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1.
J Neurol Neurosurg Psychiatry ; 74(2): 175-82, 2003 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-12531943

RESUMEN

OBJECTIVE: To investigate cognitive and behavioural effects of bilateral lead implants for high frequency stimulation (HFS) of the subthalamic nucleus in patients with Parkinson's disease; and to discriminate between HFS and the effects of surgical intervention on cognitive function by carrying out postoperative cognitive assessments with the stimulators turned on or off. METHODS: Motor, cognitive, behavioural, and functional assessments were undertaken in 20 patients with Parkinson's disease before implantation and then at three, six, and 12 months afterwards. Nine patients were also examined 18 months after surgery. Postoperative cognitive assessments were carried out with stimulators turned off at three and 18 months, and turned on at six and 12 months. RESULTS: Cognitive assessment showed a significant postoperative decline in performance on tasks of letter verbal fluency (across all postoperative assessments, but more pronounced at three months) and episodic verbal memory (only at three months, with stimulators off). At three, six, and 12 months after surgery, there was a significant improvement in the mini-mental state examination and in a task of executive function (modified Wisconsin card sorting test). On all postoperative assessments, there was an improvement in parkinsonian motor symptoms, quality of life, and activities of daily living while off antiparkinsonian drugs. A significant postoperative decrease in depressive and anxiety symptoms was observed across all assessments. Similar results were seen in the subgroup of nine patients with an 18 month follow up. Following implantation, three patients developed transient manic symptoms and one showed persistent psychic akinesia. CONCLUSIONS: Bilateral HFS of the subthalamic nucleus is a relatively safe procedure with respect to long term cognitive and behavioural morbidity, although individual variability in postoperative cognitive and behavioural outcome invites caution. Stimulation of the subthalamic nucleus does not per se appear to impair cognitive performance in patients with Parkinson's disease and may alleviate the postoperative decline in verbal fluency.


Asunto(s)
Trastornos del Conocimiento/terapia , Terapia por Estimulación Eléctrica , Pruebas Neuropsicológicas , Enfermedad de Parkinson/terapia , Trastorno de la Conducta Social/terapia , Núcleo Subtalámico/fisiopatología , Anciano , Trastornos del Conocimiento/diagnóstico , Trastornos del Conocimiento/fisiopatología , Evaluación de la Discapacidad , Dominancia Cerebral/fisiología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Examen Neurológico , Evaluación de Procesos y Resultados en Atención de Salud , Enfermedad de Parkinson/diagnóstico , Enfermedad de Parkinson/fisiopatología , Trastorno de la Conducta Social/diagnóstico , Trastorno de la Conducta Social/fisiopatología , Conducta Verbal/fisiología
2.
J Neurol Neurosurg Psychiatry ; 73(6): 733-8, 2002 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-12438479

RESUMEN

OBJECTIVES: Advances in neuroimaging studies have recently improved the understanding of the functional anatomy of the calculation processes, having in particular underlined the central role of the angular gyrus (AG). In this study, the authors applied this knowledge to the surgical resection of a glioma invading the left AG, by localising and sparing the cortical areas involved in two different components of calculation (multiplication and subtraction), using direct electrical stimulations. METHODS: A calculation mapping was performed in a patient without deficit except a slightly impaired performance for serial arithmetic subtraction, during the resection under local anaesthesia of a left parieto-occipital glioma invading the dominant AG. After somatosensory and language mappings, cortical areas involved in single digit multiplications and subtractions of seven were mapped using the method of electrostimulation, before glioma removal. RESULTS: Distinct sites specifically involved in multiplication or subtraction were detected within the left AG, with a precise spatial distribution and overlapping. All the eloquent (somatosensory, language, and calculation) areas were surgically spared. Postoperatively, the patient had a transient complete deficit for arithmetic subtraction, without either multiplication or language disturbance. The tumour removal was complete. CONCLUSIONS: These findings suggest: firstly, the usefulness of an intraoperative calculation mapping during the removal of a lesion involving the left dominant AG, to avoid permanent postoperative deficit of arithmetic processes while optimising the quality of tumour resection; secondly, the possible existence of a well ordered and dynamic anatomo-functional organisation for different components of calculation within the left AG.


Asunto(s)
Mapeo Encefálico , Neoplasias Encefálicas/cirugía , Corteza Cerebral/fisiopatología , Dominancia Cerebral/fisiología , Glioma/cirugía , Lóbulo Parietal/cirugía , Solución de Problemas/fisiología , Adulto , Atención/fisiología , Neoplasias Encefálicas/fisiopatología , Estimulación Eléctrica , Femenino , Estudios de Seguimiento , Glioma/fisiopatología , Humanos , Imagen por Resonancia Magnética , Matemática , Lóbulo Occipital/fisiopatología , Lóbulo Occipital/cirugía , Lóbulo Parietal/fisiopatología , Complicaciones Posoperatorias/diagnóstico , Complicaciones Posoperatorias/fisiopatología
3.
Bioorg Med Chem Lett ; 11(24): 3179-82, 2001 Dec 17.
Artículo en Inglés | MEDLINE | ID: mdl-11720869

RESUMEN

Two novel 3'-substituted carboxycylopropylglycines, (2S,1'S,2'S,3'R)-2-(3'-xanthenylmethyl-2'-carboxycyclopropyl)glycine (8a) and (2S,1'S,2'S,3'R)-2-(3'-xanthenylethyl-2'-carboxycyclopropyl)glycine (8b), were synthesized and evaluated as mGluR ligands. Compound 8b showed to be a potent group II antagonist with submicromolar activity.


Asunto(s)
Antagonistas de Aminoácidos Excitadores/síntesis química , Antagonistas de Aminoácidos Excitadores/farmacología , Glicina/síntesis química , Glicina/farmacología , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Animales , Células CHO , Cricetinae , Evaluación Preclínica de Medicamentos , Glicina/análogos & derivados
4.
Neuropharmacology ; 41(4): 523-7, 2001 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-11543773

RESUMEN

We have previously demonstrated that neuronal release of the excitatory amino acid glutamate is facilitated by the selective activation of presynaptic Group I metabotropic autoreceptors. Here we report the release inhibiting actions of the novel mGlu(5) receptor-selective antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP), both in vitro and in vivo. These data provide compelling evidence for the presence of functional positive modulatory mGlu(5) subtype autoreceptors in the mammalian central nervous system.


Asunto(s)
Antagonistas de Aminoácidos Excitadores/farmacología , Ácido Glutámico/metabolismo , Piridinas/farmacología , Receptores de Ácido Kaínico/antagonistas & inhibidores , Animales , Química Encefálica/efectos de los fármacos , Estimulación Eléctrica , Glicina/análogos & derivados , Glicina/farmacología , Técnicas In Vitro , Masculino , Microdiálisis , Ratas , Ratas Wistar , Resorcinoles/farmacología
5.
Neuropharmacology ; 41(1): 1-7, 2001 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-11445180

RESUMEN

Glutamate receptors play an essential role in fear-related learning and memory. The present study was designed to assess the role of the group I metabotropic glutamate receptor (mGluR) subtype 5 in the acquisition and retrieval of conditioned fear in rats. The selective mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) was applied systemically (0.0, 0.3, 3.0, 30.0 mg/kg per os) 60 min before the acquisition training and before the expression of conditioned fear, respectively, in the fear-potentiated startle paradigm. MPEP dose-dependently blocked the acquisition of fear. This effect was not due to state-dependent learning. MPEP also prevented the expression of fear at a dose of 30.0 mg/kg. As a positive control for these effects, we showed that the benzodiazepine anxiolytic compound diazepam (1.25 mg/kg intraperitoneally) also blocked acquisition and expression of fear potentiated startle. MPEP did not affect the baseline startle magnitude, short-term habituation of startle, sensitisation of startle by footshocks or prepulse inhibition of startle. These data indicate a crucial role for mGluR5 in the regulation of fear conditioning. In the highest dose MPEP might exert anxiolytic properties.


Asunto(s)
Condicionamiento Psicológico/efectos de los fármacos , Antagonistas de Aminoácidos Excitadores/farmacología , Miedo/efectos de los fármacos , Piridinas/farmacología , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Estimulación Acústica , Animales , Electrochoque , Miedo/psicología , Habituación Psicofisiológica/efectos de los fármacos , Aprendizaje/efectos de los fármacos , Masculino , Memoria/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Reflejo de Sobresalto/efectos de los fármacos
6.
Br J Pharmacol ; 127(5): 1057-9, 1999 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-10455248

RESUMEN

Our previous work has shown that Group I mGlu receptors participate in thalamic sensory processing in vivo. However, unequivocal demonstration of mGlu5 participation has not been possible due to the lack of specific ligands. We have therefore made a preliminary study of the in vivo actions of the agonist (R,S)-2-Chloro-5-hydroxyphenylglycine [CHPG] and the novel mGlu5 antagonist 6-methyl-2-(phenylethynyl)-pyridine [MPEP] in order to characterize their suitability for functional studies. Iontophoretically administered MPEP selectively antagonized excitatory responses of single rat thalamic neurones to CHPG compared to the broad-spectrum mGlu agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate. In contrast, the established mGlu1 and mGlu5 antagonist (S)-4-carboxyphenylglycine reduced responses to both agonists. These findings are the first demonstration of an in vivo action of CHPG and its antagonism by a selective mGlu5 antagonist. Furthermore MPEP appears to be a good tool for functional studies of mGlu5.


Asunto(s)
Agonistas de Aminoácidos Excitadores/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Glicina/análogos & derivados , Fenilacetatos/farmacología , Piridinas/farmacología , Receptores de Glutamato Metabotrópico/efectos de los fármacos , Tálamo/efectos de los fármacos , Animales , Cicloleucina/análogos & derivados , Cicloleucina/farmacología , Glicina/farmacología , Ratas , Ratas Wistar
7.
Eur J Neurosci ; 9(1): 12-7, 1997 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-9042564

RESUMEN

We investigated the expression and coupling to the phospholipase C signal transduction pathway of metabotropic glutamate receptor (mGluR) subtypes by Western blot analysis and agonist-stimulated inositol monophosphate formation in several brain regions of postnatal day 9 (P9) and adult rats. In the cerebral cortex, hippocampus, corpus striatum, olfactory bulb, cerebellum and hypothalamus, the expression level of mGluR5 was greater at P9 than in adulthood. The mGluR5 signal was very low or absent in the adult cerebellum and hypothalamus. The expression of mGluR1a was slightly greater at P9 in the hypothalamus, hippocampus and olfactory bulb, whereas it substantially increased with age in the cerebellum, and did not change in the cerebral cortex and corpus striatum. mGluR1b and -1c were nearly undetectable by Western blot analysis. The expression level of mGluR5, but not that of mGluR1a, was significantly correlated with the extent of phosphoinositide hydrolysis stimulated by mGluR agonists in slices prepared from these brain regions. The mGluR antagonist cyclopropan[b]chromen-1a-carboxylic acid ethylester (CPCCOEt), potently antagonized responses mediated by mGluR1, but much less potently those mediated by mGluR5a in recombinant cells. CPCCOEt, at a concentration which efficiently blocks mGluR1 responses, did not substantially affect the polyphosphoinositide response in hippocampal or cerebellar slices from newborn animals, and antagonized only a minor component of the polyphosphoinositide response in adult hippocampal slices. CPCCOEt, however, prevented the small stimulation of polyphosphoinositide hydrolysis by mGluR agonists in adult cerebellar slices. We conclude that (i) the efficient mGluR-mediated polyphosphoinositide hydrolysis in 9-day-old rats is mediated by mGluR5; (ii) the increased expression of mGluR1 in the adult cerebellum does not substitute for the decline of mGluR5 expression in the ability to mediate polyphosphoinositide hydrolysis; and therefore (iii) mGluR1a might couple less efficiently than mGluR5 to polyphosphoinositide hydrolysis.


Asunto(s)
Animales Recién Nacidos/metabolismo , Química Encefálica/fisiología , Fosfatidilinositoles/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Envejecimiento/metabolismo , Secuencia de Aminoácidos , Animales , Western Blotting , Química Encefálica/efectos de los fármacos , ADN Complementario/biosíntesis , Agonistas de Aminoácidos Excitadores/farmacología , Humanos , Hidrólisis , Técnicas In Vitro , Datos de Secuencia Molecular , Ratas , Ratas Sprague-Dawley , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores
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