TIME DEPENDENT ALTERATIONS IN CENTRAL NERVOUS SYSTEM DOPAMINE RECEPTORS INDUCED BY DOPAMINE AGONIST TREATMENT

Levodopa, the precursor of dopamine, is currently the drug of choice in the treatment of Parkinson's disease. Recently, two direct dopamine agonists, bromocriptine and pergolide, have been tested for the treatment of Parkinson's disease because of reduced side effects compared to levodopa. Few studies have evaluated the effects of long-term treatment of dopamine agonists on dopamine receptor regulation in the central nervous system. Thus, the purpose of this study was to determine whether chronic dopamine agonist treatment produces a down-regulation of striatal dopamine receptor function and to compare the results of the two classes of dopaminergic drugs.^ Levodopa with carbidopa, a peripheral decarboxylase inhibitor, was administered orally to rats whereas bromocriptine and pergolide were injected intraperitoneally once daily. Several neurochemical parameters were examined from 1 to 28 days.^ Levodopa minimally decreased striatal D-1 receptor activity but increased the number of striatal D-2 binding sites. Levodopa increased the V(,max) of tyrosine hydroxylase (TH) in all brain regions tested. Protein blot analysis of striatal TH indicated a significant increase in the amount of TH present. Dopamine-beta-hydroxylase (DBH) activity was markedly decreased in all brain regions studied and mixing experiments of control and drug-treated cortices did not show the presence of an increased level of endogenous inhibitors.^ Bromocriptine treatment decreased the number of D-2 binding sites. Striatal TH activity was decreased and protein blot analysis indicated no change in TH quantity. The specificity of bromocriptine for striatal TH suggested that bromocriptine preferentially interacts with dopamine autoreceptors.^ Combination levodopa-bromocriptine was administered for 12 days. There was a decrease in both D-1 receptor activity and D-2 binding sites, and a decrease in brain HVA levels suggesting a postsynaptic receptor action. Pergolide produced identical results to the combination levodopa-bromocriptine studies.^ In conclusion, combination levodopa-bromocriptine and pergolide treatments exhibited the expected down-regulation of dopamine receptor activity. In contrast, levodopa appeared to up-regulate dopamine receptor activity. Thus, these data may help to explain, on a biochemical basis, the decrease in the levodopa-induced side effects noted with combination levodopa-bromocriptine or pergolide therapies in the treatment of Parkinson's disease. ^

A doença de Parkinson no doente idoso

Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2014

Dopamine and semantic activation: An investigation of masked direct and indirect priming

To investigate the effects of dopamine on the dynamics of semantic activation, 39 healthy volunteers were randomly assigned to ingest either a placebo (n = 24) or a levodopa (it = 16) capsule. Participants then performed a lexical decision task that implemented a masked priming paradigm. Direct and indirect semantic priming was measured across stimulus onset asynchronies (SOAs) of 250, 500 and 1200 ms. The results revealed significant direct and indirect semantic priming effects for the placebo group at SOAs of 250 ms and 500 ms, but no significant direct or indirect priming effects at the 1200 ms SOA. In contrast, the levodopa group showed significant direct and indirect semantic priming effects at the 250 ms SOA, while no significant direct or indirect priming effects were evident at the SOAs of 500 ins or 1200 ms. These results suggest that dopamine has a role in modulating both automatic and attentional aspects of semantic activation according to a specific time course. The implications of these results for current theories of dopaminergic modulation of semantic activation are discussed.

Summation of semantic priming and complex sentence comprehension in Parkinson's disease

Research has suggested that the integrity of semantic processing may be compromised in Parkinson's disease (PD), which may account for difficulties in complex sentence comprehension. In order to investigate the time course and integrity of semantic activation in PD, 20 patients with PD and 23 healthy controls performed a lexical decision task based on the multi-priming paradigm. Semantic priming effects were measured across stimulus onset asynchronies of 250 ms, 600 ms, and 1200 ms. Further, PD participants performed an auditory comprehension task. The results revealed significantly different patterns of semantic priming for the PD group at the 250-ms and 1200-ms SOAs. In addition, a delayed time course of semantic activation was evident for PD patients with poor comprehension of complex sentences. These results provide further support to suggest that both automatic and controlled aspects of semantic activation may be compromised in PD. Furthermore, the results also suggest that some sentence comprehension deficits in PD may be related to a reduction in information processing speed.

The influence of dopamine on semantic activation in Parkinson's disease: Evidence from a multipriming task

Research has suggested that semantic processing deficits in Parkinson's disease (PD) are related to striatal dopamine deficiency. As an investigation of the influence of dopamine on semantic activation in PD, 7 participants with PD performed a lexical-decision task when on and off levodopa medication. Seven healthy controls matched to the participants with PD in terms of sex, age, and education also participated in the study. By use of a multipriming paradigm, whereby 2 prime words were presented prior to the target word, semantic priming effects were measured across stimulus onset asynchronies (SOAs) of 250 Ins and 1,200 Ins. The results revealed a similar pattern of priming across SOAs for the control group and the PD participants on medication. In contrast, within-group comparisons revealed that automatic semantic activation was compromised in PD participants when off medication. The implications of these results for the neuromodulatory influence of dopamine on semantic processing in PD are discussed.

Gallium-transferrin binding in treated and untreated Parkinson's disease

The binding of gallium (Ga) to transferrin (Tf) was studied in plasma from control patients, in patients with untreated Parkinson's disease (PD) and in patients with PD treated either with levodopa (L-dopa) alone or in combination with selegiline. Mean percentage Ga-Tf binding was significantly reduced in untreated and treated PD compared with controls. Binding, however, was significantly greater in treated than in untreated patients. There was no difference in binding between patients treated with L-dopa alone and those treated with L-dopa and selegiline. The data support the hypothesis that oxidation reactions may be of pathogenic significance in PD.

Estudio longitudinal del rendimiento neuropsicológico, neuropsiquiátrico y motor en la enfermedad de Parkinson

La enfermedad de Parkinson (EP) es una enfermedad progresiva, crónica e incapacitante cuyos síntomas principales son el temblor de reposo, la rigidez y la bradicinesia, apareciendo en el transcurso del tiempo la inestabilidad postural. Las alteraciones cognitivas y del estado de ánimo son otra de las características de esta enfermedad, pudiendo constituir una de sus complicaciones más incapacitantes. Ni el deterioro cognitivo leve (DCL) ni la demencia (D-EP) son fáciles de definir ni de evaluar. Algunos autores describen el DCL como una fase premórbida de la demencia (Pigott et al, 2015) aunque no todos los pacientes evolucionan a D-EP. La prevalencia de la D-EP es de 20-40% (Aarsland, Anderson et al, 2001), siendo algunos de los factores de riesgo la edad avanzada al diagnóstico, los síntomas motores más graves, sobre todo los relacionados con el trastorno de la marcha y la inestabilidad postural, el deterioro cognitivo leve, la depresión, el déficit temprano en fluidez verbal, la aparición de alucinaciones o la escasa respuesta al tratamiento con levodopa (Emre, 2003). El perfil de demencia en la EP es de tipo frontosubcortical, con déficits en las funciones atencionales y ejecutivas, mnésicas, visoespaciales, la fluidez verbal y las praxias...

Motor complications in an incident Parkinson’s disease cohort

Funded by •Parkinson's UK •Scottish Chief Scientist Office •BMA Doris Hillier Award •RS Macdonald Trust •BUPA Foundation •NHS Grampian Endowments •SPRING •National Institute of Health Research, and Engineering and Physical Sciences Research Council

Motor complications in an incident Parkinson’s disease cohort

Funded by •Parkinson's UK •Scottish Chief Scientist Office •BMA Doris Hillier Award •RS Macdonald Trust •BUPA Foundation •NHS Grampian Endowments •SPRING •National Institute of Health Research, and Engineering and Physical Sciences Research Council

Simulazione di finger tapping attraverso un modello neurale

Il seguente elaborato ha lo scopo di analizzare, attraverso modelli neuro-computazionali, le possibili alterazioni delle risposte in pazienti con malattia di Parkinson, sia indotte da alterazioni del livello di dopamina, sia indotte da modificazioni sinaptiche. Il punto chiave per comprendere i sintomi di PD e il loro deterioramento temporale si deve cercare nel rapporto tra l'attività dei neuroni in BG (in particolare nello striato) e i livelli di dopamina (o levodopa) nel cervello. Di conseguenza, l'obiettivo di questo elaborato è quello di quantificare la connessione tra i livelli di levodopa e performance del finger tapping per mezzo di modelli biologici e simulazioni al computer.

El dolor en la enfermedad de Parkinson. Implicaciones autonómicas y afectivas

Introducción y objetivo: La enfermedad de Parkinson (EP) es una enfermedad neurodegenerativa, la segunda con mayor prevalencia, después de la enfermedad de Alzheimer (EA). La enfermedad presenta tanto síntomas motores como “no motores”, entre los que se encuentra disfunción autonómica, dolor, deterioro cognitivo, ansiedad, depresión, entre otros. El dolor en la EP, a pesar de su frecuencia, sigue siendo un síntoma infravalorado, infradiagnosticado e infratratado. Nuestro objetivo principal es evaluar la frecuencia y configuración del dolor en la EP y sus implicaciones afectivas y autonómicas. Pacientes, material y métodos: Estudio multicéntrico, transversal, de carácter retrospectivo y prospectivo. Se incluyeron 407 pacientes con enfermedad de Parkinson (EP) de los que un 70% estaban en una situación leve-moderada (estadios 2 o 3 de Hoehn y Yahr), con edad media de 65,01 años y 7,07 años de duración de la EP. Se administraron las escalas SCOPA-Motor, SCOPA-Autonómica, SCOPA-Cog, Parkinson’s Psychosis Rating Scale modificada, Hoehn & Yarh, las Escala Hospitalaria de Ansiedad y Depresión, Dolor (EVA frecuencia), EQ-5D y estudios neurofisiológicos específicos de Sistema Nervioso Autónomo (SNA). El análisis estadístico se ha realizado con el programa de cálculo estadístico SPSS versión 22. Resultados: En nuestro estudio encontramos una prevalencia del dolor elevada (72%) y los pacientes afirman mayoritariamente (79,2%) que su dolor tiene relación con la EP. La duración de la enfermedad se correlaciona con la intensidad y frecuencia del dolor (dolor intensidad: r: 0,138; p< 0,01; dolor frecuencia: r: 0,168; p< 0,01 ). A mayor evolución de la EP mayor es la percepción del dolor. El 60% de los pacientes de EP manifiestan sentir dolor cuando aparecen episodios de rigidez y tirantez en alguno de los miembros superiores o inferiores frente a un 40% que no. Curiosamente un número mayor (el 76% de los pacientes) siente dolor durante los episodios de discinesias frente a un 24% que no lo percibe. Sin embargo, en la EP el dolor se relaciona más con la situación afectiva que con la motora, como hemos podido demostrar la relación entre el Dolor Total y la HADS (Depresión) Total y la Escala Hoehn & Yahr. El coeficiente de contingencia es mayor en la depresión (C: 0,894; N=403) que en la situación motora (C: 0,637; N=401). El dolor evoluciona y se percibe de forma paralela a otros síntomas no motores (ánimo, nicturia, alteración del control vesical, estreñimiento, etc.) pero con lo que se relaciona más es con la situación afectiva del paciente parkinsoniano (ansiedad (r: 0,40; p < 0,01), depresión (r: 0.28; p < 0,01). La mayor asociación se encuentra entre la ansiedad y el dolor, seguida de la depresión y en menor grado nicturia y sialorrea. Existe una correlación positiva entre las dos subescalas de la HADS (depresión y ansiedad). Existe una alta prevalencia de alteración de la memoria inmediata como síntoma “no motor” (SNM) en nuestra serie (96,5%). En base a nuestros resultados el sexo femenino se asocia al dolor en la EP. Con respecto a la fenomenología el dolor en la EP es muy variable. Se percibe con mayor frecuencia como una corriente eléctrica (64%), calor (60%), frialdad (60%), punzante (52%), difuso (52%), interno (40%), acorchamiento u hormigueo (40%), La frecuencia de la cantidad de tipos de dolor es la siguiente: un tipo de dolor (12%), dos tipos de dolores (16%) y tres tipos de dolores (72%). La media de tipos de dolor en nuestro estudio es superior a 2 tipos (x ̅: 2,60 ± 0,63; rango: 1-3). En los casos que toman levodopa les sigue unas tres cuartas partes que lo perciben como palpitante, tirante, punzante. En los casos que toman agonista dopaminérgico lo perciben en un 75% como adormecimiento, interno, descarga eléctrica, frialdad y calor. El dolor en la EP respecto a su configuración es multimodal. Los parámetros neurofisiológicos están relacionados con los umbrales de dolor. La actividad simpática y la sensibilidad nociceptiva están disminuidas en la EP. Los enfermos con EP tienen un umbral menor para el frío según los datos del estudio del Cold-Ice. En lo referente a la terapéutica el tratamiento dopaminérgico es eficaz para el control del dolor en el 48% de los pacientes mientras que el tratamiento analgésico estándar prescrito mejora el dolor en un 78,8%. Por último, casi la mitad de la población de nuestro estudio (47,52%) evaluada con la EQ-5D tiene problemas en alguna de las dimensiones de la calidad de vida. Hay una relación positiva entre la escala analógica visual del dolor (EVA) y la EQ-5D que evalúa la CVRS y entre la intensidad de dolor y la CVRS (r:-0,298; p < 0,01). Es decir, una mayor vivencia de dolor empeora la CVRS del paciente con EP. Conclusiones: En la enfermedad de Parkinson el dolor es un síntoma no motor de elevada prevalencia, íntimamente relacionado con la afectación de los sistemas afectivos y autonómicos medido con test neuro-vegetativos específicos. El presente estudio confirma su relación con el lado más afecto de la enfermedad, las fluctuaciones motoras, el tiempo de evolución, con la situación anímica (depresión y ansiedad) y con el sexo femenino, así como su carácter multimodal y gran variedad de expresión sintomática. Es muy llamativa su asociación con el déficit mnésico. Por último esta vivencia repercute en forma llamativa en la calidad de vida relacionada con la salud por lo que sería importante conocer y manejar mejor estos aspectos de la enfermedad de Parkinson.

A model of increased impulsivity in rats with bilateral parkinsonism treated with Pramipexole

Impulse control disorders (ICD) is a common side effect of the dopaminergic treatment in patients with Parkinson's disease, which is more associated with dopamine agonists than with levodopa. To understand its pathophysiology, reliable animal models are essential. Using the variable delay-to-signal (VDS) paradigm, impulsivity was evaluated in bilateral parkinsonian rats treated with pramipexole (PPX). In this test, rats have to introduce the snout into a nose poke that is signaled by a light (presented at variable delays) triggering the delivery of a food reward after a correct response. Reaching a stable baseline performance, a partial bilateral dopaminergic lesion with 6-OHDA was induced in the dorsolateral striatum (AP: +1mm, L: ±3.4mm, V:-4.7 mm, Bregma). Rats undertook the VDS test under 5 conditions: basal state, 6-OHDA-induced lesion, the effect of two doses of PPX (0,25mg/kg and 3mg/kg; Latin-square design), and the day after the last dose of PPX. Only the acute administration of 3 mg/kg of PPX significantly rised the number of premature responses, indicating an increase of impulsive behavior, in parkinsonian but not in sham rats. Both doses of PPX significantly decreased the accuracy of responding (correct/total number of responses) and increased the incorrect and perseverative (compulsive behavior) responses in both parkinsonian and sham treated groups when compared with saline-treated groups. In conclusion, PPX induced attention deficit (lack of accuracy) as well as compulsive behavior in control and parkinsonian rats, but increased impulsivity only in the parkinsonian animals. This model could constitute a valid tool to investigate the pathophysiology of ICD.

Manejo farmacoterapéutico del paciente hospitalizado con enfermedad de Parkinson

236 p.

Highly specific changes in antioxidant levels and lipid peroxidation in Parkinson's disease and its progression : disease and staging biomarkers and new drug targets.

There is evidence that immune-inflammatory, stress of reactive oxygen and nitrogen species (IO&NS) processes play a role in the neurodegenerative processes observed in Parkinson's disease (PD). The aim of the present study was to investigate peripheral IO&NS biomarkers in PD. We included 56 healthy individuals and 56 PD patients divided in two groups: early PD stage and late PD stage. Plasma lipid hydroperoxides (LOOH), malondialdehyde (MDA), nitric oxide metabolites (NOx), sulfhydryl (SH) groups, catalase (CAT) activity, superoxide dismutase (SOD) activity, paraoxonase (PON)1 activity, total radical trapping antioxidant parameter (TRAP) and C-reactive protein (CRP) were measured. PD is characterized by increased LOOH, MDA and SOD activity and lowered CAT activity. A combination of five O&NS biomarkers highly significantly predicts PD with a sensitivity of 94.5% and a specificity of 86.8% (i.e., MDA, SOD activity, TRAP, SH-groups and CAT activity). The single best biomarker of PD is MDA, while LOOH and SOD activity are significantly associated with late PD stage, but not early PD stage. Antiparkinson drugs did not affect O&NS biomarkers, but levodopa+carbidopa significantly increased CRP. It is suggested that MDA may serve as a disease biomarker, while LOOH and SOD activity are associated with late PD stage characteristic. New treatments for PD should not only target dopamine but also lipid peroxidation.