RESUMEN

TITLE: Cervantes y la enfermedad de Parkinson.

Asunto(s)

Medicina en la Literatura , Enfermedad de Parkinson , Drama , Humanos , Literatura Moderna

RESUMEN

Hereditary spastic paraplegias constitute a heterogeneous group of neurodegenerative diseases encompassing pure and complicated forms, for which at least 52 loci and 31 causative genes have been identified. Although mutations in the SPAST gene explain approximately 40% of the pure autosomal dominant forms, molecular diagnosis can be challenging for the sporadic and recessive forms, which are often complicated and clinically overlap with a broad number of movement disorders. The validity of exome sequencing as a routine diagnostic approach in the movement disorder clinic needs to be assessed. The main goal of this study was to explore the usefulness of an exome analysis for the diagnosis of a complicated form of spastic paraplegia. Whole-exome sequencing was performed in two Spanish siblings with a neurodegenerative syndrome including upper and lower motor neuron, ocular and cerebellar signs. Exome sequencing revealed that both patients carry a novel homozygous nonsense mutation in exon 15 of the SPG11 gene (c.2678G>A; p.W893X), which was not found in 584 Spanish control chromosomes. After many years of follow-up and multiple time-consuming genetic testing, we were able to diagnose these patients by making use of whole-exome sequencing, showing that this is a cost-efficient diagnostic tool for the movement disorder specialist.

Asunto(s)

Exoma/genética , Técnicas de Diagnóstico Molecular/métodos , Proteínas/genética , Paraplejía Espástica Hereditaria/diagnóstico , Paraplejía Espástica Hereditaria/genética , Codón sin Sentido/genética , Cartilla de ADN/genética , Femenino , Genes Recesivos/genética , Humanos , Masculino , Linaje , Análisis de Secuencia de ADN , España

RESUMEN

Huntington's disease (HD) is a neurodegenerative disease characterized by progressive motor, cognitive and psychiatric deficits, associated with predominant loss of striatal neurons and caused by a polyglutamine expansion in the huntingtin protein. There is so far neither cure nor approved disease-slowing therapy for HD, though recent clinical studies have shown a beneficial long-term effect of pridopidine in patients with HD. The nature of this effect, purely symptomatic or, in addition, neuroprotective, is difficult to elucidate in clinical trials. Pridopidine and (-)-OSU6162 are members of a new family of compounds referred to as dopaminergic stabilizers, which normalize abnormal dopamine neurotransmission. We investigated the effects of (-)-OSU6162 on huntingtin knocked-in striatal neurons in culture. Control neurons had normal full-length huntingtin with 7 glutamines while "mutant" neurons had large expansions (Q=111). We studied the dose-effect curves of (-)-OSU6162 on mitochondrial activity, LDH levels, necrosis and apoptosis in untreated Q7 and Q111 cells. In addition, we investigated the effects of (-)-OSU6162 on Q7 and Q111 neurons challenged with different neurotoxins such as sodium glutamate, H(2)O(2), rotenone and 3-nitropropionic acid (3NP). As we found prevention of toxicity of some of these neurotoxins, we investigated the putative neuroprotective mechanisms of action of (-)-OSU6162 measuring the effects of this dopaminergic stabilizer on expression and release of BDNF, the ratios of Bcl2/Bax proteins and of p-ERK/ERK, the levels of chaperones and GSH, and the effects of (-)-OSU6162 on dopamine uptake and release. We found that (-)-OSU6162, 3-150 µM, produces a dose dependent increase of mitochondrial activity and a reduction of cell death. (-)-OSU6162 does not change glutamate toxicity, but it partially prevents that of H(2)O(2), rotenone and 3-nitropropionic acid. (-)-OSU6162 increases the intracellular levels of BDNF and Bcl2/Bax and decreases those of p-ERK/ERK and CHIP in Q111 cells. (-)-OSU6162 increased (3)H-dopamine uptake and amphetamine-induced (3)H-dopamine release in E13 mouse mid brain neurons. Our studies demonstrate that (-)-OSU6162 improves survival and mitochondrial function in striatal Q111 neurons and the resistance of these cells to several striatal neurotoxins, suggesting that (-)-OSU6162 and related compounds should be tested for neuroprotection in animal models and, eventually, in patients with HD.

Asunto(s)

Cuerpo Estriado/citología , Dopaminérgicos/farmacología , Peróxido de Hidrógeno/toxicidad , Proteínas del Tejido Nervioso/genética , Neuronas/efectos de los fármacos , Péptidos/metabolismo , Piperidinas/farmacología , Rotenona/toxicidad , Análisis de Varianza , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Dopamina/metabolismo , Relación Dosis-Respuesta a Droga , Embrión de Mamíferos , Ensayo de Inmunoadsorción Enzimática , Ácido Glutámico/toxicidad , Glutatión/metabolismo , Humanos , Proteína Huntingtina , Ratones , Ratones Endogámicos C57BL , Mutación/genética , Proteínas del Tejido Nervioso/química , Péptidos/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Transfección/métodos , Tritio/metabolismo

RESUMEN

Neurodegenerative diseases like Parkinson's disease, Alzheimer's disease, Huntington's disease and others are due to accumulation of abnormal proteins which fold improperly and impair neuronal function. Accumulation of these proteins could be achieved by several mechanisms including mutation, overproduction or impairment of its degradation. Inhibition of the normal protein degradation is produced by blockade of the ubiquitin proteasome system. We have shown that epoxomicin, a proteasome inhibitor, increases the levels of proteins involved in neurodegenerative disorders such as α-synuclein and hyper phosphorylated tau in NB69 human neuroblastoma cells and that such increase correlates with an enhanced rate of cell death. We then investigated whether the stimulation of autophagy, an alternative mechanism for elimination of abnormal proteins, by treatment with trehalose, counteracts the effects of proteasomal blockade. Trehalose, a disaccharide present in many non-mammalian species, known to enhance autophagy, protects cells against various environmental stresses. Treatment with trehalose produced a dose and time-dependent increase in the number of autophagosomes and markers of autophagy in NB69 cells. Trehalose did not change the number of total neither the number of dividing cells in the culture but it completely prevented the necrosis of NB69 induced by epoxomicin. In addition, the treatment with trehalose reverted the accumulation, induced by epoxomicin, of polyubiquitinated proteins, total and phosphorylated tau, p-GSK-3, and α-synuclein, as well as the α-synuclein intracellular aggregates. The effects of trehalose were not mediated through activation of free radical scavenging compounds, like GSH, or mitochondrial proteins, like DJ1, but trehalose reduced the activation of ERK and chaperone HSP-70 induced by epoxomicin. Inhibition of ERK phosphorylation prevented the epoxomicin-induced cell death. Inhibition of autophagy reverted the neuroprotective effects of trehalose in epoxomicin-induced cell death. These results suggest that trehalose is a powerful modifier of abnormal protein accumulation in neurodegenerative diseases.

Asunto(s)

Autofagia/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Neuroblastoma/metabolismo , Inhibidores de Proteasoma , Proteínas/metabolismo , Trehalosa/metabolismo , Western Blotting , Línea Celular Tumoral , Proliferación Celular , Supervivencia Celular , Humanos , Inmunohistoquímica , Neuroblastoma/patología , Oligopéptidos/farmacología

Asunto(s)

Neurología , Enfermedad de Parkinson , Historia del Siglo XX , Humanos , Levodopa/uso terapéutico , Neurología/historia , Neurocirugia/historia , Enfermedad de Parkinson/historia , Enfermedad de Parkinson/fisiopatología , Enfermedad de Parkinson/terapia , Investigadores , España , Recursos Humanos

RESUMEN

Tauopathies with parkinsonism represent a spectrum of disease entities unified by the pathologic accumulation of hyperphosphorylated tau protein fragments within the central nervous system. These pathologic characteristics suggest shared pathogenetic pathways and possible molecular targets for disease-modifying therapeutic interventions. Natural history studies, for instance, in progressive supranuclear palsy, frontotemporal dementia with parkinsonism linked to chromosome 17, corticobasal degeneration, and Niemann-Pick disease type C as well as in amyotrophic lateral sclerosis/Parkinson-dementia complex permit clinical characterization of the disease phenotypes and are crucial to the development and validation of biological markers for differential diagnostics and disease monitoring, for example, by use of neuroimaging or proteomic approaches. The wide pathologic and clinical spectrum of the tauopathies with parkinsonism is reviewed in this article, and perspectives on future advances in the understanding of the pathogenesis are given, together with potential therapeutic strategies.

Asunto(s)

Trastornos Parkinsonianos/complicaciones , Tauopatías/complicaciones , Animales , Biomarcadores , Demencia/complicaciones , Demencia/genética , Demencia/fisiopatología , Diseño de Fármacos , Geografía , Humanos , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina , Modelos Biológicos , Mutación , Enfermedad de Niemann-Pick Tipo C/complicaciones , Enfermedad de Niemann-Pick Tipo C/diagnóstico , Enfermedad de Niemann-Pick Tipo C/fisiopatología , Enfermedad de Parkinson Posencefalítica/complicaciones , Enfermedad de Parkinson Posencefalítica/fisiopatología , Trastornos Parkinsonianos/patología , Trastornos Parkinsonianos/fisiopatología , Trastornos Parkinsonianos/terapia , Enfermedad de Pick/complicaciones , Enfermedad de Pick/patología , Proteínas Serina-Treonina Quinasas/genética , Parálisis Supranuclear Progresiva/complicaciones , Parálisis Supranuclear Progresiva/diagnóstico , Parálisis Supranuclear Progresiva/fisiopatología , Tauopatías/patología , Tauopatías/fisiopatología , Tauopatías/terapia , Proteínas tau/genética

RESUMEN

Parkin mutations produce Parkinson's disease (PD) in humans and nigrostriatal dopamine lesions related to increased free radicals in mice. We examined the effects of NP7, a synthetic, marine derived, free radical scavenger which enters the brain, on H(2)O(2) toxicity in cultured neurons and glia from wild-type (WT) and parkin null mice (PK-KO). NP7, 5-10 microM, prevented the H(2)O(2) induced apoptosis and necrosis of midbrain neuronal and glial cultures from WT and PK-KO mice. NP7 suppressed microglial activation and the H(2)O(2) induced drop-out of dopamine neurons(.) Furthermore, NP7 prevented the increased phosphorylation of ERK and AKT induced by H(2)O(2). NP7 may be a promising neuroprotector against oxidative stress in PD.

Asunto(s)

Antioxidantes/farmacología , Antiparkinsonianos/farmacología , Citoprotección , Depuradores de Radicales Libres/farmacología , Mesencéfalo/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Estrés Oxidativo/efectos de los fármacos , Animales , Células Cultivadas , Peróxido de Hidrógeno/farmacología , Mesencéfalo/citología , Ratones , Ratones Noqueados , Neuroglía/citología , Neuroglía/efectos de los fármacos , Neuronas/citología , Neuronas/efectos de los fármacos , Ubiquitina-Proteína Ligasas/genética

RESUMEN

Parkinson's disease (PD) is a neurodegenerative disorder affecting nearly 3 million patients in Europe and North America, characterized by a core phenotype of motor deficits, akinesia, rigidity, postural disturbance and tremor, which is complicated by other neurological deficits during its long progression. Our knowledge about the pathophisiology of PD was limited, up to 25 years ago, to the observation of the lesion of the nigro-striatal dopamine neurons in these patients. The subjects who developed PD as a consequence of exposure to neurotoxic compounds, increased our knowledge about the pathogenesis of this disease. More recently, genetic alterations have been found in patients with PD. The function of the proteins coded by the genes involved in PD has been investigated in genetic models of this disease from invertebrate to rodents. Mutated proteins responsible for PD have been tested in vivo and in vitro, in cellular models or in artificial constructs. A wealth of important information about the function of alpha-synuclein, parkin, DJ-1, PINK and dardarin is available, most notably about the first two causes of familial PD discovered, alpha-synuclein and parkin, responsible for autosomal dominant and autosomal recessive PD, respectively. Different animal models of alpha-synuclein and parkin have been extensively investigated. The in vitro and in vivo studies performed in genetic models of PD have shown that the proteins involved in the pathogenesis of PD interact with one another and have multiple mechanisms of cell toxicity. From the available data, it is clear that the mechanisms leading to cell degeneration in PD are variable in the different subtypes of this disease. Neuroprotective therapies should, therefore, be multiple and tailored according to the factors involved in the different cases. In this study, we review what we have learned from the genetic models of PD and the putative strategies to be tested in the near future.

Asunto(s)

Fármacos Neuroprotectores/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/genética , Animales , Humanos , Modelos Neurológicos , Enfermedad de Parkinson/metabolismo , Unión Proteica , alfa-Sinucleína/química , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo

RESUMEN

We analyzed (18)F-dopa PET data from 11 members of kindreds with familial progressive supranuclear palsy (PSP) to characterize their cerebral dopaminergic dysfunction. Three clinically-affected PSP patients showed reduced (18)F-dopa uptake in the striatum, orbitofrontal cortex and amygdala. One asymptomatic subject exhibited progressive putamen dopaminergic dysfunction. 60% of subjects with abnormal (18)F-dopa scans developed PSP subsequently. This is the first in vivo documentation of cortical dopaminergic deficiency in PSP. Reduced striatal (18)F-dopa uptake in susceptible relatives may predict later clinical disease.

Asunto(s)

Dihidroxifenilalanina/análogos & derivados , Dopamina/metabolismo , Sistema Límbico/diagnóstico por imagen , Sistema Límbico/metabolismo , Parálisis Supranuclear Progresiva/diagnóstico por imagen , Parálisis Supranuclear Progresiva/metabolismo , Anciano , Amígdala del Cerebelo/diagnóstico por imagen , Amígdala del Cerebelo/metabolismo , Amígdala del Cerebelo/fisiopatología , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/metabolismo , Corteza Cerebral/fisiopatología , Cuerpo Estriado/diagnóstico por imagen , Cuerpo Estriado/metabolismo , Cuerpo Estriado/fisiopatología , Dihidroxifenilalanina/farmacocinética , Progresión de la Enfermedad , Regulación hacia Abajo/fisiología , Femenino , Predisposición Genética a la Enfermedad , Humanos , Sistema Límbico/fisiopatología , Masculino , Trastornos Neurocognitivos/diagnóstico por imagen , Trastornos Neurocognitivos/metabolismo , Trastornos Neurocognitivos/fisiopatología , Linaje , Tomografía de Emisión de Positrones/métodos , Valor Predictivo de las Pruebas , Valores de Referencia , Parálisis Supranuclear Progresiva/fisiopatología

RESUMEN

Abnormal deposition of protein tau takes place in the brain of patients with several neurodegenerative diseases. Few of these patients present frontotemporal dementia with parkinsonism and amyotrophy (FTDPA-17), an autosomal dominant tauopathy related to mutations of the gene that codes for protein tau, localized in chromosome 17. The great majority of patients with tauopathies such as Alzheimer's disease, sporadic frontotemporal dementia or progressive supranuclear palsy do not show a Mendelian pattern of inheritance. We have occasionally seen tauopathies in patients with parkin mutations and, therefore, hypothesized that the protein tau interacts with parkin. We have tested that hypothesis in mice with combined genetic modifications of tau (over-expression of human tau with three mutations known to produce FTDPA-17) and parkin (deleted) proteins. Homozygote parkin null or over-expressing mutated-human tau mice have subtle behavioral and molecular abnormalities but do not express a clinical phenotype of neurodegenerative disease. Mice with combined homozygous mutations of these two genes show progressively abnormal walking already noticeable at 3 months of age, loss of dopamine and dopamine markers in striatum, nuclear tau immunoreactive deposits in motor neurons of the spinal cord, abnormal expression of glial markers and enhanced levels of pro-apoptotic proteins; findings that were absent or less pronounced in homozygote animals with deletions of parkin or over-expression of tau. The double transgenic mice do not express normal mechanisms of adaptation to stress such as increased levels of GSH and Hsp-70. In addition, they have reduced levels of CHIP-Hsc70, a complex known to attenuate aggregation of tau and to enhance ubiquitination of phosphorylated tau. We have found high levels of phosphorylated tau in parkin-/-+tau(VLW) mice and a relative decrease of the inactivated pSer9 to total GSK-3 levels. Our data reveal that there are interactions between tau and parkin that could be relevant for the pathogenesis and treatment of tauopathies. Similarly, we hope that the double transgenic parkin-/-+tau(VLW) mice could be useful for testing of compounds with putative therapeutic value in human tauopathies.

Asunto(s)

Cuerpo Estriado/metabolismo , Neuronas Motoras/metabolismo , Sustancia Negra/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Proteínas tau/metabolismo , Animales , Monoaminas Biogénicas/metabolismo , Western Blotting , Encéfalo/metabolismo , Encéfalo/patología , Cuerpo Estriado/patología , Femenino , Genotipo , Glutatión/metabolismo , Glucógeno Sintasa Quinasa 3/metabolismo , Glucógeno Sintasa Quinasa 3 beta , Proteínas del Choque Térmico HSC70/metabolismo , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Actividad Motora/genética , Neuronas Motoras/patología , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Mutación , Médula Espinal/metabolismo , Médula Espinal/patología , Sustancia Negra/patología , Ubiquitina-Proteína Ligasas/genética , Proteínas tau/genética

RESUMEN

AIMS: The purpose of this paper is to report the case of a patient with Kluver-Bucy syndrome caused by adult-type ceroid lipofuscinosis (Kufs' disease) and to review the literature dealing with the causes of this syndrome. CASE REPORT: A 38-year-old male examined because of behavioural changes and cognitive impairment. Brain biopsy findings were characteristic of adult-type ceroid lipofuscinosis. This patient fulfilled the criteria of Kufs' disease, since he had mixed clinical features belonging to both type A (neuropsychiatric disorders) and B (aphasia-apraxia-agnosia syndrome) of the disease. The initial symptoms included several clinical features of Klüver-Bucy syndrome (probable visual agnosia, apathy, increased sexual activity, lack of sexual inhibition, hypermetamorphopsia, increased oral behaviour and changes in dietary habits). CONCLUSIONS: Adult-type ceroid lipofuscinosis is an infrequent clinical entity that is difficult to diagnose owing to the absence of peripheral biological markers and the need to confirm such a diagnosis by means of a histopathological study.

Asunto(s)

Síndrome de Kluver-Bucy/diagnóstico , Síndrome de Kluver-Bucy/etiología , Lipofuscinosis Ceroideas Neuronales/complicaciones , Lipofuscinosis Ceroideas Neuronales/diagnóstico , Adulto , Humanos , Síndrome de Kluver-Bucy/patología , Síndrome de Kluver-Bucy/fisiopatología , Masculino , Lipofuscinosis Ceroideas Neuronales/patología , Lipofuscinosis Ceroideas Neuronales/fisiopatología

RESUMEN

Objetivos. Presentar un paciente con síndrome de Klüver-Bucy causado por ceroidolipo fuscinosis del adulto (enfermedad de Kufs) y revisar la literatura sobre a las causas de dicho síndrome. Caso clínico. Se trata de un varón de 38 años de edad valorado por cambios conductuales y deterioro cognitivo. La biopsia cerebral fue característica de ceroidolipo fuscinosis del adulto. Este paciente cumplía los criterios de la enfermedad de Kufs definida, ya que presentaba características clínicas mixtas de los tipos A (alteraciones neuropsiquiátricas) y B (síndrome afaso-apractoagnósico) de dicha enfermedad. Los síntomas iniciales incluyeron varias características clínicas del síndrome de Klüver-Bucy (probable agnosia visual, apatía, aumento de la actividad sexual, falta de inhibición sexual, hiper-metamorfopsia, aumento de la conducta oral y cambios en los hábitos dietéticos). Conclusiones. La ceroidolipo fuscinosis del adulto es una entidad infrecuente y de difícil diagnóstico dada la ausencia de marcadores biológicos periféricos y la necesidad de la confirmación de dicho diagnóstico mediante un estudio histopatológico

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Aims. The purpose of this paper is to report the case of a patient with Klüver-Bucy syndrome caused by adult-type ceroid lipofuscinosis (Kufs’ disease) and to review the literature dealing with the causes of this syndrome. Case report. A38-year-old male examined because of behavioural changes and cognitive impairment. Brain biopsy findings were characteristic of adult-type ceroid lipofuscinosis. This patient fulfilled the criteria of Kufs’ disease, since he had mixedclinical features belonging to both type A (neuropsychiatric disorders) and B (aphasia-apraxia-agnosia syndrome) of the disease. The initial symptoms included several clinical features of Klüver-Bucy syndrome (probable visual agnosia, apathy, increased sexual activity, lack of sexual inhibition, hypermetamorphopsia, increased oral behaviour and changes in dietaryhabits). Conclusions. Adult-type ceroid lipofuscinosis is an infrequent clinical entity that is difficult to diagnose owing to the absence of peripheral biological markers and the need to confirm such a diagnosis by means of a histopathological study

Asunto(s)

Masculino , Adulto , Humanos , Síndrome de Kluver-Bucy/etiología , Lipofuscinosis Ceroideas Neuronales/complicaciones , Trastornos del Movimiento/etiología , Biopsia , Demencia/etiología , Trastornos Mentales/etiología , Telencéfalo/patología

RESUMEN

OBJECTIVES: To study the characteristics of verbal and sign language aphasia in a patient fluent in both languages, who had had a recent left hemisphere stroke as well as to localise the site responsible for Spanish sign language aphasia. PATIENT AND METHODS: 56 years old male, with risk factors for stroke, who presented an episode of sudden onset aphasia and right hemiplegia that partially recovered in a few hours. The residual deficit of language was explored with a detailed protocol that included comprehension, denomination, oral and phonetic praxis, propositional and automatic spontaneous language, reading and writing tasks. The examination of verbal and sign language was video-recorded. The lesion was localised by magnetic resonance imaging 24 days after the stroke. RESULTS: The patient, whose infarction involved the superior temporal gyrus and sylvian operculum, presented similar abnormalities for comprehension of complex sentences, many phonemic paraphasias and no trouble to repeat single words. Oral language was not fluent, but sign language was quite fluent with a rich vocabulary, but with semantic paraphasias, agrammatism and without self-criticism for his own mistakes. CONCLUSIONS: The pattern of oral and sign language alterations is partially different, more for expressive than perceptive discourse, although both types of aphasias are caused by lesions of the left hemisphere. The regions responsible for these abnormalities of both symbolic languages are localised close to each other, but not in the same place.

Asunto(s)

Afasia de Broca , Infarto Cerebral , Lengua de Signos , Afasia de Broca/diagnóstico , Afasia de Broca/etiología , Afasia de Broca/patología , Afasia de Broca/fisiopatología , Infarto Cerebral/complicaciones , Infarto Cerebral/diagnóstico , Infarto Cerebral/patología , Infarto Cerebral/fisiopatología , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas

RESUMEN

Objetivos: Presentar las alteraciones del lenguaje verbal y de signos en un paciente oyente, bilingüe, competente para ambos idiomas, y en fase de recuperación de un infarto reciente hemisférico izquierdo, así como la localización de la afasia para signos en castellano. Paciente y métodos: Varón de 56 años, con importantes factores de riesgo cerebrovascular. Presenta un episodio súbito de afasia completa y hemiplejía derecha de los que se recupera en horas. Persiste un déficit parcial del lenguaje que se explora mediante un protocolo pormenorizado que incluye comprensión, denominación, praxias bucofonatorias, lenguaje espontáneo proposicional y automático, lectura y escritura. El estudio se realiza mediante análisis del examen filmado del lenguaje verbal y de signos. La lesión residual se localiza mediante resonancia magnética cerebral realizada 24 días después del infarto. Resultados: El paciente, con una lesión del giro temporal superior y el opérculo silviano izquierdos, presentó, de forma paralela en ambos lenguajes, trastorno de la comprensión de frases complejas, numerosas parafasias literales y conservación de la repetición de palabras. El lenguaje verbal fue poco fluente, el de signos fluido y rico en vocabulario, con parafasias semánticas, agramatismo y sin autocrítica de los errores. Conclusiones: El patrón de alteraciones lingüísticas orales y de signos es parcialmente diferente, aunque atribuible a lesiones del hemisferio izquierdo, con diferencias mayores para los contenidos expresivos que para los perceptivos. Las áreas responsables de las alteraciones lingüísticas de estos dos lenguajes de carácter simbólico están localizadas en regiones cerebrales cercanas pero no idénticas (AU)

Asunto(s)

Persona de Mediana Edad , Humanos , Masculino , Infarto Cerebral , Afasia de Broca , Lengua de Signos , Infarto Cerebral , Imagen por Resonancia Magnética , Pruebas Neuropsicológicas

RESUMEN

Mutations in the DYT1 gene cause idiopathic torsion dystonia (ITD) transmitted in families as an autosomal dominant trait with incomplete penetrance. The most common mutation, 946delGAG, has been observed in populations with different ethnic and geographic origins. We have investigated 40 individuals from 22 unrelated families with ITD originating from the Land of Valencia, Spain, for the presence of this mutation and we found 5 patients and 6 unaffected subjects from 4 families who were carriers of the mutation. This finding indicates that 18% of families may be diagnosed as DYT1 and that penetrance is reduced. We detected two different geographic and linguistic origins of the Valencian families. However, by haplotype analysis using D9S1260, D9S1261, D9S63 and D9S1262 as flanking markers, we demonstrated that all affected and unaffected carriers shared a common chromosome confirming identical origin of the mutation in the four families. We postulate a unique origin for the 946delGAG mutation in the Land of Valencia and, based on linguistic criterion, we propose that the mutation might have occurred at the beginning of the second millennium. Genetic analysis of another family from Castilla-La Mancha showed a different haplotype segregating with the disease, suggesting that at least two distinct mutational events for the 946delGAG mutation have occurred in Spain.

Asunto(s)

Proteínas Portadoras/genética , Distonía Muscular Deformante/genética , Chaperonas Moleculares , Penetrancia , Eliminación de Secuencia/genética , Alelos , Cromosomas Humanos Par 9/genética , Electroforesis en Gel de Poliacrilamida , Pruebas Genéticas , Geografía , Humanos , Repeticiones de Microsatélite/genética , Linaje , España

RESUMEN

INTRODUCTION: Glia conditioned medium (GCM) is neurotrophic for dopaminergic (DA) neurons and protects against MPP+ toxicity in vitro. We present the data from the first study in vivo of the effects of GCM. MATERIAL AND METHODS: The restorative effects were examined in rats with lesions produced by 6-hydroxy-dopamine (6-OH-DA) in the medial longitudinal fasciculus. At four weeks, animals with an apomorphine induced rotation rate above three per minute were randomised for infusion with GCM, defined medium (DM) or saline through a striatal cannula for two weeks. To investigate the protective effects of GCM, the animals received a striatal injection of GCM or vehicle at the same time as the lesion was induced by 6-OH-DA and were sacrificed three weeks later. RESULTS: In the experiments on the restorative effect, the GCM infusion produced a significant increase in dopamine (DA) levels on the side with the lesion, in the limbic system (455.8 108.4 ng/g of tissue) and in the striatum (242.1 69.2 ng/g of tissue), as compared with the controls (110.8 36,4 and 108.4 22 ng/g). In the experiments on the protective effect, GCM induced higher levels of DA, 3,4-dihydroxyphenylacetic acid and 3 methoxytyramine (3-MT). In both models, the apomorphine induced rotation in animals with lesions caused by 6-OH-DA and treated with GCM was lower than that of the animals infused with DM or saline. CONCLUSIONS: These experiments show that GCM has protective and restorative effects in an experimental model of Parkinson's disease.

Asunto(s)

Medios de Cultivo Condicionados , Neuroglía/metabolismo , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Oxidopamina/toxicidad , Animales , Apomorfina/farmacología , Encéfalo/anatomía & histología , Encéfalo/efectos de los fármacos , Encéfalo/patología , Química Encefálica , Células Cultivadas , Modelos Animales de Enfermedad , Agonistas de Dopamina/farmacología , Masculino , Neuroglía/citología , Neuronas/citología , Fármacos Neuroprotectores/química , Enfermedad de Parkinson/patología , Enfermedad de Parkinson/fisiopatología , Distribución Aleatoria , Ratas , Ratas Wistar

RESUMEN

Introducción. El medio condicionado por glía (MCG) es neurotrófico para las neuronas dopaminérgicas (DA) y protege de la toxicidad inducida por MPP+ in vitro. Presentamos los datos del primer estudio in vivo de los efectos del MCG. Material y métodos. El efecto `restaurador' se investigó en ratas lesionadas con 6-hidroxi-dopamina (6-OH-DA) en el fascículo longitudinal medial. A las cuatro semanas, los animales con una tasa de rotación inducida por apomorfina mayor de tres vueltas por minuto se aleatorizaron para la infusión de MCG, medio definido (MD) o salino durante dos semanas a través de una cánula estriatal. Para investigar los efectos `protectores' del MCG, los animales recibieron una inyección estriatal de MCG o vehículo simultánea a la lesión por 6-OH-DA y se sacrificaron tres semanas después. Resultados. La infusión de MCG produjo en los experimentos de efecto `restaurador' un incremento significativo en los niveles de dopamina (DA) en el lado lesionado, en el sistema límbico (455,8ñ 108,4 ng/g de tejido) y en el estriado (242,1ñ 69,2 ng/g de tejido), comparado con los controles (110,8ñ 36,4 y 108,4ñ 22 ng/g). En los experimentos de efecto `protector', el MCG indujo niveles más altos de DA, ácido 3,4dihidroxifenilacético (DOPAC) y 3-metoxitiramina (3-MT). En ambos modelos, la rotación que se indujo mediante apomorfina en los animales lesionados con 6-OH-DA y tratados con MCG fue menor que en los infundidos con MD o salino. Conclusiones. Estos experimentos demuestran que el MCG tiene efectos protectores y restauradores en un modelo experimental de la enfermedad de Parkinson (AU)

Asunto(s)

Persona de Mediana Edad , Ratas , Animales , Masculino , Humanos , Medios de Cultivo Condicionados , Tomografía Computarizada por Rayos X , Oxidopamina , Ratas Wistar , Fármacos Neuroprotectores , Agonistas de Dopamina , Proteínas del Tejido Nervioso , Neuroglía , Enfermedad de Parkinson , Neuronas , Distribución Aleatoria , Degeneración Cerebelosa Paraneoplásica , Anticuerpos , Apomorfina , Células Cultivadas , Modelos Animales de Enfermedad , Proteínas de Unión al ARN , Carcinoma de Células Pequeñas , Neoplasias Pancreáticas , Telencéfalo , Química Encefálica

RESUMEN

Tolcapone is a catechol-ortho-methyl-tranferase (COMT) inhibitor that increases the L-DOPA half-life and the duration of effect in Parkinson's disease. We investigated the effect of tolcapone on the plasma catecholamine levels. We measured plasma catecholamines 2h after the first daily dose of L-DOPA or L-DOPA+tolcapone while resting and 2 and 10min after standing. We also measured the pharmacokinetics of L-DOPA and 3-OM-DOPA and the clinical response to the medication for 6h after the early morning dose. The levels of dopamine, norepinephrine, adrenaline and total catecholamines significantly increased and 3-OM-DOPA decreased with tolcapone. We did not observe significant changes in the plasma L-DOPA levels at the doses of tolcapone used in this study. Tolcapone side effects included worsening of dyskinesia and psychosis, diarrhea and elevation of liver enzymes. Twenty-four-hour ambulatory recording of arterial blood pressure and heart rate did not reveal cardiovascular side effects in patients treated with tolcapone for less than 1year. Since adrenergic stimulation may increase the hepatotoxic potential of commonly used drugs, usually thought of as safe for the liver, we postulate that some of the already reported life threatening complications of tolcapone could be related to excessive adrenergic stimulation by high catecholamine levels caused by inhibition of COMT activity.

Asunto(s)

Agonistas de Dopamina/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Tiazoles/uso terapéutico , Benzotiazoles , Humanos , Pramipexol

RESUMEN

It has been recently suggested that the effects of cannabinoids on motor behavior might be different in rats with lesions of nigrostriatal dopaminergic neurons than in controls. In the present study, we examined the possible alteration in the status of cannabinoid CB1 receptors in the basal ganglia of rats with unilateral lesions of those neurons caused by 6-hydroxydopamine. We used two different experimental groups depending on the duration of the period of recovery after the lesion, and comparisons were done between the lesioned and nonlesioned sides at the level of the basal ganglia. Both groups of lesioned rats exhibited a similar marked reduction in tyrosine hydroxylase (TH)-mRNA levels, measured by in situ hybridization, in the substantia nigra of the lesioned side. In the same way, lesioned rats exhibited the characteristic rotational behavior after a single injection of apomorphine and the intensity of this rotation was stable at the two times analyzed after the lesion. Also as expected, lesioned rats exhibited an increase in proenkephalin mRNA levels in the caudate-putamen, whereas mRNA levels of substance P decreased, although differences between the two times of recovery analyzed were observed in this case. We did not find any significant changes in CB1 receptor binding, measured by [3H]WIN-55,212,2 autoradiography, or in the activation of signal transduction mechanisms, measured by WIN-55,212,2-stimulated [35S]GTPgammaS binding autoradiography, between the lesioned and nonlesioned sides at the level of the lateral caudate-putamen, globus pallidus and substantia nigra in both groups of lesioned rats. However, we found a significant increase in levels of CB1 receptor-mRNA transcripts, measured by in situ hybridization, in the lesioned side in both the lateral and medial caudate-putamen. This occurred 7-10 weeks after the lesion, but the increase was markedly waned after 17-18 weeks. In summary, the unilateral 6-hydroxydopamine lesion of nigrostriatal dopaminergic neurons originated a marked increase in CB1 receptor-mRNA levels in cell bodies of striatal efferent neurons, although accompanied by no changes in CB1 receptor binding and activation of signal transduction mechanisms. This supports a critical role for dopamine in the control of CB1 receptor gene expression. However, the magnitude of the effect significantly waned as a function of the duration of the period after lesion.

Asunto(s)

Cuerpo Estriado/fisiología , Neostriado/metabolismo , ARN Mensajero/análisis , Receptores de Droga/genética , Sustancia Negra/fisiología , Animales , Encefalinas/genética , Masculino , Oxidopamina , Precursores de Proteínas/genética , Ratas , Ratas Wistar , Receptores de Cannabinoides