RESUMEN
L-3,4-Dihydroxyphenylalanine (L-DOPA) is the therapeutic gold standard in Parkinson's disease. However, long-term treatment is complicated by the induction of debilitating abnormal involuntary movements termed L-DOPA-induced dyskinesias (LIDs). Until today the underlying mechanisms of LID pathogenesis are not fully understood. The aim of this study was to reveal new factors, which may be involved in the induction of LID. We have focused on the expression of striatal tyrosine hydroxylase-positive (TH+) neurons, which are capable of producing either L-DOPA or dopamine (DA) in target areas of ventral midbrain DAergic neurons. To address this issue, a daily L-DOPA dose was administered over the course of 15 days to mice with unilateral 6-hydroxydopamine-induced lesions of the medial forebrain bundle and LIDs were evaluated. Remarkably, the number of striatal TH+ neurons strongly correlated with both induction and severity of LID as well as ΔFosB expression as an established molecular marker for LID. Furthermore, dyskinetic mice showed a marked augmentation of serotonergic fiber innervation in the striatum, enabling the decarboxylation of L-DOPA to DA. Axial, limb and orolingual dyskinesias were predominantly associated with TH+ neurons in the lateral striatum, whereas medially located TH+ neurons triggered locomotive rotations. In contrast, identified accumbal and cortical TH+ cells did not contribute to the generation of LID. Thus, striatal TH+ cells and serotonergic terminals may cooperatively synthesize DA and subsequently contribute to supraphysiological synaptic DA concentrations, an accepted cause in LID pathogenesis.
Asunto(s)
Cuerpo Estriado/patología , Discinesia Inducida por Medicamentos/patología , Lateralidad Funcional/fisiología , Neuronas/metabolismo , Tirosina 3-Monooxigenasa/metabolismo , Anfetamina/farmacología , Animales , Antiparkinsonianos/efectos adversos , Modelos Animales de Enfermedad , Discinesia Inducida por Medicamentos/etiología , Levodopa/efectos adversos , Masculino , Haz Prosencefálico Medial/efectos de los fármacos , Haz Prosencefálico Medial/lesiones , Ratones , Ratones Endogámicos C57BL , Oxidopamina/toxicidad , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/etiología , Fosfopiruvato Hidratasa/metabolismo , Proteínas Proto-Oncogénicas c-fos/metabolismo , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Estadísticas no ParamétricasRESUMEN
Non-motor symptoms such as hyposmia and depression are often observed in Parkinson's disease (PD) and can precede the onset of motor symptoms for years. The underlying pathological alterations in the brain are not fully understood so far. Dysregulation of adult neurogenesis in the dentate gyrus of the hippocampus and the olfactory bulb has been recently suggested to be implicated in non-motor symptoms of PD. However, there is so far no direct evidence to support the relationship of non-motor symptoms and the modulation of adult neurogenesis following dopamine depletion and/or dopamine replacement. In this study, we investigated the long-term effects of l-DOPA and pramipexole, a dopamine agonist, in a mouse model of bilateral intranigral 6-OHDA lesion, in order to assess the impact of adult neurogenesis on non-motor behavior. We found that l-DOPA and pramipexole can normalize decreased neurogenesis in the hippocampal dentate gyrus and the periglomerular layer of the olfactory bulb caused by a 6-OHDA lesion. Interestingly, pramipexole showed an antidepressant and anxiolytic effect in the forced swim test and social interaction test. However, there was no significant change in learning and memory function after dopamine depletion and dopamine replacement, respectively.
Asunto(s)
Antiparkinsonianos/farmacología , Benzotiazoles/farmacología , Levodopa/farmacología , Neurogénesis/efectos de los fármacos , Trastornos Parkinsonianos/tratamiento farmacológico , Animales , Ansiedad/tratamiento farmacológico , Ansiedad/patología , Ansiedad/fisiopatología , Depresión/tratamiento farmacológico , Depresión/patología , Depresión/fisiopatología , Hipocampo/efectos de los fármacos , Hipocampo/patología , Hipocampo/fisiopatología , Masculino , Ratones Endogámicos C57BL , Neurogénesis/fisiología , Neuronas/efectos de los fármacos , Neuronas/patología , Neuronas/fisiología , Bulbo Olfatorio/efectos de los fármacos , Bulbo Olfatorio/patología , Bulbo Olfatorio/fisiopatología , Oxidopamina , Trastornos Parkinsonianos/patología , Trastornos Parkinsonianos/fisiopatología , Trastornos Parkinsonianos/psicología , Pramipexol , Distribución AleatoriaRESUMEN
Rapid eye movement (REM) sleep behavior disorder (RBD) is defined as a parasomnia characterized by loss of REM sleep-associated atonia and the presence of motor activity during dreaming typically presenting with an aggressive dream content. Epidemiological data on the prevalence of RBD are insufficient but it can be idiopathic or symptomatic. A video-audio polysomnography is essential for diagnosis. Clonazepam and melatonin are available as pharmaceutical treatment. Recent studies demonstrated that individuals suffering from idiopathic RBD carry a high specific risk (up to 80 %) for developing a neurodegenerative disorder of the α-synucleinopathy type (e.g. Parkinson's disease, dementia with Lewy bodies and multiple system atrophy) within 10-20 years. The current article provides a short overview of symptoms, epidemiology, pathophysiology, diagnosis and therapy of RBD.
Asunto(s)
Anticonvulsivantes/uso terapéutico , Enfermedades Neurodegenerativas/diagnóstico , Enfermedades Neurodegenerativas/terapia , Polisomnografía , Trastorno de la Conducta del Sueño REM/diagnóstico , Trastorno de la Conducta del Sueño REM/terapia , Humanos , Enfermedades Neurodegenerativas/complicaciones , Enfermedades Neurodegenerativas/metabolismo , Síntomas Prodrómicos , Trastorno de la Conducta del Sueño REM/complicaciones , Trastorno de la Conducta del Sueño REM/metabolismo , alfa-Sinucleína/metabolismoRESUMEN
Regulated intramembrane proteolysis by gamma-secretase cleaves proteins in their transmembrane domain and is involved in important signaling pathways. At least four different gamma-secretase complexes have been identified, but little is known about their biological role and specificity. Previous work has demonstrated the involvement of the Aph1A-gamma-secretase complex in Notch signaling, but no specific function could be assigned to Aph1B/C-gamma-secretase. We demonstrate here that the Aph1B/C-gamma-secretase complex is expressed in brain areas relevant to schizophrenia pathogenesis and that Aph1B/C deficiency causes pharmacological and behavioral abnormalities that can be reversed by antipsychotic drugs. At the molecular level we find accumulation of Nrg1 fragments in the brain of Aph1BC(-/-) mice. Our observations gain clinical relevance by the demonstration that a Val-to-Leu mutation in the Nrg1 transmembrane domain, associated with increased risk for schizophrenia, affects gamma-secretase cleavage of Nrg1. This finding suggests that dysregulation of intramembrane proteolysis of Nrg1 could increase risk for schizophrenia and related disorders.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/deficiencia , Antipsicóticos/farmacología , Endopeptidasas/deficiencia , Trastornos Neurológicos de la Marcha/etiología , Neurregulina-1/metabolismo , Subunidades de Proteína/deficiencia , Animales , Antipsicóticos/uso terapéutico , Proteínas de la Membrana , Ratones , Ratones Noqueados , Mutación Missense/fisiología , Esquizofrenia/etiologíaRESUMEN
Quantitative imaging analysis of endogenous an exogenous elements throughout entire organisms is required for studies of bioavailability, transport processes, distribution, contamination and to monitor environmental risks using indicator organisms. An imaging mass spectrometric technique using laser ablation inductively coupled plasma mass spectrometry (LA-ICPMS) was developed to analyze selenium and metal distributions in longitudinal sections (thickness, 100 microm) of entire slugs (genus arion). Slugs were fed with either a placebo or solutions containing 1000 microg mL(-1) Se. Samples (raster area, 25 mmx45 mm) were scanned together with synthetic matrix-matched standards with a focused beam of a Nd:YAG laser (wavelength, 266 nm; diameter of laser crater, 50 microm; laser power density, 3x10(9) W cm(-2)) in a large laser ablation chamber. The ablated material was transported with argon as carrier gas to the ICP ion source at a double focusing sector field ICPMS. Ion intensities of selenium (78Se+, 82Se+) were measured together with 13C+, 63Cu+, and 64Zn+ within the entire tissue section. The regression coefficient of the calibration curve was 0.998. Inhomogeneous distributions for Se but also for C, Cu, and Zn were found. Selenium was enriched in the kidney (150 microg g(-1) in Se-treated animals versus 15 microg g(-1) in the placebo-treated animal, respectively) and in the digestive gland (200 microg g(-1) versus 25 microg g(-1)). Highest Se concentrations were detected in the gut of Se-treated slugs (250 microg g(-1)), and additional Se occurred in the skin of these animals. Cu was enriched in the heart and the mucous ventral skin. Interestingly, in addition to the localization in the digestive gland, Zn was detected only in the dorsal skin but not the ventral skin. The developed analytical technique allows the quantitative imaging of selenium together with selected metals in thin sections of biological tissue with limits of detection at the submicrogram per gram range.
Asunto(s)
Cobre/análisis , Monitoreo del Ambiente/métodos , Espectrometría de Masas/métodos , Selenio/farmacocinética , Zinc/análisis , Animales , Gastrópodos , Rayos Láser , Espectrometría de Masas/normas , Distribución TisularRESUMEN
OBJECTIVE: Active or passive immunisation can mitigate plaque pathology in murine models of Alzheimer's disease (AD). Recently, it has been shown that antibodies against beta-amyloid (Abeta) are present in human immunoglobulin preparations (IVIgG), which specifically recognise and inhibit the neurotoxic effects of Abeta. This study reports the results from a pilot study using IVIgG in patients with AD. METHODS: Five patients with AD were enrolled and received monthly IVIgG over a 6 month period. Efficacy assessment included total Abeta/Abeta(1-42) measured in the CSF/serum as well as effects on cognition (ADAS-cog; CERAD) at baseline and at 6 months following IVIgG. RESULTS: Following IVIgG, total Abeta levels in the CSF decreased by 30.1% (17.3-43.5%) compared to baseline (p<0.05). Total Abeta increased in the serum by 233% (p<0.05). No significant change was found in Abeta(1-42) levels in the CSF/serum. Using ADAS-cog, an improvement of 3.7+/-2.9 points was detected. Scores in the MMSE were essentially unchanged (improved in four patients, stable in one patient) following IVIgG compared to baseline. CONCLUSION: Although the sample size of this pilot study is too small to draw a clear conclusion, the results of this pilot study provide evidence for a more detailed investigation of IVIgG for the treatment of AD.
Asunto(s)
Enfermedad de Alzheimer/inmunología , Enfermedad de Alzheimer/terapia , Péptidos beta-Amiloides/inmunología , Inmunoglobulinas Intravenosas/inmunología , Inmunoglobulinas Intravenosas/uso terapéutico , Péptidos beta-Amiloides/farmacología , Formación de Anticuerpos , Trastornos del Conocimiento/etiología , Trastornos del Conocimiento/terapia , Femenino , Humanos , Masculino , Escala del Estado Mental , Persona de Mediana Edad , Resultado del TratamientoAsunto(s)
Enfermedad de Alzheimer/genética , Cistatinas/genética , Inhibidores de Cisteína Proteinasa/metabolismo , Polimorfismo Genético/genética , Regiones Promotoras Genéticas/genética , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Cistatina C , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Factores de RiesgoRESUMEN
The cholinergic gene locus (CGL) was first identified in 1994 as the site (human chromosome 10q11.2) at which choline acetyltransferase and a functional vesicular acetylcholine transporter are co-localized. Here, we present recent neuroanatomical, developmental, and evolutionary insights into the chemical coding of cholinergic neurotransmission that have been gleaned from the study of the CGL, and its protein products VAChT and ChAT, which comprise a synthesis-sequestration pathway that functionally defines the cholinergic phenotype.