediating neuronal dysfunction in SCA3. MATERIALS AND METHODS: Light- and electronmicroscopic immunohistochemistry was performed on SCA3 tissues derived from five patients from unrelated families with genetically confirmed diagnosis, and six individuals without a history of neurological or inflammatory disease. RESULTS: NI were found almost exclusively in brain regions that also showed neuronal cell loss, i.e. in pons and dentate nucleus neurons, rarely in putamen and thalamus, but not in cerebral or cerebellar cortex. NI displayed an irregular surface and were mostly attached to the nucleoli. Quantitative analysis of NI in the pons revealed an inverse relation of NI and cell loss, i.e. patients with more severe neuronal cell loss had a smaller proportion of neurons with NI. Thus, formation of NI is not necessarily an indicator of cell death but could exert a protective effect. We found increased expression of IL-1beta, IL-1ra, IL-6 and C/EBPdelta only in pons and dentate nucleus neurons and both in neurons with and without NI, suggesting that NI are not a prerequisite for transcriptional changes. CONCLUSIONS: Our data suggest that the selectively affected neuronal populations in SCA3 undergo a complex alteration of gene expression independent from the formation of NI.


Assuntos
Encéfalo/patologia , Citocinas/metabolismo , Corpos de Inclusão Intranuclear/patologia , Doença de Machado-Joseph/patologia , Neurônios/patologia , Idoso , Ataxina-3 , Biomarcadores/metabolismo , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Proteína delta de Ligação ao Facilitador CCAAT/metabolismo , Morte Celular/fisiologia , Núcleo Celular/metabolismo , Núcleo Celular/patologia , Citocinas/genética , Feminino , Regulação da Expressão Gênica/fisiologia , Humanos , Imuno-Histoquímica , Fator Regulador 1 de Interferon/metabolismo , Proteína Antagonista do Receptor de Interleucina 1/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Corpos de Inclusão Intranuclear/genética , Corpos de Inclusão Intranuclear/metabolismo , Doença de Machado-Joseph/metabolismo , Doença de Machado-Joseph/fisiopatologia , Masculino , Microscopia Imunoeletrônica , Pessoa de Meia-Idade , Degeneração Neural/metabolismo , Degeneração Neural/patologia , Degeneração Neural/fisiopatologia , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Repressoras/metabolismo
15.
J Neurosci ; 21(15): 5389-96, 2001 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-11466410

RESUMO

Spinocerebellar ataxia type 3 (SCA3) is a polyglutamine disorder caused by a CAG repeat expansion in the coding region of a gene encoding ataxin-3. To study putative alterations of gene expression induced by expanded ataxin-3, we performed PCR-based cDNA subtractive hybridization in a cell culture model of SCA3. In rat mesencephalic CSM14.1 cells stably expressing expanded ataxin-3, we found a significant upregulation of mRNAs encoding the endopeptidase matrix metalloproteinase 2 (MMP-2), the transmembrane protein amyloid precursor protein, the interleukin-1 receptor-related Fos-inducible transcript, and the cytokine stromal cell-derived factor 1alpha (SDF1alpha). Immunohistochemical studies of the corresponding or associated proteins in human SCA3 brain tissue confirmed these findings, showing increased expression of MMP-2 and amyloid beta-protein (Abeta) in pontine neurons containing nuclear inclusions. In addition, extracellular Abeta-immunoreactive deposits were detected in human SCA3 pons. Furthermore, pontine neurons of SCA3 brains strongly expressed the antiinflammatory interleukin-1 receptor antagonist, the proinflammatory cytokine interleukin-1beta, and the proinflammatory chemokine SDF1. Finally, increased numbers of reactive astrocytes and activated microglial cells were found in SCA3 pons. These results suggest that inflammatory processes are involved in the pathogenesis of SCA3.


Assuntos
Encéfalo/metabolismo , Inflamação/metabolismo , Doença de Machado-Joseph/metabolismo , Proteínas de Membrana , Proteínas do Tecido Nervoso/biossíntese , Regulação para Cima , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Ataxina-3 , Encéfalo/patologia , Células Cultivadas , Quimiocina CXCL12 , Quimiocinas CXC/genética , Quimiocinas CXC/metabolismo , Perfilação da Expressão Gênica , Humanos , Imuno-Histoquímica , Inflamação/genética , Proteína 1 Semelhante a Receptor de Interleucina-1 , Subunidade alfa de Receptor de Interleucina-18 , Doença de Machado-Joseph/patologia , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Proteínas do Tecido Nervoso/genética , Neurônios/metabolismo , Neurônios/patologia , Proteínas Nucleares , Ponte/metabolismo , Ponte/patologia , Proteínas/genética , Proteínas/metabolismo , RNA Mensageiro/metabolismo , Ratos , Receptores de Superfície Celular , Receptores de Interleucina , Receptores de Interleucina-18 , Proteínas Repressoras , Fatores de Transcrição , Expansão das Repetições de Trinucleotídeos/genética
16.
Cell Death Differ ; 5(10): 847-57, 1998 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-10203688

RESUMO

In rats, striatal histotoxic hypoxic lesions produced by the mitochondrial toxin malonate resemble those of focal cerebral ischemia. Intrastriatal injections of malonate induced cleavage of caspase-2 beginning at 6 h, and caspase-3-like activity as identified by DEVD biotin affinity-labeling within 12 h. DEVD affinity-labeling was prevented and lesion volume reduced in transgenic mice overexpressing BCL-2 in neuronal cells. Intrastriatal injection of the tripeptide, N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD-fmk), a caspase inhibitor, at 3 h, 6 h, or 9 h after malonate injections reduced the lesion volume produced by malonate. A combination of pretreatment with the NMDA antagonist, dizocilpine (MK-801), and delayed treatment with zVAD-fmk provided synergistic protection compared with either treatment alone and extended the therapeutic window for caspase inhibition to 12 h. Treatment with cycloheximide and zVAD-fmk, but not with MK-801, blocked the malonate-induced cleavage of caspase-2. NMDA injections alone resulted in a weak caspase-2 cleavage. These results suggest that malonate toxicity induces neuronal death by more than one pathway. They strongly implicate early excitotoxicity and delayed caspase activation in neuronal loss after focal ischemic lesions and offer a new strategy for the treatment of stroke.


Assuntos
Clorometilcetonas de Aminoácidos/farmacologia , Encéfalo/patologia , Inibidores de Caspase , Corpo Estriado/efeitos dos fármacos , Maleato de Dizocilpina/farmacologia , Genes bcl-2 , Hipóxia Encefálica/prevenção & controle , Fármacos Neuroprotetores/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Clorometilcetonas de Aminoácidos/uso terapêutico , Animais , Apoptose , Encéfalo/efeitos dos fármacos , Caspase 2 , Caspase 3 , Caspases/metabolismo , Corpo Estriado/patologia , Corpo Estriado/fisiologia , Cicloeximida/farmacologia , Inibidores de Cisteína Proteinase/farmacologia , Inibidores de Cisteína Proteinase/uso terapêutico , Maleato de Dizocilpina/uso terapêutico , Sinergismo Farmacológico , Humanos , Hipóxia Encefálica/induzido quimicamente , Hipóxia Encefálica/patologia , Marcação In Situ das Extremidades Cortadas , Masculino , Malonatos/toxicidade , Camundongos , Camundongos Transgênicos , Fármacos Neuroprotetores/uso terapêutico , Proteínas Proto-Oncogênicas c-bcl-2/genética , Ratos , Ratos Sprague-Dawley
17.
Appl Radiat Isot ; 63(4): 433-5, 2005 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16024252

RESUMO

2-[18F]F-A85380 is the first subtype selective PET-radiotracer to visualize the distribution of alpha4beta2 nicotinic acetylcholine receptors in human brain in vivo. We investigated a fast and safe automated production of 2-[18F]F-A85380 by purification of the BOC-protected intermediate product with a combination of solid phase extraction cartridges. After deprotection, adjustment of the pH and sterile filtration n.c.a. 2-[18F]F-A85380 was applicable for the use in human studies with a high specific activity and an overall radiochemical yield of 55% in 35 minutes.


Assuntos
Azetidinas/síntese química , Piridinas/síntese química , Compostos Radiofarmacêuticos/síntese química , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Tomografia por Emissão de Pósitrons , Receptores Nicotínicos/metabolismo
18.
Arch Neurol ; 50(8): 803-6, 1993 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-8352664

RESUMO

OBJECTIVE--To clarify the nosological classification of late-onset Friedreich's ataxia (LOFA), ie, patients who have later onset of Friedreich's ataxia (FRDA), often after 25 years of age. DESIGN--Comparison of clinical examination data, nerve conduction studies, electronystagmographic recording, and magnetic resonance imaging of a family with LOFA with a group of patients with FRDA. Genetic linkage analysis was performed in the family with LOFA. SETTING--Referral center. PATIENTS--Thirteen patients satisfied classic diagnostic criteria of FRDA, and three patients from one family satisfied all diagnostic criteria of FRDA but with disease onset after 25 years. RESULTS--Results of nerve conduction studies, electronystagmographic recording, and magnetic resonance imaging in patients with LOFA closely corresponded to observations made in patients with FRDA. In addition, genetic linkage analysis using markers tightly linked to the FRDA locus on chromosome 9 showed that all affected members of the LOFA family, but not their unaffected siblings, had inherited identical paternal and maternal genotypes. CONCLUSIONS--Data suggest that LOFA may also result from mutation within the FRDA locus.


Assuntos
Encéfalo/patologia , Ataxia de Friedreich/genética , Ataxia de Friedreich/fisiopatologia , Adolescente , Adulto , Criança , Pré-Escolar , Eletronistagmografia , Ligação Genética , Humanos , Imageamento por Ressonância Magnética , Condução Nervosa/fisiologia , Linhagem , Fatores de Tempo
19.
Neurology ; 43(2): 318-25, 1993 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-8437696

RESUMO

We used magnetic resonance imaging (MRI) to study brain and spinal cord morphology in hereditary and idiopathic ataxia. Our interest was in whether the classical neuropathologic categories--cerebellar cortical atrophy (CCA), olivopontocerebellar atrophy (OPCA), and spinal atrophy (SA)--could be identified in vivo and which clinical phenotype corresponded to which morphologic category. To this end, we measured the size of the cerebellar vermis, cerebellar hemispheres, fourth ventricle, middle cerebellar peduncles, basis pontis, medulla oblongata, and cervical spinal cord on T1-weighted images of 61 patients and 24 healthy controls. Five patients with Friedreich's ataxia (n = 7) and all with late-onset Friedreich's ataxia (n = 3) had SA without major involvement of the brainstem or cerebellum. Morphologic findings in patients with early-onset cerebellar ataxia with retained tendon reflexes (n = 11) were heterogeneous: six patients had MRI findings compatible with CCA, and two patients had a combination of SA and CCA. The three remaining patients had an atypical pattern of atrophy. Similarly, the morphologic changes in patients with autosomal-dominant cerebellar ataxia with additional noncerebellar symptoms (ADCA-I; n = 13) were nonuniform: atrophic changes typical for CCA, OPCA, or SA were each present in one case, four patients had a combination of OPCA and SA, and the remaining patients could not be assigned to one of the morphologic categories. In autosomal-dominant cerebellar ataxia with a pure cerebellar syndrome (ADCA-III; n = 6), all patients except one had CCA.(ABSTRACT TRUNCATED AT 250 WORDS)


Assuntos
Ataxia Cerebelar/patologia , Degenerações Espinocerebelares/patologia , Adulto , Idoso , Encéfalo/patologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Medula Espinal/patologia
20.
Neuropharmacology ; 31(7): 713-5, 1992 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-1357577

RESUMO

Experiments in MPTP-treated non-human primates testing potential antiparkinsonian action have shown both, beneficial and adverse effects of gutamate receptor antagonists. To investigate this matter further, the novel competitive NMDA antagonist CGP40.116 was administered systemically to three adult MPTP-treated marmosets. When coadministered subcutaneously with a subthreshold dose of L-DOPA, 2 mg/kg, CGP40.116 25-250 micrograms/kg, increased locomotor activity. However, when administered alone, CGP40.116 had no effect on locomotor activity.


Assuntos
1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/farmacologia , 2-Amino-5-fosfonovalerato/análogos & derivados , Levodopa/farmacologia , Atividade Motora/efeitos dos fármacos , N-Metilaspartato/antagonistas & inibidores , 2-Amino-5-fosfonovalerato/farmacologia , Animais , Callithrix , Relação Dose-Resposta a Droga , Sinergismo Farmacológico
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